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Bao Y, Shang X, Hu G, Wang J, Liu C, Lv Q, Che H, Han J, Shao T, Wang G. Stevia rebaudiana root polysaccharide modulates liver metabolism, bile acid, and gut microbiota improving HFD-induced NAFLD: Potential roles of ACSL1 and FADS2. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 141:156680. [PMID: 40220428 DOI: 10.1016/j.phymed.2025.156680] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/02/2025] [Revised: 02/27/2025] [Accepted: 03/20/2025] [Indexed: 04/14/2025]
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is a prevalent metabolic disorder characterized by liver lipid accumulation and insulin resistance. However, effective therapeutic drugs for NAFLD are currently unavailable. Stevia rebaudiana root polysaccharides (SRRP) are inulin-type polysaccharides known for their hypoglycemic properties. Despite this, the effects of SRRP on improving NAFLD and the underlying mechanisms remain poorly understood. PURPOSE This study aims to evaluate the potential of SRRP in alleviating NAFLD and to explore its mechanisms of action. METHODS NAFLD was induced in male C57BL/6 J mice through high-fat diet (HFD) feeding, with subsequent SRRP administration over 8 weeks. Comprehensive assessments included serum biochemical profiling, hepatic histopathological examination, and proinflammatory enzyme activity quantification. Mechanistic investigations employed tripartite analytical approaches: gut microbiota analysis via 16S rRNA sequencing, hepatic metabolomic profiling and bile acid profiling, and validation of transport protein expression through Western blot (WB) techniques. RESULTS SRRP administration significantly alleviated NAFLD through reduced serum lipid concentrations, ameliorated inflammatory responses and oxidative stress, and decreased hepatic lipid deposition mechanistically, SRRP improved the structure of the gut microbiota by enhancing the proliferation of beneficial bacterial, including Lactobacillales and Bifidobacteriales, which subsequently elevated circulating Cholic acid (CA) and Chenodeoxycholic acid (CDCA), and improved hepatic lipid metabolites. Notably, KEGG from metabolomics indicated that the linoleic acid pathway might be associated with the improvement in hepatic lipid metabolite levels by SRRP. In Western blot analysis, SRRP significantly upregulated hepatic ACSL1 and FADS2 in NAFLD mice, demonstrating that the alleviation of NAFLD by SRRP may be achieved through the reduction of hepatic lipid accumulation. CONCLUSIONS SRRP exerts effects on improving NAFLD by modulating the gut microbiota, hepatic metabolites, bile acid levels, and the expression of ACSL1 and FADS2 proteins, providing more scientific evidence and support for the improvement of NAFLD by SRRP.
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Affiliation(s)
- Yulong Bao
- School of Pharmacy, Wannan Medical College, Wuhu 241002, China
| | - Xiaolong Shang
- School of Pharmacy, Wannan Medical College, Wuhu 241002, China
| | - Guangdong Hu
- School of Pharmacy, Wannan Medical College, Wuhu 241002, China
| | - Jiapeng Wang
- School of Pharmacy, Wannan Medical College, Wuhu 241002, China
| | - Chunyan Liu
- School of Pharmacy, Wannan Medical College, Wuhu 241002, China
| | - Qiuyue Lv
- School of Pharmacy, Wannan Medical College, Wuhu 241002, China; Anhui Provincial Engineering Research Center for Polysaccharide Drugs, Anhui Provincial Engineering Laboratory for Screening and Re-evaluation of Active Compounds of Herbal Medicines in Southern Anhui, Anhui Innovative Center for Drug Basic Research of Metabolic Diseases, Wuhu 241002, China
| | - Hui Che
- School of Pharmacy, Wannan Medical College, Wuhu 241002, China; Anhui Provincial Engineering Research Center for Polysaccharide Drugs, Anhui Provincial Engineering Laboratory for Screening and Re-evaluation of Active Compounds of Herbal Medicines in Southern Anhui, Anhui Innovative Center for Drug Basic Research of Metabolic Diseases, Wuhu 241002, China
| | - Jun Han
- Anhui Provincial Engineering Research Center for Polysaccharide Drugs, Anhui Provincial Engineering Laboratory for Screening and Re-evaluation of Active Compounds of Herbal Medicines in Southern Anhui, Anhui Innovative Center for Drug Basic Research of Metabolic Diseases, Wuhu 241002, China; Center for Xin'an Medicine and Modernization of Traditional Chinese Medicine of IHM, Wannan Medical College, Wuhu, 241002, China; Anhui College of Traditional Chinese Medicine, Wuhu 241002, China.
| | - Taili Shao
- School of Pharmacy, Wannan Medical College, Wuhu 241002, China; Anhui Provincial Engineering Research Center for Polysaccharide Drugs, Anhui Provincial Engineering Laboratory for Screening and Re-evaluation of Active Compounds of Herbal Medicines in Southern Anhui, Anhui Innovative Center for Drug Basic Research of Metabolic Diseases, Wuhu 241002, China.
| | - Guodong Wang
- School of Pharmacy, Wannan Medical College, Wuhu 241002, China; Anhui Provincial Engineering Research Center for Polysaccharide Drugs, Anhui Provincial Engineering Laboratory for Screening and Re-evaluation of Active Compounds of Herbal Medicines in Southern Anhui, Anhui Innovative Center for Drug Basic Research of Metabolic Diseases, Wuhu 241002, China.
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Zhao M, Zhao J, Yang H, Ouyang Z, Lv C, Geng Z, Zhao J. The bile acid-gut microbiota axis: A central hub for physiological regulation and a novel therapeutic target for metabolic diseases. Biomed Pharmacother 2025; 188:118182. [PMID: 40413999 DOI: 10.1016/j.biopha.2025.118182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2025] [Revised: 05/18/2025] [Accepted: 05/21/2025] [Indexed: 05/27/2025] Open
Abstract
Bile acids are a family of signaling molecules synthesized in the liver and metabolized by gut bacteria. As metabolites of the intestinal microbiota, bile acids bind to various receptors, and affect the metabolism and immune function of the host, including glucose and lipid metabolism, energy homeostasis, and inflammatory response. Conversely, bile acids also shape the composition of the gut microbiota. Given their critical role in physiological regulation, disrupted bile acid signaling is closely linked to metabolic diseases. Consequently, therapeutic strategies targeting bile acids are increasingly being explored. The size, composition, and function of the bile acid pool can be modulated through direct treatments (e.g., bile acid replacement therapy, administration of bile acid receptor agonists/antagonists) or indirect treatments (e.g., gut microbiota modulation, probiotic supplementation), providing new ideas for preventing and treating metabolic diseases.
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Affiliation(s)
- Min Zhao
- Hebei Provincial Center for Clinical Laboratories, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Jiafeng Zhao
- Hebei Provincial Center for Clinical Laboratories, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Huimin Yang
- Hebei Provincial Center for Clinical Laboratories, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Zirou Ouyang
- Hebei Provincial Center for Clinical Laboratories, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Chang Lv
- Hebei Provincial Center for Clinical Laboratories, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Zijun Geng
- Hebei Provincial Center for Clinical Laboratories, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Jianhong Zhao
- Hebei Provincial Center for Clinical Laboratories, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China.
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Zhang H, Atefi N, Surendran A, Han J, Goodlett DR, Jassal DS, Shah A, Ravandi A. Conjugated bile acids are elevated in severe calcific aortic valve stenosis. J Lipid Res 2025:100830. [PMID: 40409472 DOI: 10.1016/j.jlr.2025.100830] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2025] [Revised: 05/14/2025] [Accepted: 05/18/2025] [Indexed: 05/25/2025] Open
Abstract
INTRODUCTION Calcific aortic valve stenosis (CAVS) is a disease associated with significant morbidity and mortality in the aging population. Recently, bile acids have been shown to play a significant role in many disease processes, and untargeted metabolomic analyses of CAVS patient valves has shown a disrupted bile acid pathway. AIM We aimed to understand the changes in human valvular bile acids in relation to CAVS severity. METHODS A total of 100 human aortic valves were collected from patients undergoing aortic valve replacement surgery. Bile acids were quantified by ultrahigh performance liquid chromatography coupled to tandem mass spectrometry. RESULTS Patients with mild aortic stenosis (AS) showed a distinct valvular bile acid composition compared to moderate and severe AS groups, with five bile acids being significantly elevated in patients with moderate and severe AS. These included norcholic, nordeoxycholic, glycodeoxycholic, glycocholic and taurodeoxycholic acid. When classified by calcification score, five species were significantly different between mild and severe AS groups; four bile acids were similar when stratified based on AS severity. Using k means clustering we were able to distinguish valve severity by their bile acid composition. Grouping bile acids by conjugation and by primary versus secondary revealed that conjugated primary and secondary bile acids were significantly increased in stenotic valves compared to the mild AS group. CONCLUSION Conjugated bile acids are significantly elevated in the valvular tissue of patients with severe calcific aortic stenosis. These findings suggest a potential link between liverand gut microbiome physiologyand bile acid pathways in contributing to the pathophysiology of valvular stenosis.
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Affiliation(s)
- Hannah Zhang
- Cardiovascular Lipidomics Laboratory, St. Boniface Hospital, Albrechtsen Research Centre; Department of Physiology and Pathophysiology, Rady Faculty of Health Sciences, University of Manitoba(3)Mass Spectrometry & Proteomics Core Facility, Rajiv Gandhi Centre for Biotechnology, Kerala
| | - Negar Atefi
- Cardiovascular Lipidomics Laboratory, St. Boniface Hospital, Albrechtsen Research Centre; Genome British Columbia Proteomics Centre, University of Victoria, Victoria, BC, Canada
| | - Arun Surendran
- Cardiovascular Lipidomics Laboratory, St. Boniface Hospital, Albrechtsen Research Centre; Department of Physiology and Pathophysiology, Rady Faculty of Health Sciences, University of Manitoba(3)Mass Spectrometry & Proteomics Core Facility, Rajiv Gandhi Centre for Biotechnology, Kerala
| | - Jun Han
- Genome British Columbia Proteomics Centre, University of Victoria, Victoria, BC, Canada; Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
| | - David R Goodlett
- Genome British Columbia Proteomics Centre, University of Victoria, Victoria, BC, Canada; Department of Biology and Microbiology, University of Victoria, Victoria, BC, Canada
| | - Davinder S Jassal
- Department of Physiology and Pathophysiology, Rady Faculty of Health Sciences, University of Manitoba(3)Mass Spectrometry & Proteomics Core Facility, Rajiv Gandhi Centre for Biotechnology, Kerala; Section of Cardiology, Department of Internal Medicine, Rady Faculty of Health Sciences, University of Manitoba
| | - Ashish Shah
- Department of Physiology and Pathophysiology, Rady Faculty of Health Sciences, University of Manitoba(3)Mass Spectrometry & Proteomics Core Facility, Rajiv Gandhi Centre for Biotechnology, Kerala; Precision Cardiovascular Medicine Group, St. Boniface Hospital Research; Section of Cardiology, Department of Internal Medicine, Rady Faculty of Health Sciences, University of Manitoba
| | - Amir Ravandi
- Cardiovascular Lipidomics Laboratory, St. Boniface Hospital, Albrechtsen Research Centre; Department of Physiology and Pathophysiology, Rady Faculty of Health Sciences, University of Manitoba(3)Mass Spectrometry & Proteomics Core Facility, Rajiv Gandhi Centre for Biotechnology, Kerala; Precision Cardiovascular Medicine Group, St. Boniface Hospital Research; Section of Cardiology, Department of Internal Medicine, Rady Faculty of Health Sciences, University of Manitoba.
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He Y, Shaoyong W, Chen Y, Li M, Gan Y, Sun L, Liu Y, Wang Y, Jin M. The functions of gut microbiota-mediated bile acid metabolism in intestinal immunity. J Adv Res 2025:S2090-1232(25)00307-8. [PMID: 40354934 DOI: 10.1016/j.jare.2025.05.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2025] [Revised: 04/19/2025] [Accepted: 05/08/2025] [Indexed: 05/14/2025] Open
Abstract
BACKGROUND Bile acids, derived from cholesterol in the liver, consist a steroidal core. Primary bile acids and secondary bile acids metabolized by the gut microbiota make up the bile acid pool, which modulate nuclear hormone receptors to regulate immunity. Disruptions in the crosstalk between bile acids and the gut flora are intimately associated with the development and course of gastrointestinal inflammation. AIM OF REVIEW This review provides an extensive summary of bile acid production, transport and metabolism. It also delves into the impact of bile acid metabolism on the body and explores the involvement of bile acid-microbiota interactions in various disease states. Furthermore, the potential of targeting bile acid signaling as a means to prevent and treat inflammatory bowel disease is proposed. KEY SCIENTIFIC CONCEPTS OF REVIEW In this review, we primarily address the functions of bile acid-microbiota crosstalk in diseases. Firstly, we summarize bile acid signalling and the factors influencing bile acid metabolism, with highlighting the immune function of microbially conjugated bile acids and the unique roles of different receptors. Subsequently, we emphasize the vital role of bile acids in maintaining a healthy gut microbiota and regulating the intestinal barrier function, energy metabolism and immunity. Finally, we explore differences of bile acid metabolism in different disease states, offering new perspectives on restoring the host's health and the gastrointestinal ecosystem by targeting the gut microbiota-bile acid-bile acid receptor axis.
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Affiliation(s)
- Yanmin He
- Institute of Feed Science, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China; Key Laboratory of Molecular Animal Nutrition, Ministry of Education, Hangzhou 310058, China; Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture and Rural Affairs, Hangzhou 310058, China; Zhejiang Key Laboratory of Nutrition and Breeding for High-quality Animal Products, Hangzhou 310058, China; National Engineering Research Center for Green Feed and Healthy Breeding, Hangzhou 310058, China
| | - Weike Shaoyong
- Institute of Feed Science, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China; Key Laboratory of Molecular Animal Nutrition, Ministry of Education, Hangzhou 310058, China; Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture and Rural Affairs, Hangzhou 310058, China; Zhejiang Key Laboratory of Nutrition and Breeding for High-quality Animal Products, Hangzhou 310058, China; National Engineering Research Center for Green Feed and Healthy Breeding, Hangzhou 310058, China
| | - Yanli Chen
- Institute of Feed Science, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China; Key Laboratory of Molecular Animal Nutrition, Ministry of Education, Hangzhou 310058, China; Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture and Rural Affairs, Hangzhou 310058, China; Zhejiang Key Laboratory of Nutrition and Breeding for High-quality Animal Products, Hangzhou 310058, China; National Engineering Research Center for Green Feed and Healthy Breeding, Hangzhou 310058, China
| | - Menglin Li
- State Key Laboratory of Animal Nutrition and Feeding, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China
| | - Yujie Gan
- Institute of Feed Science, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China; Key Laboratory of Molecular Animal Nutrition, Ministry of Education, Hangzhou 310058, China; Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture and Rural Affairs, Hangzhou 310058, China; Zhejiang Key Laboratory of Nutrition and Breeding for High-quality Animal Products, Hangzhou 310058, China; National Engineering Research Center for Green Feed and Healthy Breeding, Hangzhou 310058, China
| | - Lu Sun
- Institute of Feed Science, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China; Key Laboratory of Molecular Animal Nutrition, Ministry of Education, Hangzhou 310058, China; Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture and Rural Affairs, Hangzhou 310058, China; Zhejiang Key Laboratory of Nutrition and Breeding for High-quality Animal Products, Hangzhou 310058, China; National Engineering Research Center for Green Feed and Healthy Breeding, Hangzhou 310058, China
| | - Yalin Liu
- Institute of Feed Science, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China; Key Laboratory of Molecular Animal Nutrition, Ministry of Education, Hangzhou 310058, China; Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture and Rural Affairs, Hangzhou 310058, China; Zhejiang Key Laboratory of Nutrition and Breeding for High-quality Animal Products, Hangzhou 310058, China; National Engineering Research Center for Green Feed and Healthy Breeding, Hangzhou 310058, China
| | - Yizhen Wang
- Institute of Feed Science, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China; Key Laboratory of Molecular Animal Nutrition, Ministry of Education, Hangzhou 310058, China; Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture and Rural Affairs, Hangzhou 310058, China; Zhejiang Key Laboratory of Nutrition and Breeding for High-quality Animal Products, Hangzhou 310058, China; National Engineering Research Center for Green Feed and Healthy Breeding, Hangzhou 310058, China
| | - Mingliang Jin
- Institute of Feed Science, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China; Key Laboratory of Molecular Animal Nutrition, Ministry of Education, Hangzhou 310058, China; Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture and Rural Affairs, Hangzhou 310058, China; Zhejiang Key Laboratory of Nutrition and Breeding for High-quality Animal Products, Hangzhou 310058, China; National Engineering Research Center for Green Feed and Healthy Breeding, Hangzhou 310058, China.
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Mok K, Tomtong P, Ogawa T, Nagai K, Torrungruang P, Charoensiddhi S, Nakayama J, Wanikorn B, Nitisinprasert S, Vongsangnak W, Nakphaichit M. Synbiotic-driven modulation of the gut microbiota and metabolic functions related to obesity: insights from a human gastrointestinal model. BMC Microbiol 2025; 25:250. [PMID: 40289100 PMCID: PMC12034176 DOI: 10.1186/s12866-025-03953-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2024] [Accepted: 04/07/2025] [Indexed: 04/30/2025] Open
Abstract
Synbiotic interventions have gained increasing attention for modulating gut microbiota and metabolic functions in obesity-related disorders. This study evaluated the effects of Limosilactobacillus reuteri KUB-AC5 (10⁸ CFU) and Wolffia globosa powder (6 g/day) using an in vitro continuous human gastrointestinal model. Fecal samples from obese donors were used to simulate the ascending and descending colon, with microbial viability, diversity, and metabolite production assessed over 14 days via culture-dependent and culture-independent methods. Synbiotic supplementation increased anaerobic bacterial counts by 2.6 log CFU/mL in the ascending colon and 2.2 log CFU/mL in the descending colon, with notable increases in lactic acid bacteria and reductions in Enterobacteriaceae. Metagenomic analysis revealed an increasing trend in microbial diversity and evenness after 7 days of treatment, though the changes were not statistically significant. PERMANOVA analysis confirmed significant shift in microbial community composition between stabilization, treatment, and washout periods (p < 0.05). Additionally, butyrate levels significantly increased (p < 0.05), while p-cresol, a deleterious metabolite, significantly decreased (p < 0.05). Bile acid composition was modulated, with increased tertiary bile acid 3-oxo-LCA and enhanced bile acid deconjugation, suggesting improved lipid metabolism and potential weight management benefits. These findings highlight the potential of synbiotic supplementation to enhance beneficial bacterial populations, improve microbial diversity, and support metabolic health in obesity management.
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Grants
- FF(KU)51.67 Kasetsart University Research and Development Institute (KURDI) under the research topic "Center for Microbiota Innovation: Empowering Health via Probiotics, Prebiotics, Postbiotics, and Functional Products"
- FF(KU)51.67 Kasetsart University Research and Development Institute (KURDI) under the research topic "Center for Microbiota Innovation: Empowering Health via Probiotics, Prebiotics, Postbiotics, and Functional Products"
- FF(KU)51.67 Kasetsart University Research and Development Institute (KURDI) under the research topic "Center for Microbiota Innovation: Empowering Health via Probiotics, Prebiotics, Postbiotics, and Functional Products"
- Agro-Industrial Scholarship for International Students, Kasetsart University
- The Department of Biotechnology, Faculty of Agro-Industry, Kasetsart University
- Science and Technology Research Partnership for Sustainable Development (SATREPS), JICA, Japan; Kasetsart University through the Graduate School Fellowship Program
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Affiliation(s)
- Kevin Mok
- Department of Biotechnology, Faculty of Agro-Industry, Kasetsart University, Bangkok, 10900, Thailand
- Center of Excellence for Microbiota Innovation, Faculty of Agro-Industry, Kasetsart University, Bangkok, 10900, Thailand
| | - Putsawee Tomtong
- Center of Excellence for Microbiota Innovation, Faculty of Agro-Industry, Kasetsart University, Bangkok, 10900, Thailand
- Department of Food Science and Technology, Faculty of Agro-Industry, Kasetsart University, Bangkok, 10900, Thailand
| | - Takuma Ogawa
- Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka, 819- 0395, Japan
| | - Kenshiro Nagai
- Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka, 819- 0395, Japan
| | - Pitchsupang Torrungruang
- Department of Biotechnology, Faculty of Agro-Industry, Kasetsart University, Bangkok, 10900, Thailand
| | - Suvimol Charoensiddhi
- Center of Excellence for Microbiota Innovation, Faculty of Agro-Industry, Kasetsart University, Bangkok, 10900, Thailand
- Department of Food Science and Technology, Faculty of Agro-Industry, Kasetsart University, Bangkok, 10900, Thailand
| | - Jiro Nakayama
- Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka, 819- 0395, Japan
| | - Bandhita Wanikorn
- Department of Biotechnology, Faculty of Agro-Industry, Kasetsart University, Bangkok, 10900, Thailand
- Specialized Research Unit: Functional Food and Human Health Laboratory, Faculty of Agro-Industry, Kasetsart University, Bangkok, 10900, Thailand
| | - Sunee Nitisinprasert
- Department of Biotechnology, Faculty of Agro-Industry, Kasetsart University, Bangkok, 10900, Thailand
- Center of Excellence for Microbiota Innovation, Faculty of Agro-Industry, Kasetsart University, Bangkok, 10900, Thailand
| | - Wanwipa Vongsangnak
- Department of Zoology, Faculty of Science, Kasetsart University, Bangkok, 10900, Thailand
- Omics Center for Agriculture, Bioresources, Food, and Health, Kasetsart University (OmiKU), Bangkok, 10900, Thailand
| | - Massalin Nakphaichit
- Department of Biotechnology, Faculty of Agro-Industry, Kasetsart University, Bangkok, 10900, Thailand.
- Center of Excellence for Microbiota Innovation, Faculty of Agro-Industry, Kasetsart University, Bangkok, 10900, Thailand.
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Xiao T, Huang F, Guo Z, Cheng X, Duan J, Dai W, Yang B, Zhang Y, Tao L, Shen X. Black Raspberry Polyphenols Shape Metabolic Dysregulation and Perturbation in Gut Microbiota to Promote Lipid Metabolism and Liver Regeneration. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2025; 73:7833-7856. [PMID: 40130403 DOI: 10.1021/acs.jafc.5c00702] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/26/2025]
Abstract
Black raspberry as a functional food is a potential modulator of human metabolic disease. However, the role of black raspberry polyphenols (HSM) in shaping metabolic dysregulation and perturbation in gut microbiota (GM) to promote lipid metabolism and liver regeneration is unclear. In this work, the effects of HSM in mitigating metabolic disturbances and hepatic damage induced by a high-fat diet (HFD) and antibiotics (Abs) in mice were measured. HSM significantly alleviated HFD-induced obesity, insulin resistance, lipid and glucose metabolic dysregulation, as well as hepatic damage by activating the PI3K/AKT pathway and pregnane X receptor (PXR)-farnesoid X receptor (FXR) axis with improved GM, which was evidenced by short-chain fatty acids, 16S, and nontarget metabolism analysis. Excellent results were also evident in mice treated with Abs. Besides, HSM markedly inhibited key digestive enzymes associated with metabolic syndrome and also significantly enhanced antioxidant capacity after metabolized by GM. The discoveries underscored the potential of dietary HSM to manage lipid metabolism and liver regeneration within GM homeostasis.
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Affiliation(s)
- Ting Xiao
- State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine & School of Pharmaceutical Sciences, Guizhou Medical University, No. 6 Ankang Avenue, Guian New District, Guiyang, Guizhou 561113, China
- The Department of Pharmacology of Materia Medica (the High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province, the Key Laboratory of Optimal Utilization of Natural Medicine Resources), School of Pharmaceutical Sciences, Guizhou Medical University, No. 6 Ankang Avenue, Guian New District, Guiyang, Guizhou 561113, China
- The Department of Pharmaceutics of TCM (the High Educational Key Laboratory of Guizhou Province for Natural Medicinal Pharmacology and Druggability, the Union Key Laboratory of Guiyang City-Guizhou Medical University), School of Pharmaceutical Sciences, Guizhou Medical University, No. 6 Ankang Avenue, Guian New District, Guiyang, Guizhou 561113, China
- The National Engineering Research Center of Miao's Medicines, Guizhou Yibai Pharmaceutical Co., Ltd., Guiyang 550008, China
| | - Feilong Huang
- State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine & School of Pharmaceutical Sciences, Guizhou Medical University, No. 6 Ankang Avenue, Guian New District, Guiyang, Guizhou 561113, China
- The Department of Pharmacology of Materia Medica (the High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province, the Key Laboratory of Optimal Utilization of Natural Medicine Resources), School of Pharmaceutical Sciences, Guizhou Medical University, No. 6 Ankang Avenue, Guian New District, Guiyang, Guizhou 561113, China
- The Department of Pharmaceutics of TCM (the High Educational Key Laboratory of Guizhou Province for Natural Medicinal Pharmacology and Druggability, the Union Key Laboratory of Guiyang City-Guizhou Medical University), School of Pharmaceutical Sciences, Guizhou Medical University, No. 6 Ankang Avenue, Guian New District, Guiyang, Guizhou 561113, China
| | - Zhenghong Guo
- School of Pharmacy, Guizhou University of Traditional Chinese Medicine, Guiyang 550025, China
| | - Xingyan Cheng
- State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine & School of Pharmaceutical Sciences, Guizhou Medical University, No. 6 Ankang Avenue, Guian New District, Guiyang, Guizhou 561113, China
- The Department of Pharmacology of Materia Medica (the High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province, the Key Laboratory of Optimal Utilization of Natural Medicine Resources), School of Pharmaceutical Sciences, Guizhou Medical University, No. 6 Ankang Avenue, Guian New District, Guiyang, Guizhou 561113, China
- The Department of Pharmaceutics of TCM (the High Educational Key Laboratory of Guizhou Province for Natural Medicinal Pharmacology and Druggability, the Union Key Laboratory of Guiyang City-Guizhou Medical University), School of Pharmaceutical Sciences, Guizhou Medical University, No. 6 Ankang Avenue, Guian New District, Guiyang, Guizhou 561113, China
| | - Jinchang Duan
- State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine & School of Pharmaceutical Sciences, Guizhou Medical University, No. 6 Ankang Avenue, Guian New District, Guiyang, Guizhou 561113, China
- The Department of Pharmacology of Materia Medica (the High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province, the Key Laboratory of Optimal Utilization of Natural Medicine Resources), School of Pharmaceutical Sciences, Guizhou Medical University, No. 6 Ankang Avenue, Guian New District, Guiyang, Guizhou 561113, China
- The Department of Pharmaceutics of TCM (the High Educational Key Laboratory of Guizhou Province for Natural Medicinal Pharmacology and Druggability, the Union Key Laboratory of Guiyang City-Guizhou Medical University), School of Pharmaceutical Sciences, Guizhou Medical University, No. 6 Ankang Avenue, Guian New District, Guiyang, Guizhou 561113, China
| | - Weiyan Dai
- State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine & School of Pharmaceutical Sciences, Guizhou Medical University, No. 6 Ankang Avenue, Guian New District, Guiyang, Guizhou 561113, China
- The Department of Pharmacology of Materia Medica (the High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province, the Key Laboratory of Optimal Utilization of Natural Medicine Resources), School of Pharmaceutical Sciences, Guizhou Medical University, No. 6 Ankang Avenue, Guian New District, Guiyang, Guizhou 561113, China
- The Department of Pharmaceutics of TCM (the High Educational Key Laboratory of Guizhou Province for Natural Medicinal Pharmacology and Druggability, the Union Key Laboratory of Guiyang City-Guizhou Medical University), School of Pharmaceutical Sciences, Guizhou Medical University, No. 6 Ankang Avenue, Guian New District, Guiyang, Guizhou 561113, China
| | - Bo Yang
- Department of Pharmacy, Zhejiang Academy of Traditional Chinese Medicine, Zhejiang Provincial Tongde Hospital, 234 Gucui Road, Hangzhou, Zhejiang 310013, China
| | - Yiquan Zhang
- State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine & School of Pharmaceutical Sciences, Guizhou Medical University, No. 6 Ankang Avenue, Guian New District, Guiyang, Guizhou 561113, China
- The Department of Pharmacology of Materia Medica (the High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province, the Key Laboratory of Optimal Utilization of Natural Medicine Resources), School of Pharmaceutical Sciences, Guizhou Medical University, No. 6 Ankang Avenue, Guian New District, Guiyang, Guizhou 561113, China
- Guizhou Hengba Pharmaceutical Co., Ltd., Jinyang Industry Knowledge Park, Guiyang National High-tech Industrial Development Zone, Guiyang 550008, China
| | - Ling Tao
- State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine & School of Pharmaceutical Sciences, Guizhou Medical University, No. 6 Ankang Avenue, Guian New District, Guiyang, Guizhou 561113, China
- The Department of Pharmacology of Materia Medica (the High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province, the Key Laboratory of Optimal Utilization of Natural Medicine Resources), School of Pharmaceutical Sciences, Guizhou Medical University, No. 6 Ankang Avenue, Guian New District, Guiyang, Guizhou 561113, China
- The Department of Pharmaceutics of TCM (the High Educational Key Laboratory of Guizhou Province for Natural Medicinal Pharmacology and Druggability, the Union Key Laboratory of Guiyang City-Guizhou Medical University), School of Pharmaceutical Sciences, Guizhou Medical University, No. 6 Ankang Avenue, Guian New District, Guiyang, Guizhou 561113, China
| | - Xiangchun Shen
- State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine & School of Pharmaceutical Sciences, Guizhou Medical University, No. 6 Ankang Avenue, Guian New District, Guiyang, Guizhou 561113, China
- The Department of Pharmacology of Materia Medica (the High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province, the Key Laboratory of Optimal Utilization of Natural Medicine Resources), School of Pharmaceutical Sciences, Guizhou Medical University, No. 6 Ankang Avenue, Guian New District, Guiyang, Guizhou 561113, China
- The Department of Pharmaceutics of TCM (the High Educational Key Laboratory of Guizhou Province for Natural Medicinal Pharmacology and Druggability, the Union Key Laboratory of Guiyang City-Guizhou Medical University), School of Pharmaceutical Sciences, Guizhou Medical University, No. 6 Ankang Avenue, Guian New District, Guiyang, Guizhou 561113, China
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Delzenne NM, Bindels LB, Neyrinck AM, Walter J. The gut microbiome and dietary fibres: implications in obesity, cardiometabolic diseases and cancer. Nat Rev Microbiol 2025; 23:225-238. [PMID: 39390291 DOI: 10.1038/s41579-024-01108-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/04/2024] [Indexed: 10/12/2024]
Abstract
Dietary fibres constitute a heterogeneous class of nutrients that are key in the prevention of various chronic diseases. Most dietary fibres are fermented by the gut microbiome and may, thereby, modulate the gut microbial ecology and metabolism, impacting human health. Dietary fibres may influence the occurrence of specific bacterial taxa, with this effect varying between individuals. The effect of dietary fibres on microbial diversity is a matter of debate. Most intervention studies with dietary fibres in the context of obesity and related metabolic disorders reveal the need for an accurate assessment of the microbiome to better understand the variable response to dietary fibres. Epidemiological studies confirm that a high dietary fibre intake is strongly associated with a reduced occurrence of many types of cancer. However, there is a need to determine the impact of intervention with specific dietary fibres on cancer risk, therapy efficacy and toxicity, as well as in cancer cachexia. In this Review, we summarize the mechanisms by which the gut microbiome can mediate the physiological benefits of dietary fibres in the contexts of obesity, cardiometabolic diseases and cancer, their incidence being clearly linked to low dietary fibre intake.
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Affiliation(s)
- Nathalie M Delzenne
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium.
| | - Laure B Bindels
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium
- WELBIO Department, WEL Research Institute, Wavre, Belgium
| | - Audrey M Neyrinck
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium
| | - Jens Walter
- APC Microbiome Ireland, University College Cork, Cork, Ireland
- Department of Medicine, University College Cork, Cork, Ireland
- School of Microbiology, University College Cork, Cork, Ireland
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8
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Amadieu C, Ahmed H, Leclercq S, Koistinen V, Leyrolle Q, Stärkel P, Bindels LB, Layé S, Neyrinck AM, Kärkkäinen O, De Timary P, Hanhineva K, Delzenne NM. Effect of inulin supplementation on fecal and blood metabolome in alcohol use disorder patients: A randomised, controlled dietary intervention. Clin Nutr ESPEN 2025; 66:361-371. [PMID: 39864520 DOI: 10.1016/j.clnesp.2025.01.046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Revised: 01/17/2025] [Accepted: 01/20/2025] [Indexed: 01/28/2025]
Abstract
BACKGROUND AND AIMS Alcohol Use Disorder (AUD) is a psychiatric disorder characterized notably by gut microbial dysbiosis and insufficient dietary fiber (DF) intake. This study aims to investigate the effect of DF placebo-controlled intervention in patients suffering from AUD during a three-week period of alcohol withdrawal, in order to discover microbial-derived metabolites that could be involved in metabolic and behavioral status. METHODS A randomized, double-blind, placebo-controlled study was performed with 50 AUD patients supplemented with inulin (prebiotic DF) or maltodextrin (placebo) during 17 days. Fecal microbiota composition, plasma and fecal metabolomics (liquid chromatography coupled to mass spectrometry), blood markers of inflammation and hepatic alterations, and psychological assessment (questionnaires) were analyzed before and after the intervention. RESULTS Fecal metabolomics revealed 14 metabolites significantly modified by inulin versus placebo treatment (increased N8-acetylspermidine and decreased indole-3-butyric acid, 5-amino valeric acid betaine (5-AVAB) and bile acids). Thirteen plasma metabolites differentiated both treatments (higher levels of long-chain fatty acids, medium-chain acylcarnitines and sphingomyelin species, and reduced 3-methylhistidine by inulin versus placebo). Fecal Lachnoclostridium correlated with 6 of the identified fecal metabolites, whereas plasma lipidic moieties positively correlated with fecal Ruminococcus torques group and Flavonifractor. Interestingly, parameters reflecting liver alterations inversely correlated with sphingomyelin (SM 36:2). CONCLUSIONS Three weeks of inulin supplementation during alcohol withdrawal leads to specific and different changes in the plasma and fecal metabolome of AUD patients, some of these gut microbiota-related metabolites being correlated with liver function. TRIAL REGISTRATION NCT03803709, https://clinicaltrials.gov/ct2/show/NCT03803709.
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Affiliation(s)
- Camille Amadieu
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Brussels, Belgium; Université de Bordeaux, INRAE, Bordeaux INP, NutriNeurO, UMR 1286, F-33000 Bordeaux, France
| | - Hany Ahmed
- Food Sciences Unit, Department of Life Technologies, University of Turku, Turku, Finland
| | - Sophie Leclercq
- Laboratory of Nutritional Psychiatry, Institute of Neuroscience, UCLouvain, Université catholique de Louvain, Brussels, Belgium
| | - Ville Koistinen
- Food Sciences Unit, Department of Life Technologies, University of Turku, Turku, Finland; School of Medicine, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
| | - Quentin Leyrolle
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Brussels, Belgium; Université de Bordeaux, INRAE, Bordeaux INP, NutriNeurO, UMR 1286, F-33000 Bordeaux, France
| | - Peter Stärkel
- Department of Gastro-enterology, Cliniques Universitaires Saint Luc, Brussels, Belgium
| | - Laure B Bindels
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Brussels, Belgium; WELBIO Department, WEL Research Institute, Wavre, Belgium
| | - Sophie Layé
- Université de Bordeaux, INRAE, Bordeaux INP, NutriNeurO, UMR 1286, F-33000 Bordeaux, France
| | - Audrey M Neyrinck
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Brussels, Belgium
| | - Olli Kärkkäinen
- School of Pharmacy, University of Eastern Finland, Kuopio, Finland
| | - Philippe De Timary
- Department of Adult Psychiatry, Cliniques Universitaires Saint-Luc and Institute of Neuroscience, UCLouvain, Université catholique de Louvain, Brussels, Belgium
| | - Kati Hanhineva
- Food Sciences Unit, Department of Life Technologies, University of Turku, Turku, Finland; School of Medicine, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
| | - Nathalie M Delzenne
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Brussels, Belgium.
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9
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Gan HJ, Chen S, Yao K, Lin XY, Juhasz AL, Zhou D, Li HB. Simulated Microplastic Release from Cutting Boards and Evaluation of Intestinal Inflammation and Gut Microbiota in Mice. ENVIRONMENTAL HEALTH PERSPECTIVES 2025; 133:47004. [PMID: 40042913 PMCID: PMC11980920 DOI: 10.1289/ehp15472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Revised: 01/21/2025] [Accepted: 01/29/2025] [Indexed: 04/10/2025]
Abstract
BACKGROUND Plastic cutting boards are commonly used in food preparation, increasing human exposure to microplastics (MPs). However, the health implications are still not well understood. OBJECTIVES The objective of this study was to assess the impacts of long-term exposure to MPs released from cutting boards on intestinal inflammation and gut microbiota. METHODS MPs were incorporated into mouse diets by cutting the food on polypropylene (PP), polyethylene (PE), and willow wooden (WB) cutting boards, and the diets were fed to mice over periods of 4 and 12 wk. Serum levels of C-reactive protein (CRP), tumor necrosis factor-α (TNF-α ), interleukin-10 (IL-10), lipopolysaccharide (LPS, an endotoxin), and carcinoembryonic antigen (CEA), along with ileum and colon levels of interleukin-1β (IL-1 β ), TNF-α , malondialdehyde (MDA), superoxide dismutase (SOD), secretory immunoglobulin A (sIgA), and myosin light chain kinase (MLCK), were measured using mouse enzyme-linked immunosorbent assay (ELISA) kits. The mRNA expression of mucin 2 and intestinal tight junction proteins in mouse ileum and colon tissues was quantified using real-time quantitative reverse transcription polymerase chain reaction. Fecal microbiota, fecal metabolomics, and liver metabolomics were characterized. RESULTS PP and PE cutting boards released MPs, with concentrations reaching 1,088 ± 95.0 and 1,211 ± 322 μ g / g in diets, respectively, and displaying mean particle sizes of 10.4 ± 0.96 vs. 27.4 ± 1.45 μ m . Mice fed diets prepared on PP cutting boards for 12 wk exhibited significantly higher serum levels of LPS, CRP, TNF-α , IL-10, and CEA, as well as higher levels of IL-1β , TNF-α , MDA, SOD, and MLCK in the ileum and colon compared with mice fed diets prepared on WB cutting boards. These mice also showed lower relative expression of Occludin and Zonula occludens-1 in the ileum and colon. In contrast, mice exposed to diets prepared on PE cutting boards for 12 wk did not show evident inflammation; however, there was a significant decrease in the relative abundance of Firmicutes and an increase in Desulfobacterota compared with those fed diets prepared on WB cutting boards, and exposure to diets prepared on PE cutting boards over 12 wk also altered mouse fecal and liver metabolites compared with those fed diets prepared on WB cutting boards. DISCUSSION The findings suggest that MPs from PP cutting boards impair intestinal barrier function and induce inflammation, whereas those from PE cutting boards affect the gut microbiota, gut metabolism, and liver metabolism in the mouse model. These findings offer crucial insights into the safe use of plastic cutting boards. https://doi.org/10.1289/EHP15472.
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Affiliation(s)
- Hai-Jun Gan
- State Key Laboratory of Pollution Control and Resource Reuse, Jiangsu Key Laboratory of Vehicle Emissions Control, School of Environment, Nanjing University, Nanjing, China
| | - Shan Chen
- State Key Laboratory of Pollution Control and Resource Reuse, Jiangsu Key Laboratory of Vehicle Emissions Control, School of Environment, Nanjing University, Nanjing, China
| | - Ke Yao
- State Key Laboratory of Pollution Control and Resource Reuse, Jiangsu Key Laboratory of Vehicle Emissions Control, School of Environment, Nanjing University, Nanjing, China
| | - Xin-Ying Lin
- State Key Laboratory of Pollution Control and Resource Reuse, Jiangsu Key Laboratory of Vehicle Emissions Control, School of Environment, Nanjing University, Nanjing, China
| | - Albert L. Juhasz
- Future Industries Institute, University of South Australia, Mawson Lakes, South Australia, Australia
| | - Dongmei Zhou
- State Key Laboratory of Pollution Control and Resource Reuse, Jiangsu Key Laboratory of Vehicle Emissions Control, School of Environment, Nanjing University, Nanjing, China
| | - Hong-Bo Li
- State Key Laboratory of Pollution Control and Resource Reuse, Jiangsu Key Laboratory of Vehicle Emissions Control, School of Environment, Nanjing University, Nanjing, China
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10
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Jiang X, Ren J, Yu G, Wu W, Chen M, Zhao Y, He C. Targeting Bile-Acid Metabolism: Nutritional and Microbial Approaches to Alleviate Ulcerative Colitis. Nutrients 2025; 17:1174. [PMID: 40218932 PMCID: PMC11990178 DOI: 10.3390/nu17071174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2025] [Revised: 03/19/2025] [Accepted: 03/26/2025] [Indexed: 04/14/2025] Open
Abstract
Ulcerative colitis (UC) is a chronic inflammatory disease affecting the colorectum, posing a significant global health burden. Recent studies highlight the critical role of gut microbiota and its metabolites, particularly bile acids (BAs), in UC's pathogenesis. The relationship between BAs and gut microbiota is bidirectional: microbiota influence BA composition, while BAs regulate microbiota diversity and activity through receptors like Farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5). Targeting bile-acid metabolism to reshape gut microbiota presents a promising therapeutic strategy for UC. This review examines the classification and synthesis of BAs, their interactions with gut microbiota, and the potential of nutritional and microbial interventions. By focusing on these therapies, we aim to offer innovative approaches for effective UC management.
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Affiliation(s)
| | | | | | | | | | | | - Canxia He
- School of Public Health, Health Science Center, Ningbo University, Ningbo 315211, China
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11
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Gong X, Liu D, Liu L, Yang G, Lei Y, Li N, Chen Y, Yu H, Li X, Xiang D. Plasma bile acid profile analysis by liquid chromatography-tandem mass spectrometry and its application in healthy subjects and IBD patients. J Pharm Biomed Anal 2025; 255:116639. [PMID: 39709683 DOI: 10.1016/j.jpba.2024.116639] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Revised: 12/03/2024] [Accepted: 12/14/2024] [Indexed: 12/24/2024]
Abstract
Bile acids (BAs), not only promote the absorption of fat-soluble nutrients and regulate the metabolism of multiple substances but also have a potential role as diagnostic and prognostic indicators in a variety of diseases such as cholestasis, hepatocellular carcinoma, and diabetes mellitus. Here, a rapid and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous quantification of 50 BAs was developed and validated. Sample preparation included internal standard spiking, followed by protein precipitation, centrifugation, solvent evaporation, and reconstitution. Baseline separation of all isobaric BA species was achieved on an Ultimate XS-C18 column (5 μm, 150 mm × 4.6 mm). The method showed good linearity with high regression coefficients (>0.990) with acceptable accuracy and precision for intra-day and inter-day analyses and achieved good recovery rates for representative analytes. No apparent carryover or matrix effect was observed. The analytical method was successfully applied to the determination of the plasma BA profile in healthy subjects and patients with inflammatory bowel disease (IBD). The routine instrumentation, low sample volume, simple pretreatment, wide range of BAs, and good separation make this LC-MS/MS method suitable for use as a BA profile assay in clinical and basic research studies. This method could be poised to identify possible BA biomarkers for non-invasive early diagnosis and therapeutic evaluation of IBD.
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Affiliation(s)
- Xuepeng Gong
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Dong Liu
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Lu Liu
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Guangjie Yang
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Yongfang Lei
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - NingHong Li
- Department of Pharmacy, The Third Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330008, China
| | - Yufei Chen
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Hengyi Yu
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Xiping Li
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Dong Xiang
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
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Wu S, Bu X, Chen D, Wu X, Wu H, Caiyin Q, Qiao J. Molecules-mediated bidirectional interactions between microbes and human cells. NPJ Biofilms Microbiomes 2025; 11:38. [PMID: 40038292 PMCID: PMC11880406 DOI: 10.1038/s41522-025-00657-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2024] [Accepted: 01/22/2025] [Indexed: 03/06/2025] Open
Abstract
Complex molecules-mediated interactions, which are based on the bidirectional information exchange between microbes and human cells, enable the defense against diseases and health maintenance. Recently, diverse single-direction interactions based on active metabolites, immunity factors, and quorum sensing signals have largely been summarized separately. In this review, according to a simplified timeline, we proposed the framework of Molecules-mediated Bidirectional Interactions (MBI) between microbe and humans to decipher and understand their intricate interactions systematically. About the microbe-derived interactions, we summarized various molecules, such as short-chain fatty acids, bile acids, tryptophan catabolites, and quorum sensing molecules, and their corresponding human receptors. Concerning the human-derived interactions, we reviewed the effect of human molecules, including hormones, cytokines, and other circulatory metabolites on microbial characteristics and phenotypes. Finally, we discussed the challenges and trends for developing and deciphering molecule-mediated bidirectional interactions and their potential applications in the guard of human health.
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Affiliation(s)
- Shengbo Wu
- School of Chemical Engineering and Technology, Tianjin University, Tianjin, 300350, China
- Zhejiang Institute of Tianjin University, Shaoxing, Shaoxing, 312300, Zhejiang, China
| | - Xueying Bu
- School of Chemical Engineering and Technology, Tianjin University, Tianjin, 300350, China
| | - Danlei Chen
- School of Chemical Engineering and Technology, Tianjin University, Tianjin, 300350, China
- Zhejiang Institute of Tianjin University, Shaoxing, Shaoxing, 312300, Zhejiang, China
| | - Xueyan Wu
- School of Chemical Engineering and Technology, Tianjin University, Tianjin, 300350, China
| | - Hao Wu
- School of Chemical Engineering and Technology, Tianjin University, Tianjin, 300350, China.
- Zhejiang Institute of Tianjin University, Shaoxing, Shaoxing, 312300, Zhejiang, China.
| | - Qinggele Caiyin
- School of Chemical Engineering and Technology, Tianjin University, Tianjin, 300350, China.
- Zhejiang Institute of Tianjin University, Shaoxing, Shaoxing, 312300, Zhejiang, China.
- Key Laboratory of Systems Bioengineering, Ministry of Education (Tianjin University), Tianjin, 300072, China.
- Frontiers Science Center for Synthetic Biology (Ministry of Education), Tianjin University, Tianjin, 300072, China.
| | - Jianjun Qiao
- School of Chemical Engineering and Technology, Tianjin University, Tianjin, 300350, China.
- Zhejiang Institute of Tianjin University, Shaoxing, Shaoxing, 312300, Zhejiang, China.
- Key Laboratory of Systems Bioengineering, Ministry of Education (Tianjin University), Tianjin, 300072, China.
- Frontiers Science Center for Synthetic Biology (Ministry of Education), Tianjin University, Tianjin, 300072, China.
- State Key Laboratory of Synthetic Biology, Tianjin University, Tianjin, 300072, China.
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Yang Z, Lin Z, You Y, Zhang M, Gao N, Wang X, Peng J, Wei H. Gut Microbiota-Derived Hyocholic Acid Enhances Type 3 Immunity and Protects Against Salmonella enterica Serovar Typhimurium in Neonatal Rats. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2412071. [PMID: 39737849 PMCID: PMC11905087 DOI: 10.1002/advs.202412071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/28/2024] [Revised: 12/18/2024] [Indexed: 01/01/2025]
Abstract
This study investigates how microbiome colonization influences the development of intestinal type 3 immunity in neonates. The results showed that reduced oxygen levels in the small intestine of neonatal rats induced by Saccharomyces boulardii accelerated microbiome colonization and type 3 immunity development, which protected against Salmonella enterica serovar Typhimurium infection. Microbiome maturation increased the abundance of microbiome-encoded bile salt hydrolase (BSH) genes and hyocholic acid (HCA) levels. Furthermore, reducing oxygen levels in the intestine increased the abundance of Limosilactobacillus reuteri, a bacterium encoding BSH, and promoted intestinal type 3 immunity. However, inhibition of BSH blocked the L. reuteri-induced development of intestinal type 3 immunity. Mechanistically, HCA promoted the development of gamma-delta T cells and type 3 innate lymphoid cells by stabilizing the mRNA expression of RAR-related orphan receptor C via the farnesoid X receptor-WT1-associated protein-N6-methyl-adenosine axis. These results reveal that gut microbiota-derived HCA plays a crucial role in promoting the development of intestinal type 3 immunity in neonates. This discovery introduces potential therapeutic avenues for strengthening intestinal immunity in early life or treating bacterial infections by targeting microbial metabolites.
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Affiliation(s)
- Zhipeng Yang
- Department of Animal Nutrition and Feed ScienceCollege of Animal Science and TechnologyHuazhong Agricultural UniversityWuhan430070China
| | - Zhiyuan Lin
- Department of Animal Nutrition and Feed ScienceCollege of Animal Science and TechnologyHuazhong Agricultural UniversityWuhan430070China
| | - Yaojie You
- Department of Animal Nutrition and Feed ScienceCollege of Animal Science and TechnologyHuazhong Agricultural UniversityWuhan430070China
| | - Mei Zhang
- Department of Animal Nutrition and Feed ScienceCollege of Animal Science and TechnologyHuazhong Agricultural UniversityWuhan430070China
| | - Ning Gao
- Department of Animal Nutrition and Feed ScienceCollege of Animal Science and TechnologyHuazhong Agricultural UniversityWuhan430070China
| | - Xinru Wang
- Department of Animal Nutrition and Feed ScienceCollege of Animal Science and TechnologyHuazhong Agricultural UniversityWuhan430070China
| | - Jian Peng
- Department of Animal Nutrition and Feed ScienceCollege of Animal Science and TechnologyHuazhong Agricultural UniversityWuhan430070China
- The Cooperative Innovation Center for Sustainable Pig ProductionWuhan430070China
- Frontiers Science Center for Animal Breeding and Sustainable ProductionWuhan430070China
- Hubei Hongshan LaboratoryWuhan430070China
| | - Hongkui Wei
- Department of Animal Nutrition and Feed ScienceCollege of Animal Science and TechnologyHuazhong Agricultural UniversityWuhan430070China
- The Cooperative Innovation Center for Sustainable Pig ProductionWuhan430070China
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Li Z, Deng L, Cheng M, Ye X, Yang N, Fan Z, Sun L. Emerging role of bile acids in colorectal liver metastasis: From molecular mechanism to clinical significance (Review). Int J Oncol 2025; 66:24. [PMID: 39981904 PMCID: PMC11844338 DOI: 10.3892/ijo.2025.5730] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Accepted: 01/20/2025] [Indexed: 02/22/2025] Open
Abstract
Liver metastasis is the leading cause of colorectal cancer (CRC)‑related mortality. Microbiota dysbiosis serves a role in the pathogenesis of colorectal liver metastases. Bile acids (BAs), cholesterol metabolites synthesized by intestinal bacteria, contribute to the metastatic cascade of CRC, encompassing colorectal invasion, migration, angiogenesis, anoikis resistance and the establishment of a hepatic pre‑metastatic niche. BAs impact inflammation and modulate the immune landscape within the tumor microenvironment by activating signaling pathways, which are used by tumor cells to facilitate metastasis. Given the widespread distribution of BA‑activated receptors in both tumor and immune cells, strategies aimed at restoring BA homeostasis and blocking metastasis‑associated signaling are of importance in cancer therapy. The present study summarizes the specific role of BAs in each step of colorectal liver metastasis, elucidating the association between BA and CRC progression to highlight the potential of BAs as predictive biomarkers for colorectal liver metastasis and their therapeutic potential in developing novel treatment strategies.
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Affiliation(s)
- Zhaoyu Li
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing 100044, P.R. China
| | - Lingjun Deng
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China, P.R. China
| | - Mengting Cheng
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China, P.R. China
| | - Xiandong Ye
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China, P.R. China
| | - Nanyan Yang
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China, P.R. China
| | - Zaiwen Fan
- Department of Oncology, Air Force Medical Center of People's Liberation Army, Air Force Medical University, Beijing 100010, P.R. China
| | - Li Sun
- Department of Oncology, Air Force Medical Center of People's Liberation Army, Air Force Medical University, Beijing 100010, P.R. China
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Li S, Zhuge A, Chen H, Han S, Shen J, Wang K, Xia J, Xia H, Jiang S, Wu Y, Li L. Sedanolide alleviates DSS-induced colitis by modulating the intestinal FXR-SMPD3 pathway in mice. J Adv Res 2025; 69:413-426. [PMID: 38582300 PMCID: PMC11954817 DOI: 10.1016/j.jare.2024.03.026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Revised: 03/28/2024] [Accepted: 03/29/2024] [Indexed: 04/08/2024] Open
Abstract
INTRODUCTION Inflammatory bowel disease (IBD) is a global disease with limited therapy. It is reported that sedanolide exerts anti-oxidative and anti-inflammatory effects as a natural phthalide, but its effects on IBD remain unclear. OBJECTIVES In this study, we investigated the impacts of sedanolide on dextran sodium sulfate (DSS)-induced colitis in mice. METHODS The mice were administered sedanolide or vehicle followed by DSS administration, after which colitis symptoms, inflammation levels, and intestinal barrier function were evaluated. Transcriptome analysis, 16S rRNA sequencing, and targeted metabolomics analysis of bile acids and lipids were performed. RESULTS Sedanolide protected mice from DSS-induced colitis, suppressed the inflammation, restored the weakened epithelial barrier, and modified the gut microbiota by decreasing bile salt hydrolase (BSH)-expressing bacteria. The downregulation of BSH activity by sedanolide increased the ratio of conjugated/unconjugated bile acids (BAs), thereby inhibiting the intestinal farnesoid X receptor (FXR) pathway. The roles of the FXR pathway and gut microbiota were verified using an intestinal FXR-specific agonist (fexaramine) and germ-free mice, respectively. Furthermore, we identified the key effector ceramide, which is regulated by sphingomyelin phosphodiesterase 3 (SMPD3). The protective effects of ceramide (d18:1/16:0) against inflammation and the gut barrier were demonstrated in vitro using the human cell line Caco-2. CONCLUSION Sedanolide could reshape the intestinal flora and influence BA composition, thus inhibiting the FXR-SMPD3 pathway to stimulate the synthesis of ceramide, which ultimately alleviated DSS-induced colitis in mice. Overall, our research revealed the protective effects of sedanolide against DSS-induced colitis in mice, which indicated that sedanolide may be a clinical treatment for colitis. Additionally, the key lipid ceramide (d18:1/16:0) was shown to mediate the protective effects of sedanolide, providing new insight into the associations between colitis and lipid metabolites.
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Affiliation(s)
- Shengjie Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Aoxiang Zhuge
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Hui Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Shengyi Han
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Jian Shen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Kaicen Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Jiafeng Xia
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - He Xia
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Shiman Jiang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Youhe Wu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; Jinan Microecological Biomedicine Shandong Laboratory, Jinan 250000, China.
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16
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Tuerhongjiang G, Li Y, Meng Z, Gao X, Wei Y, Muhetaer G, Li P, Zhang Y, Zhang J, Wu Y, Liu J. Deoxycholic acid ameliorates obesity and insulin resistance by enhancing lipolysis and thermogenesis. Lipids Health Dis 2025; 24:70. [PMID: 40001126 PMCID: PMC11852518 DOI: 10.1186/s12944-025-02485-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2024] [Accepted: 02/12/2025] [Indexed: 02/27/2025] Open
Abstract
BACKGROUND Bile acids are essential for energy metabolism. Deoxycholic acid (DCA) in particular is associated with metabolic disorders such as type 2 diabetes mellitus (T2DM) and obesity. However, the direct effects of DCA on metabolism and body composition have yet to be studied in depth. METHODS Targeted metabolomics analysis of human feces was performed. C57BL/6J mice fed a high-fat diet (HFD) were gavaged with DCA, and the effects were measured by metabolic tolerance tests and metabolic cages. Body composition was evaluated by echoMRI. To evaluate the beneficial function of DCA on thermogenesis and lipolysis, histological staining and qPCR were carried out. RESULTS There was negative correlation between fecal DCA levels and serum glucose levels, as well as the Homeostatic Model Assessment for Insulin Resistance (HOMA) index in humans. Our findings confirmed that DCA could ameliorate glucose metabolism and insulin sensitivity in mice fed with HFD. DCA supplementation alleviated HFD-induced obesity and decreased the fat mass significantly by promoting lipolysis. Moreover, DCA significantly enhanced energy expenditure and thermogenesis in brown adipose tissue in mice with obesity induced by HFD. CONCLUSIONS Based on the results of our mouse model, DCA may have applications in alleviating obesity and its related metabolic disorders in humans.
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Affiliation(s)
- Gulinigaer Tuerhongjiang
- Department of Cardiovascular, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, China
| | - Yang Li
- Department of Cardiovascular, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, China
| | - Zixuan Meng
- Department of Cardiovascular, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, China
| | - Xiyu Gao
- Department of Cardiovascular, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, China
| | - Yuanyuan Wei
- Department of Cardiology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Gulinigaer Muhetaer
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Peiqi Li
- Department of Cardiovascular, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, China
| | - Yi Zhang
- Center for Immunological and Metabolic Diseases (CIMD), MED-X Institute, The First Affiliated Hospital of Xi'an Jiaotong University, XianYang, China
| | - Jiaming Zhang
- Department of Clinical Laboratory, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Yue Wu
- Department of Cardiovascular, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
- Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, China.
| | - Junhui Liu
- Department of Clinical Laboratory, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
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Zhou XP, Sun LB, Liu WH, Zhu WM, Li LC, Song XY, Xing JP, Gao SH. The complex relationship between gut microbiota and Alzheimer's disease: A systematic review. Ageing Res Rev 2025; 104:102637. [PMID: 39662839 DOI: 10.1016/j.arr.2024.102637] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2024] [Revised: 12/06/2024] [Accepted: 12/06/2024] [Indexed: 12/13/2024]
Abstract
Alzheimer's disease (AD) is a progressive, degenerative disorder of the central nervous system. Despite extensive research conducted on this disorder, its precise pathogenesis remains unclear. In recent years, the microbiota-gut-brain axis has attracted considerable attention within the field of AD. The gut microbiota communicates bidirectionally with the central nervous system through the gut-brain axis, and alterations in its structure and function can influence the progression of AD. Consequently, regulating the gut microbiota to mitigate the progression of AD has emerged as a novel therapeutic approach. Currently, numerous studies concentrate on the intrinsic relationship between the microbiota-gut-brain axis and AD. In this paper, we summarize the multifaceted role of the gut microbiota in AD and present detailed therapeutic strategies targeting the gut microbiota, including the treatment of AD with Traditional Chinese Medicine (TCM), which has garnered increasing attention in recent years. Finally, we discuss potential therapeutic strategies for modulating the gut microbiota to alleviate the progression of AD, the current challenges in this area of research, and provide an outlook on future research directions in this field.
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Affiliation(s)
- Xuan-Peng Zhou
- China-Japan Union Hospital of Jilin University, Changchun, Jilin 130000, PR China
| | - Luan-Biao Sun
- China-Japan Union Hospital of Jilin University, Changchun, Jilin 130000, PR China
| | - Wen-Hao Liu
- China-Japan Union Hospital of Jilin University, Changchun, Jilin 130000, PR China
| | - Wu-Ming Zhu
- China-Japan Union Hospital of Jilin University, Changchun, Jilin 130000, PR China
| | - Lin-Chun Li
- China-Japan Union Hospital of Jilin University, Changchun, Jilin 130000, PR China
| | - Xin-Yuan Song
- The Chinese University of Hong Kong, New Territories 999077, Hong Kong
| | - Jian-Peng Xing
- China-Japan Union Hospital of Jilin University, Changchun, Jilin 130000, PR China.
| | - Shuo-Hui Gao
- China-Japan Union Hospital of Jilin University, Changchun, Jilin 130000, PR China.
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18
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Bai SH, Chandnani A, Cao S. Bile Acids in Inflammatory Bowel Disease: From Pathophysiology to Treatment. Biomedicines 2024; 12:2910. [PMID: 39767816 PMCID: PMC11673883 DOI: 10.3390/biomedicines12122910] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Revised: 12/11/2024] [Accepted: 12/16/2024] [Indexed: 01/11/2025] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic condition that affects about 7 million people worldwide, and new therapies are needed. Understanding the complex roles that bile acids (BAs) play in IBD may lead to the development of novel IBD treatments independent of direct immunosuppression. This review discusses the latest discoveries in the roles BAs play in IBD pathogenesis and explores how these discoveries offer promising new therapeutic targets to treat IBD and improve patient outcomes. Several therapies discussed include specific BA receptor (BAR) agonists, dietary therapies, supplements, probiotics, and mesenchymal stem cell therapies that have all been shown to decrease IBD disease activity.
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Affiliation(s)
| | | | - Siyan Cao
- Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; (S.H.B.); (A.C.)
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19
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Li J, Liu H, Hu X, Zhang S, Yu Q, Kuang G, Liu L, Yu D, Huang J, Xia Y, Wang T, Xiong N. NR1H4 ameliorates Parkinson's disease via inhibiting astrocyte activation and neuroinflammation in a CEBPβ/NF-κB dependent manner. Int Immunopharmacol 2024; 142:113087. [PMID: 39241522 DOI: 10.1016/j.intimp.2024.113087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2024] [Revised: 08/29/2024] [Accepted: 09/02/2024] [Indexed: 09/09/2024]
Abstract
Parkinson's Disease (PD) is a degenerative disease driven by neuroinflammation. Nuclear receptor subfamily 1 group H member 4 (NR1H4), a nuclear receptor involved in metabolic and inflammatory regulation, is found to be widely expressed in central nervous system. Previous studies suggested the protective role of NR1H4 in various diseases related to inflammation, whether NR1H4 participates in PD progression remains unknown. To investigate the role of NR1H4 in neuroinflammation regulation, especially astrocyte activation during PD, siRNA and adenovirus were used to manipulate Nr1h4 expression. RNA-sequencing (RNA-seq), quantitative real-time PCR, enzyme-linked immunosorbent assay, Chromatin immunoprecipitation and western blotting were performed to further study the underlying mechanisms. We identified that NR1H4 was down-regulated during PD progression. In vitro experiments suggested that Nr1h4 knockdown led to inflammatory response, reactive oxygen species generation and astrocytes activation whereasNr1h4 overexpressionhad the opposite effects. The results of RNA-seq on astrocytes revealed that NR1H4 manipulated neuroinflammation in a CEBPβ/NF-κB dependent manner. Additionally, pharmacological activation of NR1H4 via Obeticholic acid ameliorated neuroinflammation and promoted neuronal survival. Our study first proved the neuroprotective effects of NR1H4against PD via inhibiting astrocyte activation and neuroinflammation in a CEBPβ/NF-κB dependent manner.
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Affiliation(s)
- Jingwen Li
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430000, China
| | - Hanshu Liu
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430000, China
| | - Xinyu Hu
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430000, China
| | - Shurui Zhang
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430000, China
| | - Qinwei Yu
- Wuhan Red Cross Hospital, Wuhan, Hubei, China
| | | | - Long Liu
- Wuhan Red Cross Hospital, Wuhan, Hubei, China
| | - Danfang Yu
- Wuhan Red Cross Hospital, Wuhan, Hubei, China
| | - Jinsha Huang
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430000, China
| | - Yun Xia
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430000, China
| | - Tao Wang
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430000, China.
| | - Nian Xiong
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430000, China.
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20
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Cartes-Velásquez R, Vera A, Torres-Quevedo R, Medrano-Díaz J, Pérez A, Muñoz C, Carrillo-Bestagno H, Nova-Lamperti E. The Immunomodulatory Role of Vitamin D in Regulating the Th17/Treg Balance and Epithelial-Mesenchymal Transition: A Hypothesis for Gallbladder Cancer. Nutrients 2024; 16:4134. [PMID: 39683528 DOI: 10.3390/nu16234134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Revised: 11/04/2024] [Accepted: 11/07/2024] [Indexed: 12/18/2024] Open
Abstract
The etiology of gallbladder cancer (GBC) is multifactorial, with chronic inflammation resulting from infections, autoimmune diseases, and lifestyle factors playing a pivotal role. Vitamin D deficiency (VDD) has been implicated in the pathogenesis of autoimmune disorders and various malignancies, including GBC. Research on autoimmune diseases highlights the anti-inflammatory properties of vitamin D, suggesting its potential to mitigate disease progression. In oncology, VDD has similarly been linked to increased inflammation, which may contribute to both the initiation and progression of cancer. A critical component in carcinogenesis, as well as in the immunomodulatory effects of vitamin D in autoimmune conditions, is the balance between T-helper 17 (Th17) cells and regulatory T (Treg) cells. We hypothesize that vitamin D may inhibit epithelial-mesenchymal transition (EMT) in GBC by modulating the spatial distribution of tumor-infiltrating T cells, particularly through the regulation of the Th17/Treg balance at the tumor margins. This Th17/Treg imbalance may act as a mechanistic link between VDD and the progression of GBC carcinogenesis. Investigating the role of an Th17/Treg imbalance as a mediator in VDD-induced EMT in GBC not only provides deeper insights into the pathogenesis of GBC but also sheds light on broader mechanisms relevant to the development of other solid organ cancers, given the expanding recognition of the roles of VDD and Th17/Treg cells in cancer biology.
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Affiliation(s)
| | - Agustín Vera
- Molecular and Translational Immunology Laboratory, Department of Clinical Biochemistry and Immunology, Pharmacy Faculty, University of Concepcion, Concepcion 4070409, Chile
| | - Rodrigo Torres-Quevedo
- School of Medicine, University of Concepcion, Concepcion 4070409, Chile
- Hepatopancreatobiliary Surgical Unit, Service of Surgery, Hospital Guillermo Grant Benavente, Concepcion 4070022, Chile
| | - Jorge Medrano-Díaz
- Hepatopancreatobiliary Surgical Unit, Service of Surgery, Hospital Las Higueras, Talcahuano 4270918, Chile
| | - Andy Pérez
- Department of Instrumental Analysis, Pharmacy Faculty, University of Concepcion, Concepcion 4070409, Chile
| | - Camila Muñoz
- Molecular and Translational Immunology Laboratory, Department of Clinical Biochemistry and Immunology, Pharmacy Faculty, University of Concepcion, Concepcion 4070409, Chile
- Facultad de Odontología y Ciencias de la Rehabilitación, Universidad San Sebastián, Concepción 4080871, Chile
| | - Hernán Carrillo-Bestagno
- School of Medicine, University of Concepcion, Concepcion 4070409, Chile
- Service of Medicine, Hospital Las Higueras, Talcahuano 4270918, Chile
| | - Estefanía Nova-Lamperti
- Molecular and Translational Immunology Laboratory, Department of Clinical Biochemistry and Immunology, Pharmacy Faculty, University of Concepcion, Concepcion 4070409, Chile
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21
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Wu Y, Liu W, Wang R, Lian Y, Cheng X, Yang R, Wang X, Mi S. Capsaicin and Quercitrin Maintained Lipid Homeostasis of Hyperlipidemic Mice: Serum Metabolomics and Signaling Pathways. Foods 2024; 13:3727. [PMID: 39682799 DOI: 10.3390/foods13233727] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Revised: 10/30/2024] [Accepted: 11/09/2024] [Indexed: 12/18/2024] Open
Abstract
Capsaicin and quercitrin have proved to be two major ingredients in fresh chili pepper. However, the effect of these two compounds on hyperlipidemia and the related molecular mechanisms were still unclear. This work was performed to examine the hypolipidemic capacity of capsaicin and quercitrin as well as the related signaling pathways. Hyperlipidemia was induced in mice by feeding them with a high-fat diet for 4 weeks. Both capsaicin and quercitrin were beneficial to inhibit a rise in fasting glucose, total cholesterol, total triglycerides, low-density lipoprotein cholesterol, and total bile acids and to lift the level of high-density lipoprotein cholesterol in the serum. The optimal lipid-lowering data were achieved in the capsaicin and quercitrin/3:1 group. Supplementation with capsaicin and quercitrin both singly and together in the feed caused a significant influence on the metabolite profiles of mouse serum. The signaling pathway for the hypolipidemic effect of capsaicin and quercitrin was related to the down-regulation of epidermal growth factor receptor (EGFR) but the up-regulation of phosphatidylin-ositol-3-kinase (PI3K), protein kinase Bb(Akt), farnesoid X receptor 1 (FXR1), and cholesterol 7α-hydroxylase (CYP7A1). This study confirmed the jointly hypolipidemic effect of capsaicin and quercitrin, which would benefit the valorization of chili pepper resources.
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Affiliation(s)
- Yanxia Wu
- College of Food Science and Technology, Hebei Agricultural University, No. 2596 Lekai South Street, Baoding 071000, China
| | - Weihua Liu
- College of Food Science and Technology, Hebei Agricultural University, No. 2596 Lekai South Street, Baoding 071000, China
| | - Rongrong Wang
- College of Food Science and Technology, Hebei Agricultural University, No. 2596 Lekai South Street, Baoding 071000, China
| | - Yunhe Lian
- Chenguang Biotech Group Co., Ltd., Handan 057250, China
| | - Xinying Cheng
- Hebei Chenguang Testing Technical Services Co., Ltd., Handan 057250, China
| | - Ruili Yang
- Hebei Chenguang Testing Technical Services Co., Ltd., Handan 057250, China
| | - Xianghong Wang
- College of Food Science and Technology, Hebei Agricultural University, No. 2596 Lekai South Street, Baoding 071000, China
| | - Si Mi
- College of Food Science and Technology, Hebei Agricultural University, No. 2596 Lekai South Street, Baoding 071000, China
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22
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Liu P, Jin M, Hu P, Sun W, Tang Y, Wu J, Zhang D, Yang L, He H, Xu X. Gut microbiota and bile acids: Metabolic interactions and impacts on diabetic kidney disease. CURRENT RESEARCH IN MICROBIAL SCIENCES 2024; 7:100315. [PMID: 39726973 PMCID: PMC11670419 DOI: 10.1016/j.crmicr.2024.100315] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2024] Open
Abstract
The intestinal microbiota comprises approximately 1013-1014 species of bacteria and plays a crucial role in host metabolism by facilitating various chemical reactions. Secondary bile acids (BAs) are key metabolites produced by gut microbiota.Initially synthesized by the liver, BA undergoes structural modifications through the activity of various intestinal microbiota enzymes, including eukaryotic, bacterial, and archaeal enzymes. These modified BA then activate specific receptors that regulate multiple metabolic pathways in the host, such as lipid and glucose metabolism, energy balance, inflammatory response, and cell proliferation and death. Recent attention has been given to intestinal flora disorders in diabetic kidney disease (DKD), where activation of BA receptors has shown promise in alleviating diabetic kidney damage by modulating renal lipid metabolism and mitochondrial production. Imbalances in the intestinal flora can influence the progression of DKD through the regulation of bile acid and its receptor pathways. This review aims to propose a mechanism involving the gut-BA-diabetes and nephropathy axes with the goal of optimizing new strategies for treating DKD.
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Affiliation(s)
| | | | - Ping Hu
- Division of Nephrology, Minhang Hospital, Fudan University, Shanghai, China
| | - Weiqian Sun
- Division of Nephrology, Minhang Hospital, Fudan University, Shanghai, China
| | - Yuyan Tang
- Division of Nephrology, Minhang Hospital, Fudan University, Shanghai, China
| | - Jiajun Wu
- Division of Nephrology, Minhang Hospital, Fudan University, Shanghai, China
| | - Dongliang Zhang
- Division of Nephrology, Minhang Hospital, Fudan University, Shanghai, China
| | - Licai Yang
- Division of Nephrology, Minhang Hospital, Fudan University, Shanghai, China
| | - Haidong He
- Division of Nephrology, Minhang Hospital, Fudan University, Shanghai, China
| | - Xudong Xu
- Division of Nephrology, Minhang Hospital, Fudan University, Shanghai, China
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23
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Chang H, Ouyang J, Tian M, Yang J, Gao J, Yang M, Zhang M, Yuan H, Zheng Y, Wang Y, Chen Z. The associations between modifiable risk factors and constipation: a comprehensive mendelian randomization study. BMC Gastroenterol 2024; 24:370. [PMID: 39420266 PMCID: PMC11488088 DOI: 10.1186/s12876-024-03384-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Accepted: 08/24/2024] [Indexed: 10/19/2024] Open
Abstract
OBJECTIVE Early identification of modifiable risk factors is crucial for the prevention of constipation. This study systematically investigated the relationship between genetically predicted modifiable risk factors and constipation. METHODS The inverse variance weighting (IVW) method was employed as the primary analytical approach. For similar exposure indicators, the multivariate Mendelian randomization (MVMR) method was used to adjust for potential biases in univariate MR analysis. The robustness of the results was further evaluated using the MR-Egger intercept test, Cochran's Q test, and leave-one-out analysis. Bonferroni correction was applied to reduce the false positive rate in the results. RESULTS The IVW analysis indicated a significant causal association between genetically predicted gastroesophageal reflux disease [OR (95% CI) = 1.192 (1.079-1.315), P = 0.0005], atorvastatin use [OR (95% CI) = 16.995 (3.327-86.816), P = 0.0007], and constipation. Additionally, there was a potential causal association between education level [OR (95% CI) = 0.859 (0.767-0.964), P = 0.009], major depressive disorder [OR (95% CI) = 1.206 (1.041-1.399), P = 0.013], hypothyroidism [OR (95% CI) = 2.299 (1.327-3.985), P = 0.003], and aspirin use [OR (95% CI) = 4.872 (1.174-20.221), P = 0.029] with constipation. No causal associations were found for the other included indicators. Sensitivity analysis demonstrated the absence of evidence for heterogeneity and pleiotropy in any positive results. CONCLUSION This study identified several risk factors that could be targeted for the prevention of constipation, offering valuable insights for public health policies.
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Affiliation(s)
- Hong Chang
- Lanzhou University, Lanzhou, China
- Department of Gastroenterology, the First Hospital of Lanzhou University, Lanzhou, China
- Gansu Province Clinical Research Center for Digestive Diseases, the First Hospital of Lanzhou University, Lanzhou, China
| | - Jing Ouyang
- Lanzhou University, Lanzhou, China
- Department of Gastroenterology, the First Hospital of Lanzhou University, Lanzhou, China
- Gansu Province Clinical Research Center for Digestive Diseases, the First Hospital of Lanzhou University, Lanzhou, China
| | - Meng Tian
- Lanzhou University, Lanzhou, China
- Department of Gastroenterology, the First Hospital of Lanzhou University, Lanzhou, China
- Gansu Province Clinical Research Center for Digestive Diseases, the First Hospital of Lanzhou University, Lanzhou, China
| | - Jin Yang
- Department of Gastroenterology, the First Hospital of Lanzhou University, Lanzhou, China
- Gansu Province Clinical Research Center for Digestive Diseases, the First Hospital of Lanzhou University, Lanzhou, China
| | - Jie Gao
- Lanzhou University, Lanzhou, China
- Department of Gastroenterology, the First Hospital of Lanzhou University, Lanzhou, China
- Gansu Province Clinical Research Center for Digestive Diseases, the First Hospital of Lanzhou University, Lanzhou, China
| | - Mengjiao Yang
- Lanzhou University, Lanzhou, China
- Department of Gastroenterology, the First Hospital of Lanzhou University, Lanzhou, China
- Gansu Province Clinical Research Center for Digestive Diseases, the First Hospital of Lanzhou University, Lanzhou, China
| | - Meng Zhang
- Lanzhou University, Lanzhou, China
- Department of Gastroenterology, the First Hospital of Lanzhou University, Lanzhou, China
- Gansu Province Clinical Research Center for Digestive Diseases, the First Hospital of Lanzhou University, Lanzhou, China
| | - Hao Yuan
- Department of Gastroenterology, the First Hospital of Lanzhou University, Lanzhou, China
- Gansu Province Clinical Research Center for Digestive Diseases, the First Hospital of Lanzhou University, Lanzhou, China
| | - Ya Zheng
- Department of Gastroenterology, the First Hospital of Lanzhou University, Lanzhou, China
- Gansu Province Clinical Research Center for Digestive Diseases, the First Hospital of Lanzhou University, Lanzhou, China
| | - Yuping Wang
- Department of Gastroenterology, the First Hospital of Lanzhou University, Lanzhou, China
- Gansu Province Clinical Research Center for Digestive Diseases, the First Hospital of Lanzhou University, Lanzhou, China
| | - Zhaofeng Chen
- Department of Gastroenterology, the First Hospital of Lanzhou University, Lanzhou, China.
- Gansu Province Clinical Research Center for Digestive Diseases, the First Hospital of Lanzhou University, Lanzhou, China.
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24
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Xu R, Zhang L, Pan H, Zhang Y. Retinoid X receptor heterodimers in hepatic function: structural insights and therapeutic potential. Front Pharmacol 2024; 15:1464655. [PMID: 39478961 PMCID: PMC11521896 DOI: 10.3389/fphar.2024.1464655] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2024] [Accepted: 09/30/2024] [Indexed: 11/02/2024] Open
Abstract
Nuclear receptors (NRs) are key regulators of multiple physiological functions and pathological changes in the liver in response to a variety of extracellular signaling changes. Retinoid X receptor (RXR) is a special member of the NRs, which not only responds to cellular signaling independently, but also regulates multiple signaling pathways by forming heterodimers with various other NR. Therefore, RXR is widely involved in hepatic glucose metabolism, lipid metabolism, cholesterol metabolism and bile acid homeostasis as well as hepatic fibrosis. Specific activation of particular dimers regulating physiological and pathological processes may serve as important pharmacological targets. So here we describe the basic information and structural features of the RXR protein and its heterodimers, focusing on the role of RXR heterodimers in a number of physiological processes and pathological imbalances in the liver, to provide a theoretical basis for RXR as a promising drug target.
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Affiliation(s)
- Renjie Xu
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Linyue Zhang
- Department of Ultrasound, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hao Pan
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yong Zhang
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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25
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Van Hul M, Neyrinck AM, Everard A, Abot A, Bindels LB, Delzenne NM, Knauf C, Cani PD. Role of the intestinal microbiota in contributing to weight disorders and associated comorbidities. Clin Microbiol Rev 2024; 37:e0004523. [PMID: 38940505 PMCID: PMC11391702 DOI: 10.1128/cmr.00045-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/29/2024] Open
Abstract
SUMMARYThe gut microbiota is a major factor contributing to the regulation of energy homeostasis and has been linked to both excessive body weight and accumulation of fat mass (i.e., overweight, obesity) or body weight loss, weakness, muscle atrophy, and fat depletion (i.e., cachexia). These syndromes are characterized by multiple metabolic dysfunctions including abnormal regulation of food reward and intake, energy storage, and low-grade inflammation. Given the increasing worldwide prevalence of obesity, cachexia, and associated metabolic disorders, novel therapeutic strategies are needed. Among the different mechanisms explaining how the gut microbiota is capable of influencing host metabolism and energy balance, numerous studies have investigated the complex interactions existing between nutrition, gut microbes, and their metabolites. In this review, we discuss how gut microbes and different microbiota-derived metabolites regulate host metabolism. We describe the role of the gut barrier function in the onset of inflammation in this context. We explore the importance of the gut-to-brain axis in the regulation of energy homeostasis and glucose metabolism but also the key role played by the liver. Finally, we present specific key examples of how using targeted approaches such as prebiotics and probiotics might affect specific metabolites, their signaling pathways, and their interactions with the host and reflect on the challenges to move from bench to bedside.
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Affiliation(s)
- Matthias Van Hul
- UCLouvain, Université catholique de Louvain, Louvain Drug Research Institute (LDRI), Metabolism and Nutrition Research Group (MNUT), Brussels, Belgium
- Walloon Excellence in Life Sciences and BIOtechnology (WELBIO), WELBIO department, WEL Research Institute, Wavre, Belgium
- NeuroMicrobiota, International Research Program (IRP) INSERM/UCLouvain, France/Belgium
| | - Audrey M Neyrinck
- UCLouvain, Université catholique de Louvain, Louvain Drug Research Institute (LDRI), Metabolism and Nutrition Research Group (MNUT), Brussels, Belgium
| | - Amandine Everard
- UCLouvain, Université catholique de Louvain, Louvain Drug Research Institute (LDRI), Metabolism and Nutrition Research Group (MNUT), Brussels, Belgium
- Walloon Excellence in Life Sciences and BIOtechnology (WELBIO), WELBIO department, WEL Research Institute, Wavre, Belgium
| | | | - Laure B Bindels
- UCLouvain, Université catholique de Louvain, Louvain Drug Research Institute (LDRI), Metabolism and Nutrition Research Group (MNUT), Brussels, Belgium
- Walloon Excellence in Life Sciences and BIOtechnology (WELBIO), WELBIO department, WEL Research Institute, Wavre, Belgium
| | - Nathalie M Delzenne
- UCLouvain, Université catholique de Louvain, Louvain Drug Research Institute (LDRI), Metabolism and Nutrition Research Group (MNUT), Brussels, Belgium
| | - Claude Knauf
- NeuroMicrobiota, International Research Program (IRP) INSERM/UCLouvain, France/Belgium
- INSERM U1220, Institut de Recherche en Santé Digestive (IRSD), Université Paul Sabatier, Toulouse III, CHU Purpan, Toulouse, France
| | - Patrice D Cani
- UCLouvain, Université catholique de Louvain, Louvain Drug Research Institute (LDRI), Metabolism and Nutrition Research Group (MNUT), Brussels, Belgium
- Walloon Excellence in Life Sciences and BIOtechnology (WELBIO), WELBIO department, WEL Research Institute, Wavre, Belgium
- NeuroMicrobiota, International Research Program (IRP) INSERM/UCLouvain, France/Belgium
- UCLouvain, Université catholique de Louvain, Institute of Experimental and Clinical Research (IREC), Brussels, Belgium
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Qian G, Zang H, Tang J, Zhang H, Yu J, Jia H, Zhang X, Zhou J. Lactobacillus gasseri ATCC33323 affects the intestinal mucosal barrier to ameliorate DSS-induced colitis through the NR1I3-mediated regulation of E-cadherin. PLoS Pathog 2024; 20:e1012541. [PMID: 39250508 PMCID: PMC11412683 DOI: 10.1371/journal.ppat.1012541] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2024] [Revised: 09/19/2024] [Accepted: 08/29/2024] [Indexed: 09/11/2024] Open
Abstract
Inflammatory bowel disease (IBD) is an immune system disorder primarily characterized by colitis, the exact etiology of which remains unclear. Traditional treatment approaches currently yield limited efficacy and are associated with significant side effects. Extensive research has indicated the potent therapeutic effects of probiotics, particularly Lactobacillus strains, in managing colitis. However, the mechanisms through which Lactobacillus strains ameliorate colitis require further exploration. In our study, we selected Lactobacillus gasseri ATCC33323 from the intestinal microbiota to elucidate the specific mechanisms involved in modulation of colitis. Experimental findings in a DSS-induced colitis mouse model revealed that L. gasseri ATCC33323 significantly improved physiological damage in colitic mice, reduced the severity of colonic inflammation, decreased the production of inflammatory factors, and preserved the integrity of the intestinal epithelial structure and function. It also maintained the expression and localization of adhesive proteins while improving intestinal barrier permeability and restoring dysbiosis in the gut microbiota. E-cadherin, a critical adhesive protein, plays a pivotal role in this protective mechanism. Knocking down E-cadherin expression within the mouse intestinal tract significantly attenuated the ability of L. gasseri ATCC33323 to regulate colitis, thus confirming its protective role through E-cadherin. Finally, transcriptional analysis and in vitro experiments revealed that L. gasseri ATCC33323 regulates CDH1 transcription by affecting NR1I3, thereby promoting E-cadherin expression. These findings contribute to a better understanding of the specific mechanisms by which Lactobacillus strains alleviate colitis, offering new insights for the potential use of L. gasseri as an alternative therapy for IBD, particularly in dietary supplementation.
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Affiliation(s)
- Guanru Qian
- Department of Gastrointestinal Surgery & Hernia and Abdominal Wall Surgery, the First Hospital, China Medical University, Shenyang, China
- Department of Shenyang Medical Nutrition Clinical Medical Research Center, Shenyang, China
| | - Hui Zang
- Department of Gastrointestinal Surgery & Hernia and Abdominal Wall Surgery, the First Hospital, China Medical University, Shenyang, China
- Department of Shenyang Medical Nutrition Clinical Medical Research Center, Shenyang, China
| | - Jingtong Tang
- Department of Gastrointestinal Surgery & Hernia and Abdominal Wall Surgery, the First Hospital, China Medical University, Shenyang, China
- Department of Shenyang Medical Nutrition Clinical Medical Research Center, Shenyang, China
| | - Hao Zhang
- Department of Gastrointestinal Surgery & Hernia and Abdominal Wall Surgery, the First Hospital, China Medical University, Shenyang, China
- Department of Shenyang Medical Nutrition Clinical Medical Research Center, Shenyang, China
| | - Jiankang Yu
- Department of Gastrointestinal Surgery & Hernia and Abdominal Wall Surgery, the First Hospital, China Medical University, Shenyang, China
- Department of Shenyang Medical Nutrition Clinical Medical Research Center, Shenyang, China
| | - Huibiao Jia
- Department of Gastrointestinal Surgery & Hernia and Abdominal Wall Surgery, the First Hospital, China Medical University, Shenyang, China
- Department of Shenyang Medical Nutrition Clinical Medical Research Center, Shenyang, China
| | - Xinzhuang Zhang
- Department of Gastrointestinal Surgery & Hernia and Abdominal Wall Surgery, the First Hospital, China Medical University, Shenyang, China
- Department of Shenyang Medical Nutrition Clinical Medical Research Center, Shenyang, China
| | - Jianping Zhou
- Department of Gastrointestinal Surgery & Hernia and Abdominal Wall Surgery, the First Hospital, China Medical University, Shenyang, China
- Department of Shenyang Medical Nutrition Clinical Medical Research Center, Shenyang, China
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27
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Umemura M, Honda A, Yamashita M, Chida T, Noritake H, Yamamoto K, Honda T, Ichimura-Shimizu M, Tsuneyama K, Miyazaki T, Kurono N, Leung PSC, Gershwin ME, Suda T, Kawata K. High-fat diet modulates bile acid composition and gut microbiota, affecting severe cholangitis and cirrhotic change in murine primary biliary cholangitis. J Autoimmun 2024; 148:103287. [PMID: 39033687 DOI: 10.1016/j.jaut.2024.103287] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Revised: 07/11/2024] [Accepted: 07/13/2024] [Indexed: 07/23/2024]
Abstract
Increasing evidence suggests that, in addition to a loss of tolerance, bile acid (BA) modulates the natural history of primary biliary cholangitis (PBC). We focused on the impacts of dietary changes on the immunopathology of PBC, along with alterations in BA composition and gut microbiota. In this study, we have taken advantage of our unique PBC model, a Cyp2c70/Cyp2a12 double knockout (DKO), which includes a human-like BA composition, and develops progressive cholangitis following immunization with the PDC-E2 mimic, 2-octynoic acid (2OA). We compared the effects of a ten-week high-fat diet (HFD) (60 % kcal from fat) and a normal diet (ND) on 2OA-treated DKO mice. Importantly, we report that 2OA-treated DKO mice fed HFD had significantly exacerbated cholangitis, leading to cirrhosis, with increased hepatic expression of Th1 cytokines/chemokines and hepatic fibrotic markers. Serum lithocholic acid (LCA) levels and the ratio of chenodeoxycholic acid (CDCA)-derived BAs to cholic acid-derived BAs were significantly increased by HFD. This was also associated with downregulated expression of key regulators of BA synthesis, including Cyp8b1, Cyp3a11, and Sult2a1. In addition, there were increases in the relative abundances of Acetatifactor and Lactococcus and decreases in Desulfovibrio and Lachnospiraceae_NK4A136_group, which corresponded to the abundances of CDCA and LCA. In conclusion, HFD and HFD-induced alterations in the gut microbiota modulate BA composition and nuclear receptor activation, leading to cirrhotic change in this murine PBC model. These findings have significant implications for understanding the progression of human PBC.
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Affiliation(s)
- Masahiro Umemura
- Department of Internal Medicine II, Hamamatsu University School of Medicine, 1-20-1 Handayama, Chuo-ku, Hamamatsu, Shizuoka, 431-3192, Japan.
| | - Akira Honda
- Joint Research Center and Division of Gastroenterology and Hepatology, Tokyo Medical University Ibaraki Medical Center, 3-20-1Chuo, Ami-machi, Inashiki-gun, Ibaraki, 300-0395, Japan.
| | - Maho Yamashita
- Department of Internal Medicine II, Hamamatsu University School of Medicine, 1-20-1 Handayama, Chuo-ku, Hamamatsu, Shizuoka, 431-3192, Japan.
| | - Takeshi Chida
- Department of Internal Medicine II, Hamamatsu University School of Medicine, 1-20-1 Handayama, Chuo-ku, Hamamatsu, Shizuoka, 431-3192, Japan.
| | - Hidenao Noritake
- Department of Internal Medicine II, Hamamatsu University School of Medicine, 1-20-1 Handayama, Chuo-ku, Hamamatsu, Shizuoka, 431-3192, Japan.
| | - Kenta Yamamoto
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan.
| | - Takashi Honda
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan.
| | - Mayuko Ichimura-Shimizu
- Department of Pathology and Laboratory Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto, Tokushima, 770-8503, Japan.
| | - Koichi Tsuneyama
- Department of Pathology and Laboratory Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto, Tokushima, 770-8503, Japan.
| | - Teruo Miyazaki
- Joint Research Center and Division of Gastroenterology and Hepatology, Tokyo Medical University Ibaraki Medical Center, 3-20-1Chuo, Ami-machi, Inashiki-gun, Ibaraki, 300-0395, Japan.
| | - Nobuhito Kurono
- Department of Chemistry, Hamamatsu University School of Medicine, 1-20-1 Handayama, Chuo-ku, Hamamatsu, Shizuoka, 431-3192, Japan.
| | - Patrick S C Leung
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, 451 Health Sciences Drive, Davis, CA, 95616, USA.
| | - M Eric Gershwin
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, 451 Health Sciences Drive, Davis, CA, 95616, USA.
| | - Takafumi Suda
- Department of Internal Medicine II, Hamamatsu University School of Medicine, 1-20-1 Handayama, Chuo-ku, Hamamatsu, Shizuoka, 431-3192, Japan.
| | - Kazuhito Kawata
- Department of Internal Medicine II, Hamamatsu University School of Medicine, 1-20-1 Handayama, Chuo-ku, Hamamatsu, Shizuoka, 431-3192, Japan.
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28
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Liu Q, Xu Y, Lv X, Guo C, Zhu H, Yang L, Wang Y. 2', 3', 5'-tri-O-acetyl-N6-(3-hydroxyphenyl) adenosine alleviates diet-induced hyperlipidemia by modulating intestinal gene expression profiles and metabolic pathway. Life Sci 2024; 352:122891. [PMID: 38977060 DOI: 10.1016/j.lfs.2024.122891] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Revised: 06/24/2024] [Accepted: 07/03/2024] [Indexed: 07/10/2024]
Abstract
There is a growing body of evidence suggesting that the composition of intestinal flora plays a significant role in regulating lipid metabolism. 2', 3', 5'-tri-O-acetyl-N6-(3-hydroxyphenyl) adenosine (IMMH007) is a new candidate compound for regulating blood cholesterol and other lipids. In this study, we conducted metagenomic and metabolomic analyses on samples from high-fat diet-fed (HFD) hamsters treated with IMMH007. Our findings revealed that IMM-H007 reversed the imbalance of gut microbiota caused by a high-fat diet. Additionally, it activated adiponectin receptor and pantothenate and CoA biosynthesis pathway-related genes, which are known to regulate lipid and glucose metabolism. Furthermore, IMM-H007 promotes cholesterol metabolism by reducing the abundance of genes and species associated with 7α-dehydroxylation and bile salt hydrolase (BSH). Metabolomics and pharmacological studies have shown that IMM-H007 effectively improved glucose and lipid metabolism disorders caused by HFD, reduced the aggregation of secondary bile acids (SBAs), significantly increased the content of hyodeoxycholic acid (HDCA), and also activated the expression of VDR in the small intestine. As a result, there was a reduction in the leakage of diamine oxidase (DAO) into the bloodstream in hamsters, accompanied by an upregulation of ZO-1 expression in the small intestine. The results suggested that IMM-H007 regulated glucose and lipid metabolism, promoted cholesterol metabolism through activating the expression of VDR, inhibiting inflammatory and improving the permeability of the intestinal barrier. Thus, our study provides new understanding of how IMM-H007 interacts with intestinal function, microbiota, and relevant targets, shedding light on its mechanism of action.
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Affiliation(s)
- Qifeng Liu
- State Key Laboratory for Bioactive Substances and Functions of Natural Medicines and Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Core Facilities, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Yue Xu
- State Key Laboratory for Bioactive Substances and Functions of Natural Medicines and Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xueqi Lv
- State Key Laboratory for Bioactive Substances and Functions of Natural Medicines and Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Congcong Guo
- State Key Laboratory for Bioactive Substances and Functions of Natural Medicines and Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Haibo Zhu
- State Key Laboratory for Bioactive Substances and Functions of Natural Medicines and Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Liu Yang
- State Key Laboratory for Bioactive Substances and Functions of Natural Medicines and Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| | - Yinghong Wang
- State Key Laboratory for Bioactive Substances and Functions of Natural Medicines and Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
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29
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Zhou S, Yang L, Qiu X, Li B, Hu L, Tang Z, Li H, Li S, Fang Z, Chen H. Okra extract alleviates lipopolysaccharide-induced inflammation response through the regulation of bile acids, the receptor-mediated pathway, and gut microbiota. JOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE 2024; 104:7501-7513. [PMID: 38757804 DOI: 10.1002/jsfa.13571] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Revised: 03/24/2024] [Accepted: 04/29/2024] [Indexed: 05/18/2024]
Abstract
BACKGROUND Okra contains flavonoids and vitamin C as antioxidants and it contains polysaccharides as immunomodulators. Flavonoids regulate the inflammatory response in mice and may be related to gut microbiota. This study therefore aimed to investigate the impact of okra extract (OE) on inflammation in mice and to elucidate its underlying mechanism. METHOD Forty male Kunming (KM) mice were categorized into four groups: the control (CON) group, the lipopolysaccharide stimulation (LPS) group, the 5 mg mL-1 OE intervention (LPS + OE) group, and the 5 mg mL-1 OE supplementation plus mixed antibiotics (LPS + OE + ABX) group. RESULTS The results showed that, compared with the OE group, the expression of inflammatory signaling pathway genes was upregulated and gut barrier genes were inhibited in the OE + ABX group. The Fxr receptor was activated and the abundance of Akkermansia was increased after OE supplementation, whereas the effect was reversed in the OE + ABX group. Meanwhile, Fxr was correlated positively with Akkermansia. CONCLUSION The OE supplementation alleviated the inflammatory response in mice under LPS stimulation, accompanied by changes in gut microbiota and bile acid receptors, whereas the addition of antibiotics caused a disturbance to the gut microbiota in the OE group, thus reducing the effect of OE in alleviating the inflammatory response. © 2024 Society of Chemical Industry.
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Affiliation(s)
- Shanshan Zhou
- College of Food Science, Sichuan Agricultural University, Yaan, China
| | - Li Yang
- College of Food Science, Sichuan Agricultural University, Yaan, China
| | - Xia Qiu
- College of Food Science, Sichuan Agricultural University, Yaan, China
| | - Bohui Li
- College of Food Science, Sichuan Agricultural University, Yaan, China
| | - Liang Hu
- College of Food Science, Sichuan Agricultural University, Yaan, China
| | - Zizhong Tang
- College of Food Science, Sichuan Agricultural University, Yaan, China
| | - Hua Li
- Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, China
| | - Shanshan Li
- College of Food Science, Sichuan Agricultural University, Yaan, China
| | - Zhengfeng Fang
- Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, China
| | - Hong Chen
- College of Food Science, Sichuan Agricultural University, Yaan, China
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30
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Gonzalez E, Lee MD, Tierney BT, Lipieta N, Flores P, Mishra M, Beckett L, Finkelstein A, Mo A, Walton P, Karouia F, Barker R, Jansen RJ, Green SJ, Weging S, Kelliher J, Singh NK, Bezdan D, Galazska J, Brereton NJB. Spaceflight alters host-gut microbiota interactions. NPJ Biofilms Microbiomes 2024; 10:71. [PMID: 39209868 PMCID: PMC11362537 DOI: 10.1038/s41522-024-00545-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Accepted: 07/31/2024] [Indexed: 09/04/2024] Open
Abstract
The ISS rodent habitat has provided crucial insights into the impact of spaceflight on mammals, inducing symptoms characteristic of liver disease, insulin resistance, osteopenia, and myopathy. Although these physiological responses can involve the microbiome on Earth, host-microbiota interactions during spaceflight are still being elucidated. We explore murine gut microbiota and host gene expression in the colon and liver after 29 and 56 days of spaceflight using multiomics. Metagenomics revealed significant changes in 44 microbiome species, including relative reductions in bile acid and butyrate metabolising bacteria like Extibacter muris and Dysosmobacter welbionis. Functional prediction indicate over-representation of fatty acid and bile acid metabolism, extracellular matrix interactions, and antibiotic resistance genes. Host gene expression described corresponding changes to bile acid and energy metabolism, and immune suppression. These changes imply that interactions at the host-gut microbiome interface contribute to spaceflight pathology and that these interactions might critically influence human health and long-duration spaceflight feasibility.
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Affiliation(s)
- E Gonzalez
- Microbiome Unit, Canadian Centre for Computational Genomics, Department of Human Genetics, McGill University, Montréal, Canada
- Centre for Microbiome Research, McGill University, Montréal, Canada
| | - M D Lee
- Exobiology Branch, NASA Ames Research Centre, Moffett Field, CA, USA
- Blue Marble Space Institute of Science, Seattle, WA, USA
| | - B T Tierney
- Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA
- Department of Genetics, Harvard Medical School, Boston, MA, USA
| | - N Lipieta
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, 02142, USA
| | - P Flores
- BioServe Space Technologies, University of Colorado Boulder, Boulder, CO, USA
| | - M Mishra
- Grossman School of Medicine, New York University, New York, USA
| | - L Beckett
- University of Nottingham, Nottingham, NG7 2RD, UK
| | - A Finkelstein
- NASA GeneLab for High Schools (GL4HS) program, NASA Ames Research Centre, Moffett Field, CA, USA
| | - A Mo
- NASA GeneLab for High Schools (GL4HS) program, NASA Ames Research Centre, Moffett Field, CA, USA
| | - P Walton
- NASA GeneLab for High Schools (GL4HS) program, NASA Ames Research Centre, Moffett Field, CA, USA
| | - F Karouia
- Exobiology Branch, NASA Ames Research Centre, Moffett Field, CA, USA
- Blue Marble Space Institute of Science, Seattle, WA, USA
- Centre for Space Medicine, Baylor College of Medicine, Houston, TX, USA
| | - R Barker
- Blue Marble Space Institute of Science, Seattle, WA, USA
- Yuri GmbH, Wiesentalstr. 40, 88074, Meckenbeuren, Germany
- University of Wisconsin-Madison, Madison, WI, USA
| | - R J Jansen
- Department of Public Health, North Dakota State University, Fargo, ND, USA
- Genomics, Phenomics, and Bioinformatics Program, North Dakota State University, Fargo, ND, USA
| | - S J Green
- Genomics and Microbiome Core Facility, Rush University Medical Centre, 1653 W. Congress Parkway, Chicago, IL, 60612, USA
| | - S Weging
- Institute of Computer Science, Martin-Luther University Halle-Wittenberg, Halle, Germany
| | - J Kelliher
- Bioscience Division, Los Alamos National Laboratory, Los Alamos, NM, USA
| | - N K Singh
- Department of Industrial Relations, Division of Occupational Safety and Health, Oakland, USA
| | - D Bezdan
- University of Wisconsin-Madison, Madison, WI, USA
- Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany
- NGS Competence Centre Tübingen (NCCT), University of Tübingen, Tübingen, Germany
| | - J Galazska
- Space Biosciences Research Branch, NASA Ames Research Centre, Moffett Field, CA, USA
| | - N J B Brereton
- School of Biology and Environmental Science, University College Dublin, Dublin, Ireland.
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31
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Ma J, Li M, Bao Y, Huang W, He X, Hong Y, Wei W, Liu Z, Gao X, Yang Y, Cui Z, Wang W, Wang J, Zhu W, Zheng N, Pan L, Wang D, Ke Z, Zhou B, Sheng L, Li H. Gut microbiota-brain bile acid axis orchestrates aging-related neuroinflammation and behavior impairment in mice. Pharmacol Res 2024; 208:107361. [PMID: 39159729 DOI: 10.1016/j.phrs.2024.107361] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 08/16/2024] [Accepted: 08/16/2024] [Indexed: 08/21/2024]
Abstract
Emerging evidence shows that disrupted gut microbiota-bile acid (BA) axis is critically involved in the development of neurodegenerative diseases. However, the alterations in spatial distribution of BAs among different brain regions that command important functions during aging and their exact roles in aging-related neurodegenerative diseases are poorly understood. Here, we analyzed the BA profiles in cerebral cortex, hippocampus, and hypothalamus of young and natural aging mice of both sexes. The results showed that aging altered brain BA profiles sex- and region- dependently, in which TβMCA was consistently elevated in aging mice of both sexes, particularly in the hippocampus and hypothalamus. Furthermore, we found that aging accumulated-TβMCA stimulated microglia inflammation in vitro and shortened the lifespan of C. elegans, as well as behavioral impairment and neuroinflammation in mice. In addition, metagenomic analysis suggested that the accumulation of brain TβMCA during aging was partially attributed to reduction in BSH-carrying bacteria. Finally, rejuvenation of gut microbiota by co-housing aged mice with young mice restored brain BA homeostasis and improved neurological dysfunctions in natural aging mice. In conclusion, our current study highlighted the potential of improving aging-related neuro-impairment by targeting gut microbiota-brain BA axis.
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Affiliation(s)
- Junli Ma
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Mingxiao Li
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yiyang Bao
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Wenjin Huang
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Xiaofang He
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Ying Hong
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Wenjing Wei
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Zekun Liu
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Xinxin Gao
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yang Yang
- Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Zhengyu Cui
- Department of Traditional Chinese Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
| | - Wantao Wang
- Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Jie Wang
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, China
| | - Weize Zhu
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Ningning Zheng
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Lingyun Pan
- Experiment Center for Science and Technology, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Deheng Wang
- Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Zunji Ke
- Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Ben Zhou
- Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Lili Sheng
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| | - Houkai Li
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
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Shen H, Zhou L, Zhang H, Yang Y, Jiang L, Wu D, Shu H, Zhang H, Xie L, Zhou K, Cheng C, Yang L, Jiang J, Wang S, Han Y, Zhu J, Xu L, Liu Z, Wang H, Yin S. Dietary fiber alleviates alcoholic liver injury via Bacteroides acidifaciens and subsequent ammonia detoxification. Cell Host Microbe 2024; 32:1331-1346.e6. [PMID: 38959900 DOI: 10.1016/j.chom.2024.06.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2024] [Revised: 05/14/2024] [Accepted: 06/06/2024] [Indexed: 07/05/2024]
Abstract
The gut microbiota and diet-induced changes in microbiome composition have been linked to various liver diseases, although the specific microbes and mechanisms remain understudied. Alcohol-related liver disease (ALD) is one such disease with limited therapeutic options due to its complex pathogenesis. We demonstrate that a diet rich in soluble dietary fiber increases the abundance of Bacteroides acidifaciens (B. acidifaciens) and alleviates alcohol-induced liver injury in mice. B. acidifaciens treatment alone ameliorates liver injury through a bile salt hydrolase that generates unconjugated bile acids to activate intestinal farnesoid X receptor (FXR) and its downstream target, fibroblast growth factor-15 (FGF15). FGF15 promotes hepatocyte expression of ornithine aminotransferase (OAT), which facilitates the metabolism of accumulated ornithine in the liver into glutamate, thereby providing sufficient glutamate for ammonia detoxification via the glutamine synthesis pathway. Collectively, these findings uncover a potential therapeutic strategy for ALD involving dietary fiber supplementation and B. acidifaciens.
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Affiliation(s)
- Haiyuan Shen
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei 230032, China
| | - Liangliang Zhou
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei 230032, China
| | - Hao Zhang
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei 230032, China
| | - Yuanru Yang
- Department of Blood Transfusion, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China
| | - Ling Jiang
- Department of Nephropathy, The First Affiliated Hospital, Anhui Medical University, Hefei 230022, China
| | - Dongqing Wu
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei 230032, China
| | - Hang Shu
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei 230032, China
| | - Hejiao Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
| | - Linxi Xie
- School of Basic Medical Science, Anhui Medical University, Hefei 230032, China
| | - Kaichen Zhou
- Institute for Immunology, School of Basic Medical Science, Tsinghua University, Beijing 100084, China
| | - Chen Cheng
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei 230032, China; School of Basic Medical Science, Anhui Medical University, Hefei 230032, China
| | - Lei Yang
- School of Basic Medical Science, Anhui Medical University, Hefei 230032, China
| | - Jiali Jiang
- School of Basic Medical Science, Anhui Medical University, Hefei 230032, China
| | - Siya Wang
- Department of Geriatrics, Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei 230002, China; Anhui Key Laboratory of Geriatric Immunology and Nutrition Therapy, Hefei 230027, China
| | - Yiran Han
- Innovation and Entrepreneurship Laboratory for College Students, Anhui Medical University, Hefei 230032, China
| | - Jiayi Zhu
- Innovation and Entrepreneurship Laboratory for College Students, Anhui Medical University, Hefei 230032, China
| | - Long Xu
- School of Basic Medical Science, Anhui Medical University, Hefei 230032, China
| | - Zhihua Liu
- Institute for Immunology, School of Basic Medical Science, Tsinghua University, Beijing 100084, China.
| | - Hua Wang
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei 230032, China.
| | - Shi Yin
- Department of Geriatrics, Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei 230002, China; Anhui Key Laboratory of Geriatric Immunology and Nutrition Therapy, Hefei 230027, China.
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Jiang L, Zhao Y, Liu F, Huang Y, Zhang Y, Yuan B, Cheng J, Yan P, Ni J, Jiang Y, Wu Q, Jiang X. Concomitant targeting of FLT3 and SPHK1 exerts synergistic cytotoxicity in FLT3-ITD + acute myeloid leukemia by inhibiting β-catenin activity via the PP2A-GSK3β axis. Cell Commun Signal 2024; 22:391. [PMID: 39113090 PMCID: PMC11304842 DOI: 10.1186/s12964-024-01774-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Accepted: 08/01/2024] [Indexed: 08/11/2024] Open
Abstract
BACKGROUND Approximately 25-30% of patients with acute myeloid leukemia (AML) have FMS-like receptor tyrosine kinase-3 (FLT3) mutations that contribute to disease progression and poor prognosis. Prolonged exposure to FLT3 tyrosine kinase inhibitors (TKIs) often results in limited clinical responses due to diverse compensatory survival signals. Therefore, there is an urgent need to elucidate the mechanisms underlying FLT3 TKI resistance. Dysregulated sphingolipid metabolism frequently contributes to cancer progression and a poor therapeutic response. However, its relationship with TKI sensitivity in FLT3-mutated AML remains unknown. Thus, we aimed to assess mechanisms of FLT3 TKI resistance in AML. METHODS We performed lipidomics profiling, RNA-seq, qRT-PCR, and enzyme-linked immunosorbent assays to determine potential drivers of sorafenib resistance. FLT3 signaling was inhibited by sorafenib or quizartinib, and SPHK1 was inhibited by using an antagonist or via knockdown. Cell growth and apoptosis were assessed in FLT3-mutated and wild-type AML cell lines via Cell counting kit-8, PI staining, and Annexin-V/7AAD assays. Western blotting and immunofluorescence assays were employed to explore the underlying molecular mechanisms through rescue experiments using SPHK1 overexpression and exogenous S1P, as well as inhibitors of S1P2, β-catenin, PP2A, and GSK3β. Xenograft murine model, patient samples, and publicly available data were analyzed to corroborate our in vitro results. RESULTS We demonstrate that long-term sorafenib treatment upregulates SPHK1/sphingosine-1-phosphate (S1P) signaling, which in turn positively modulates β-catenin signaling to counteract TKI-mediated suppression of FLT3-mutated AML cells via the S1P2 receptor. Genetic or pharmacological inhibition of SPHK1 potently enhanced the TKI-mediated inhibition of proliferation and apoptosis induction in FLT3-mutated AML cells in vitro. SPHK1 knockdown enhanced sorafenib efficacy and improved survival of AML-xenografted mice. Mechanistically, targeting the SPHK1/S1P/S1P2 signaling synergizes with FLT3 TKIs to inhibit β-catenin activity by activating the protein phosphatase 2 A (PP2A)-glycogen synthase kinase 3β (GSK3β) pathway. CONCLUSIONS These findings establish the sphingolipid metabolic enzyme SPHK1 as a regulator of TKI sensitivity and suggest that combining SPHK1 inhibition with TKIs could be an effective approach for treating FLT3-mutated AML.
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MESH Headings
- fms-Like Tyrosine Kinase 3/genetics
- fms-Like Tyrosine Kinase 3/metabolism
- fms-Like Tyrosine Kinase 3/antagonists & inhibitors
- Humans
- Leukemia, Myeloid, Acute/drug therapy
- Leukemia, Myeloid, Acute/pathology
- Leukemia, Myeloid, Acute/genetics
- Leukemia, Myeloid, Acute/metabolism
- Glycogen Synthase Kinase 3 beta/metabolism
- Glycogen Synthase Kinase 3 beta/genetics
- beta Catenin/metabolism
- beta Catenin/genetics
- Phosphotransferases (Alcohol Group Acceptor)/metabolism
- Phosphotransferases (Alcohol Group Acceptor)/genetics
- Phosphotransferases (Alcohol Group Acceptor)/antagonists & inhibitors
- Animals
- Mice
- Protein Phosphatase 2/metabolism
- Protein Phosphatase 2/genetics
- Protein Phosphatase 2/antagonists & inhibitors
- Cell Line, Tumor
- Sorafenib/pharmacology
- Apoptosis/drug effects
- Protein Kinase Inhibitors/pharmacology
- Signal Transduction/drug effects
- Cell Proliferation/drug effects
- Drug Synergism
- Xenograft Model Antitumor Assays
- Drug Resistance, Neoplasm/drug effects
- Drug Resistance, Neoplasm/genetics
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Affiliation(s)
- Ling Jiang
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yu Zhao
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Department of Hematology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China
| | - Fang Liu
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yun Huang
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yujiao Zhang
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Baoyi Yuan
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jiaying Cheng
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Ping Yan
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jinle Ni
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | | | - Quan Wu
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xuejie Jiang
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
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Tenge V, Ayyar BV, Ettayebi K, Crawford SE, Hayes NM, Shen YT, Neill FH, Atmar RL, Estes MK. Bile acid-sensitive human norovirus strains are susceptible to sphingosine-1-phosphate receptor 2 inhibition. J Virol 2024; 98:e0202023. [PMID: 38884472 PMCID: PMC11265423 DOI: 10.1128/jvi.02020-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Accepted: 05/15/2024] [Indexed: 06/18/2024] Open
Abstract
Human noroviruses (HuNoVs) are a diverse group of RNA viruses that cause endemic and pandemic acute viral gastroenteritis. Previously, we reported that many HuNoV strains require bile or bile acid (BA) to infect human jejunal intestinal enteroid cultures. BA was not essential for the replication of a pandemic-causing GII.4 HuNoV strain. We found the hydrophobic BA glycochenodeoxycholic acid (GCDCA) promotes the replication of the BA-dependent strain GII.3 in jejunal enteroids. Furthermore, we found that inhibition of the G-protein-coupled BA receptor, sphingosine-1-phosphate receptor 2 (S1PR2), by JTE-013, reduced GII.3 infection dose-dependently and inhibited GII.3 cellular uptake in enteroids. Herein, we sought to determine whether S1PR2 is required for other BA-dependent HuNoV strains, the BA-independent GII.4, and whether S1PR2 is required for BA-dependent HuNoV infection in HIEs from other small intestinal segments. We found a second S1PR2 inhibitor, GLPG2938, reduces GII.3 infection dose-dependently, and an S1PR2 agonist (CYM-5520) enhances GII.3 replication in the absence of GCDCA. GII.3 replication also is abrogated in the presence of JTE-013 and CYM-5520. JTE-013 inhibition of S1PR2 in jejunal HIEs reduces GI.1, GII.3, and GII.17 (BA-dependent) but not GII.4 Sydney (BA-independent) infection, providing additional evidence of strain-specific differences in HuNoV infection. Finally, GII.3 infection of duodenal, jejunal, and ileal lines derived from the same individual is reduced with S1PR2 inhibition, indicating a common mechanism of BA-dependent infection among multiple segments of the small intestine. Our results support a model where BA-dependent HuNoVs exploit BA effects on S1PR2 to infect the entire small intestine.IMPORTANCEHuman noroviruses (HuNoVs) are important viral human pathogens that cause both outbreaks and sporadic gastroenteritis. These viruses are diverse, and many strains are capable of infecting humans. Our previous studies have identified strain-specific requirements for hydrophobic bile acids (BAs) to infect intestinal epithelial cells. Moreover, we identified a BA receptor, sphingosine-1-phosphate receptor 2 (S1PR2), required for infection by a BA-dependent strain. To better understand how various HuNoV strains enter and infect the small intestine and the role of S1PR2 in HuNoV infection, we evaluated infection by additional HuNoV strains using an expanded repertoire of intestinal enteroid cell lines. We found that multiple BA-dependent strains, but not a BA-independent strain, all require S1PR2 for infection. In addition, BA-dependent infection requires S1PR2 in multiple segments of the small intestine. Together, these results indicate that S1PR2 has value as a potential therapeutic target for BA-dependent HuNoV infection.
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Affiliation(s)
- Victoria Tenge
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, USA
| | - B. Vijayalakshmi Ayyar
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, USA
| | - Khalil Ettayebi
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, USA
| | - Sue E. Crawford
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, USA
| | - Nicole M. Hayes
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, USA
| | - Yi-Ting Shen
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, USA
| | - Frederick H. Neill
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, USA
| | - Robert L. Atmar
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, USA
- Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
| | - Mary K. Estes
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, USA
- Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
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Sun D, Xie C, Zhao Y, Liao J, Li S, Zhang Y, Wang D, Hua K, Gu Y, Du J, Huang G, Huang J. The gut microbiota-bile acid axis in cholestatic liver disease. Mol Med 2024; 30:104. [PMID: 39030473 PMCID: PMC11265038 DOI: 10.1186/s10020-024-00830-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Accepted: 05/07/2024] [Indexed: 07/21/2024] Open
Abstract
Cholestatic liver diseases (CLD) are characterized by impaired normal bile flow, culminating in excessive accumulation of toxic bile acids. The majority of patients with CLD ultimately progress to liver cirrhosis and hepatic failure, necessitating liver transplantation due to the lack of effective treatment. Recent investigations have underscored the pivotal role of the gut microbiota-bile acid axis in the progression of hepatic fibrosis via various pathways. The obstruction of bile drainage can induce gut microbiota dysbiosis and disrupt the intestinal mucosal barrier, leading to bacteria translocation. The microbial translocation activates the immune response and promotes liver fibrosis progression. The identification of therapeutic targets for modulating the gut microbiota-bile acid axis represents a promising strategy to ameliorate or perhaps reverse liver fibrosis in CLD. This review focuses on the mechanisms in the gut microbiota-bile acids axis in CLD and highlights potential therapeutic targets, aiming to lay a foundation for innovative treatment approaches.
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Affiliation(s)
- Dayan Sun
- Department of Neonatal Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, No. 56 Nalishi Road, Xicheng District, Beijing, 100045, China
| | - Chuanping Xie
- Department of Neonatal Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, No. 56 Nalishi Road, Xicheng District, Beijing, 100045, China
| | - Yong Zhao
- Department of Neonatal Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, No. 56 Nalishi Road, Xicheng District, Beijing, 100045, China
| | - Junmin Liao
- Department of Neonatal Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, No. 56 Nalishi Road, Xicheng District, Beijing, 100045, China
| | - Shuangshuang Li
- Department of Neonatal Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, No. 56 Nalishi Road, Xicheng District, Beijing, 100045, China
| | - Yanan Zhang
- Department of Neonatal Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, No. 56 Nalishi Road, Xicheng District, Beijing, 100045, China
| | - Dingding Wang
- Department of Neonatal Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, No. 56 Nalishi Road, Xicheng District, Beijing, 100045, China
| | - Kaiyun Hua
- Department of Neonatal Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, No. 56 Nalishi Road, Xicheng District, Beijing, 100045, China
| | - Yichao Gu
- Department of Neonatal Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, No. 56 Nalishi Road, Xicheng District, Beijing, 100045, China
| | - Jingbin Du
- Department of Neonatal Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, No. 56 Nalishi Road, Xicheng District, Beijing, 100045, China
| | - Guoxian Huang
- Department of Pediatric Surgery, Women and Children's Hospital, School of Medicine, Xiamen University, Xiamen, Fujian, 361000, China
| | - Jinshi Huang
- Department of Neonatal Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, No. 56 Nalishi Road, Xicheng District, Beijing, 100045, China.
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Sheng X, Zhan P, Wang P, He W, Tian H. Mitigation of high-fat diet-induced hepatic steatosis by thyme ( Thymus quinquecostatus Celak) polyphenol-rich extract (TPE): insights into gut microbiota modulation and bile acid metabolism. Food Funct 2024; 15:7333-7347. [PMID: 38305590 DOI: 10.1039/d3fo05235d] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2024]
Abstract
Our previous study demonstrated that thyme polyphenol-rich extract (TPE) mitigated hepatic injury induced by a high-fat diet (HFD) through the regulation of lipid metabolism, promotion of short-chain fatty acid production, enhancement of intestinal barrier function, and attenuation of inflammation. In this study, we aimed to further elucidate additional mechanisms underlying TPE-mediated preventive effects on hepatic steatosis, with a specific focus on its impact on the gut microbiota and bile acid (BA) metabolism in HFD-fed mice. TPE treatment resulted in a significant reduction in serum total BA levels and a notable increase in fecal total BA levels. In particular, elevations in fecal conjugated BA levels, in turn, impede intestinal farnesoid X receptor (FXR) signaling, thereby enhancing hepatic synthesis and fecal excretion of BAs. The downregulated mRNA expression levels of intestinal Fxr and Fgf15, and hepatic Fgfr4, along with the upregulated mRNA expression levels of Cyp7a1 and Cyp27a1 after TPE treatment also prove the above inference. Meanwhile, TPE appeared to promote BA efflux and enterohepatic circulation, as evidenced by changes in the mRNA levels of Bsep, Ntpc, Shp, Asbt, Ibabp, and Ostα/β. TPE also modulated the gut microbiota and was characterized by an increased relative abundance of Lactobacillus. Furthermore, antibiotic treatment depleted the intestinal flora in mice, also abrogating the hepatoprotective effect of TPE against NAFLD. These findings collectively indicate that TPE effectively mitigates HFD-induced NAFLD by modulating the gut-liver axis, specifically targeting the gut microbiota and bile acid metabolism.
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Affiliation(s)
- Xialu Sheng
- College of Food Engineering and Nutritional Science, Shaanxi Normal University, Xi'an 710119, China.
| | - Ping Zhan
- College of Food Engineering and Nutritional Science, Shaanxi Normal University, Xi'an 710119, China.
| | - Peng Wang
- College of Food Engineering and Nutritional Science, Shaanxi Normal University, Xi'an 710119, China.
| | - Wanying He
- College of Food Engineering and Nutritional Science, Shaanxi Normal University, Xi'an 710119, China.
| | - Honglei Tian
- College of Food Engineering and Nutritional Science, Shaanxi Normal University, Xi'an 710119, China.
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Li Y, Qi X, Wang Q, He Y, Li Z, Cen X, Wei L. Comprehensive analysis of key host gene-microbe networks in the cecum tissues of the obese rabbits induced by a high-fat diet. Front Cell Infect Microbiol 2024; 14:1407051. [PMID: 38947127 PMCID: PMC11211605 DOI: 10.3389/fcimb.2024.1407051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Accepted: 05/24/2024] [Indexed: 07/02/2024] Open
Abstract
The Cecum is a key site for cellulose digestion in nutrient metabolism of intestine, but its mechanisms of microbial and gene interactions has not been fully elucidated during pathogenesis of obesity. Therefore, the cecum tissues of the New Zealand rabbits and their contents between the high-fat diet-induced group (Ob) and control group (Co) were collected and analyzed using multi-omics. The metagenomic analysis indicated that the relative abundances of Corallococcus_sp._CAG:1435 and Flavobacteriales bacterium species were significantly lower, while those of Akkermansia glycaniphila, Clostridium_sp._CAG:793, Mycoplasma_sp._CAG:776, Mycoplasma_sp._CAG:472, Clostridium_sp._CAG:609, Akkermansia_sp._KLE1605, Clostridium_sp._CAG:508, and Firmicutes_bacterium_CAG:460 species were significantly higher in the Ob as compared to those in Co. Transcriptomic sequencing results showed that the differentially upregulated genes were mainly enriched in pathways, including calcium signaling pathway, PI3K-Akt signaling pathway, and Wnt signaling pathway, while the differentially downregulated genes were mainly enriched in pathways of NF-kappaB signaling pathway and T cell receptor signaling pathway. The comparative analysis of metabolites showed that the glycine, serine, and threonine metabolism and cysteine and methionine metabolism were the important metabolic pathways between the two groups. The combined analysis showed that CAMK1, IGFBP6, and IGFBP4 genes were highly correlated with Clostridium_sp._CAG:793, and Akkermansia_glycaniphila species. Thus, the preliminary study elucidated the microbial and gene interactions in cecum of obese rabbit and provided a basis for further studies in intestinal intervention for human obesity.
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Affiliation(s)
- Yanhong Li
- Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education & Key Laboratory of Medical Molecular Biology of Guizhou Province, Collaborative Innovation Center for Prevention and Control of Endemic and Ethnic Regional Diseases Co-constructed by the Province and Ministry, Guizhou Medical University, Guiyang, Guizhou, China
| | - Xiaolan Qi
- Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education & Key Laboratory of Medical Molecular Biology of Guizhou Province, Collaborative Innovation Center for Prevention and Control of Endemic and Ethnic Regional Diseases Co-constructed by the Province and Ministry, Guizhou Medical University, Guiyang, Guizhou, China
| | - Qinrong Wang
- Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education & Key Laboratory of Medical Molecular Biology of Guizhou Province, Collaborative Innovation Center for Prevention and Control of Endemic and Ethnic Regional Diseases Co-constructed by the Province and Ministry, Guizhou Medical University, Guiyang, Guizhou, China
| | - Yan He
- Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education & Key Laboratory of Medical Molecular Biology of Guizhou Province, Collaborative Innovation Center for Prevention and Control of Endemic and Ethnic Regional Diseases Co-constructed by the Province and Ministry, Guizhou Medical University, Guiyang, Guizhou, China
| | - Zhupeng Li
- Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education & Key Laboratory of Medical Molecular Biology of Guizhou Province, Collaborative Innovation Center for Prevention and Control of Endemic and Ethnic Regional Diseases Co-constructed by the Province and Ministry, Guizhou Medical University, Guiyang, Guizhou, China
| | - Xi Cen
- Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education & Key Laboratory of Medical Molecular Biology of Guizhou Province, Collaborative Innovation Center for Prevention and Control of Endemic and Ethnic Regional Diseases Co-constructed by the Province and Ministry, Guizhou Medical University, Guiyang, Guizhou, China
| | - Limin Wei
- Chongqing Key Laboratory of High Active Traditional Chinese Drug Delivery System, Chongqing Medical and Pharmaceutical College, Chongqing, China
- College of Pharmacy, Chongqing Medical University, Chongqing, China
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38
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Jin W, Zheng M, Chen Y, Xiong H. Update on the development of TGR5 agonists for human diseases. Eur J Med Chem 2024; 271:116462. [PMID: 38691888 DOI: 10.1016/j.ejmech.2024.116462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Revised: 04/20/2024] [Accepted: 04/27/2024] [Indexed: 05/03/2024]
Abstract
The G protein-coupled bile acid receptor 1 (GPBAR1) or TGR5 is widely distributed across organs, including the small intestine, stomach, liver, spleen, and gallbladder. Many studies have established strong correlations between TGR5 and glucose homeostasis, energy metabolism, immune-inflammatory responses, and gastrointestinal functions. These results indicate that TGR5 has a significant impact on the progression of tumor development and metabolic disorders such as diabetes mellitus and obesity. Targeting TGR5 represents an encouraging therapeutic approach for treating associated human ailments. Notably, the GLP-1 receptor has shown exceptional efficacy in clinical settings for diabetes management and weight loss promotion. Currently, numerous TGR5 agonists have been identified through natural product-based approaches and virtual screening methods, with some successfully progressing to clinical trials. This review summarizes the intricate relationships between TGR5 and various diseases emphasizing recent advancements in research on TGR5 agonists, including their structural characteristics, design tactics, and biological activities. We anticipate that this meticulous review could facilitate the expedited discovery and optimization of novel TGR5 agonists.
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Affiliation(s)
- Wangrui Jin
- Institute for Advanced Study, and College of Physics and Optoelectronic Engineering, Shenzhen University, Shenzhen, 518060, China; Shanghai Key Laboratory of Regulatory Biology, The Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, 200241, China
| | - Mingyue Zheng
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Yihua Chen
- School of Pharmaceutical Sciences and Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming, Yunnan, 650500, China; Shanghai Key Laboratory of Regulatory Biology, The Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, 200241, China.
| | - Hai Xiong
- Institute for Advanced Study, and College of Physics and Optoelectronic Engineering, Shenzhen University, Shenzhen, 518060, China.
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Ridlon JM, Gaskins HR. Another renaissance for bile acid gastrointestinal microbiology. Nat Rev Gastroenterol Hepatol 2024; 21:348-364. [PMID: 38383804 PMCID: PMC11558780 DOI: 10.1038/s41575-024-00896-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/16/2024] [Indexed: 02/23/2024]
Abstract
The field of bile acid microbiology in the gastrointestinal tract is going through a current rebirth after a peak of activity in the late 1970s and early 1980s. This renewed activity is a result of many factors, including the discovery near the turn of the century that bile acids are potent signalling molecules and technological advances in next-generation sequencing, computation, culturomics, gnotobiology, and metabolomics. We describe the current state of the field with particular emphasis on questions that have remained unanswered for many decades in both bile acid synthesis by the host and metabolism by the gut microbiota. Current knowledge of established enzymatic pathways, including bile salt hydrolase, hydroxysteroid dehydrogenases involved in the oxidation and epimerization of bile acid hydroxy groups, the Hylemon-Bjӧrkhem pathway of bile acid C7-dehydroxylation, and the formation of secondary allo-bile acids, is described. We cover aspects of bile acid conjugation and esterification as well as evidence for bile acid C3-dehydroxylation and C12-dehydroxylation that are less well understood but potentially critical for our understanding of bile acid metabolism in the human gut. The physiological consequences of bile acid metabolism for human health, important caveats and cautionary notes on experimental design and interpretation of data reflecting bile acid metabolism are also explored.
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Affiliation(s)
- Jason M Ridlon
- Department of Animal Sciences, University of Illinois Urbana-Champaign, Urbana, IL, USA.
- Division of Nutritional Sciences, University of Illinois Urbana-Champaign, Urbana, IL, USA.
- Carl R. Woese Institute for Genomic Biology, University of Illinois Urbana-Champaign, Urbana, IL, USA.
- Cancer Center at Illinois, University of Illinois Urbana-Champaign, Urbana, IL, USA.
- Center for Advanced Study, University of Illinois Urbana-Champaign, Urbana, IL, USA.
- Department of Microbiology & Immunology, Virginia Commonwealth University, Richmond, VA, USA.
| | - H Rex Gaskins
- Department of Animal Sciences, University of Illinois Urbana-Champaign, Urbana, IL, USA.
- Division of Nutritional Sciences, University of Illinois Urbana-Champaign, Urbana, IL, USA.
- Carl R. Woese Institute for Genomic Biology, University of Illinois Urbana-Champaign, Urbana, IL, USA.
- Cancer Center at Illinois, University of Illinois Urbana-Champaign, Urbana, IL, USA.
- Department of Biomedical and Translational Sciences, University of Illinois Urbana-Champaign, Urbana, IL, USA.
- Department of Pathobiology, University of Illinois Urbana-Champaign, Urbana, IL, USA.
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Li Y, Xu T, Zhao Y, Zhang H, Liu Z, Wang H, Huang C, Shu Z, Gao L, Xie R, Jiao T, Zhang D, Zhang D, Liang X, Zang Y, Sun Y, Liu H, Li J, Zhou Y. Discovery and Optimization of Novel Nonbile Acid FXR Agonists as Preclinical Candidates for the Treatment of Inflammatory Bowel Disease. J Med Chem 2024; 67:5642-5661. [PMID: 38547240 DOI: 10.1021/acs.jmedchem.3c02304] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/12/2024]
Abstract
Inflammatory bowel disease (IBD) is a multifactorial chronic inflammation of the intestine and has become a global public health concern. A farnesoid X receptor (FXR) was recently reported to play a key role in hepatic-intestinal circulation, intestinal metabolism, immunity, and microbial regulation, and thus, it becomes a promising therapeutic target for IBD. In this study, we identified a series of nonbile acid FXR agonists, in which 33 novel compounds were designed and synthesized by the structure-based drug design strategy from our previously identified hit compound. Compound 33 exhibited a potent FXR agonistic activity, high intestinal distribution, good anti-inflammatory activity, and the ability to repair the colon epithelium in a DSS-induced acute enteritis model. Based on the results of RNA-seq analysis, we further investigated the therapeutic potential of the combination of compound 33 with 5-ASA. Overall, the results indicated that compound 33 is a promising drug candidate for IBD treatment.
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Affiliation(s)
- Yuan Li
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Tingting Xu
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Yue Zhao
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Hui Zhang
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Zesheng Liu
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Hao Wang
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Chaoying Huang
- School of Medicine, Shanghai University, Shanghai, 200444, China
| | - Zhihao Shu
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Lixin Gao
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Rongrong Xie
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Tingying Jiao
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Dan Zhang
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Dong Zhang
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Xuewu Liang
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Yi Zang
- Lingang laboratory, Shanghai, 201203, China
| | - Yili Sun
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong 264117, China
| | - Hong Liu
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China
- School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China
| | - Jia Li
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China
- Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong 264117, China
- School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China
| | - Yu Zhou
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China
- School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China
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Myszor IT, Lapka K, Hermannsson K, Rekha RS, Bergman P, Gudmundsson GH. Bile acid metabolites enhance expression of cathelicidin antimicrobial peptide in airway epithelium through activation of the TGR5-ERK1/2 pathway. Sci Rep 2024; 14:6750. [PMID: 38514730 PMCID: PMC10957955 DOI: 10.1038/s41598-024-57251-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Accepted: 03/15/2024] [Indexed: 03/23/2024] Open
Abstract
Signals for the maintenance of epithelial homeostasis are provided in part by commensal bacteria metabolites, that promote tissue homeostasis in the gut and remote organs as microbiota metabolites enter the bloodstream. In our study, we investigated the effects of bile acid metabolites, 3-oxolithocholic acid (3-oxoLCA), alloisolithocholic acid (AILCA) and isolithocholic acid (ILCA) produced from lithocholic acid (LCA) by microbiota, on the regulation of innate immune responses connected to the expression of host defense peptide cathelicidin in lung epithelial cells. The bile acid metabolites enhanced expression of cathelicidin at low concentrations in human bronchial epithelial cell line BCi-NS1.1 and primary bronchial/tracheal cells (HBEpC), indicating physiological relevance for modulation of innate immunity in airway epithelium by bile acid metabolites. Our study concentrated on deciphering signaling pathways regulating expression of human cathelicidin, revealing that LCA and 3-oxoLCA activate the surface G protein-coupled bile acid receptor 1 (TGR5, Takeda-G-protein-receptor-5)-extracellular signal-regulated kinase (ERK1/2) cascade, rather than the nuclear receptors, aryl hydrocarbon receptor, farnesoid X receptor and vitamin D3 receptor in bronchial epithelium. Overall, our study provides new insights into the modulation of innate immune responses by microbiota bile acid metabolites in the gut-lung axis, highlighting the differences in epithelial responses between different tissues.
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Affiliation(s)
- Iwona T Myszor
- Faculty of Life and Environmental Sciences, Biomedical Center, University of Iceland, Reykjavik, Iceland
| | - Kornelia Lapka
- Faculty of Life and Environmental Sciences, Biomedical Center, University of Iceland, Reykjavik, Iceland
| | - Kristjan Hermannsson
- Faculty of Life and Environmental Sciences, Biomedical Center, University of Iceland, Reykjavik, Iceland
| | - Rokeya Sultana Rekha
- Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
- Department of Clinical Immunology and Transfusion Medicine, Karolinska University Hospital, Stockholm, Sweden
| | - Peter Bergman
- Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
- Department of Clinical Immunology and Transfusion Medicine, Karolinska University Hospital, Stockholm, Sweden
| | - Gudmundur Hrafn Gudmundsson
- Faculty of Life and Environmental Sciences, Biomedical Center, University of Iceland, Reykjavik, Iceland.
- Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
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Li Y, Zhu C, Yao J, Zhu C, Li Z, Liu HY, Zhu M, Li K, Ahmed AA, Li S, Hu P, Cai D. Lithocholic Acid Alleviates Deoxynivalenol-Induced Inflammation and Oxidative Stress via PPARγ-Mediated Epigenetically Transcriptional Reprogramming in Porcine Intestinal Epithelial Cells. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2024; 72:5452-5462. [PMID: 38428036 DOI: 10.1021/acs.jafc.3c08044] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/03/2024]
Abstract
Deoxynivalenol (DON) is a common mycotoxin that induces intestinal inflammation and oxidative damage in humans and animals. Given that lithocholic acid (LCA) has been suggested to inhibit intestinal inflammation, we aimed to investigate the protective effects of LCA on DON-exposed porcine intestinal epithelial IPI-2I cells and the underlying mechanisms. Indeed, LCA rescued DON-induced cell death in IPI-2I cells and reduced DON-stimulated inflammatory cytokine levels and oxidative stress. Importantly, the nuclear receptor PPARγ was identified as a key transcriptional factor involved in the DON-induced inflammation and oxidative stress processes in IPI-2I cells. The PPARγ function was found compromised, likely due to the hyperphosphorylation of the p38 and ERK signaling pathways. In contrast, the DON-induced inflammatory responses and oxidative stress were restrained by LCA via PPARγ-mediated reprogramming of the core inflammatory and antioxidant genes. Notably, the PPARγ-modulated transcriptional regulations could be attributed to the altered recruitments of coactivator SRC-1/3 and corepressor NCOR1/2, along with the modified histone marks H3K27ac and H3K18la. This study emphasizes the protective actions of LCA on DON-induced inflammatory damage and oxidative stress in intestinal epithelial cells via PPARγ-mediated epigenetically transcriptional reprogramming, including histone acetylation and lactylation.
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Affiliation(s)
- Yanwei Li
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, P. R. China
| | - Chuyang Zhu
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, P. R. China
| | - Jiacheng Yao
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, P. R. China
| | - Cuipeng Zhu
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, P. R. China
| | - Zhaojian Li
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, P. R. China
| | - Hao-Yu Liu
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, P. R. China
| | - Miaonan Zhu
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, P. R. China
| | - Kaiqi Li
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, P. R. China
| | - Abdelkareem A Ahmed
- Department of Veterinary Biomedical Sciences, Botswana University of Agriculture and Natural Resources, Gaborone 0027, Botswana
| | - Shicheng Li
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, P. R. China
- International Joint Research Laboratory in Universities of Jiangsu Province of China for Domestic Animal Germplasm Resources and Genetic Improvement, Yangzhou 225009, P. R. China
| | - Ping Hu
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, P. R. China
- International Joint Research Laboratory in Universities of Jiangsu Province of China for Domestic Animal Germplasm Resources and Genetic Improvement, Yangzhou 225009, P. R. China
| | - Demin Cai
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, P. R. China
- International Joint Research Laboratory in Universities of Jiangsu Province of China for Domestic Animal Germplasm Resources and Genetic Improvement, Yangzhou 225009, P. R. China
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Kim DM, Liu J, Whitmore MA, Tobin I, Zhao Z, Zhang G. Two intestinal microbiota-derived metabolites, deoxycholic acid and butyrate, synergize to enhance host defense peptide synthesis and alleviate necrotic enteritis. J Anim Sci Biotechnol 2024; 15:29. [PMID: 38429856 PMCID: PMC10908072 DOI: 10.1186/s40104-024-00995-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Accepted: 01/07/2024] [Indexed: 03/03/2024] Open
Abstract
BACKGROUND Necrotic enteritis (NE) is a major enteric disease in poultry, yet effective mitigation strategies remain elusive. Deoxycholic acid (DCA) and butyrate, two major metabolites derived from the intestinal microbiota, have independently been shown to induce host defense peptide (HDP) synthesis. However, the potential synergy between these two compounds remains unexplored. METHODS To investigate the possible synergistic effect between DCA and butyrate in regulating HDP synthesis and barrier function, we treated chicken HD11 macrophage cells and jejunal explants with DCA and sodium butyrate (NaB), either individually or in combination, for 24 h. Subsequently, we performed RNA isolation and reverse transcription-quantitative PCR to analyze HDP genes as well as the major genes associated with barrier function. To further determine the synergy between DCA and NaB in enhancing NE resistance, we conducted two independent trials with Cobb broiler chicks. In each trial, the diet was supplemented with DCA or NaB on the day-of-hatch, followed by NE induction through sequential challenges with Eimeria maxima and Clostridium perfringens on d 10 and 14, respectively. We recorded animal mortality after infection and assessed intestinal lesions on d 17. The impact of DCA and NaB on the microbiota in the ileum and cecum was evaluated through bacterial 16S rRNA gene sequencing. RESULTS We found that the combination of DCA and NaB synergistically induced multiple HDP genes in both chicken HD11 cells and jejunal explants. Additionally, the gene for claudin-1, a major tight junction protein, also exhibited synergistic induction in response to DCA and NaB. Furthermore, dietary supplementation with a combination of 0.75 g/kg DCA and 1 g/kg NaB led to a significant improvement in animal survival and a reduction in intestinal lesions compared to either compound alone in a chicken model of NE. Notably, the cecal microbiota of NE-infected chickens showed a marked decrease in SCFA-producing bacteria such as Bacteroides, Faecalibacterium, and Cuneatibacter, with lactobacilli becoming the most dominant species. However, supplementation with DCA and NaB largely restored the intestinal microbiota to healthy levels. CONCLUSIONS DCA synergizes with NaB to induce HDP and claudin-1 expression and enhance NE resistance, with potential for further development as cost-effective antibiotic alternatives.
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Affiliation(s)
- Dohyung M Kim
- Department of Animal and Food Sciences, Oklahoma State University, Stillwater, OK, USA
| | - Jing Liu
- Department of Animal and Food Sciences, Oklahoma State University, Stillwater, OK, USA
| | - Melanie A Whitmore
- Department of Animal and Food Sciences, Oklahoma State University, Stillwater, OK, USA
| | - Isabel Tobin
- Department of Animal and Food Sciences, Oklahoma State University, Stillwater, OK, USA
| | - Zijun Zhao
- Department of Animal and Food Sciences, Oklahoma State University, Stillwater, OK, USA
| | - Guolong Zhang
- Department of Animal and Food Sciences, Oklahoma State University, Stillwater, OK, USA.
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Zheng X, Xu X, Liu M, Yang J, Yuan M, Sun C, Zhou Q, Chen J, Liu B. Bile acid and short chain fatty acid metabolism of gut microbiota mediate high-fat diet induced intestinal barrier damage in Macrobrachium rosenbergii. FISH & SHELLFISH IMMUNOLOGY 2024; 146:109376. [PMID: 38218421 DOI: 10.1016/j.fsi.2024.109376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Revised: 01/08/2024] [Accepted: 01/10/2024] [Indexed: 01/15/2024]
Abstract
The limited tolerance of crustacean tissue physiology to a high-fat diet has captured the attention of researchers. Yet, investigations into the physiological response mechanisms of the crustacean intestinal barrier system to a high-fat diet are progressing slowly. Elucidating potential physiological mechanisms and determining the precise regulatory targets would be of great physiological and nutritional significance. This study established a high-fat diet-induced intestinal barrier damage model in Macrobrachium rosenbergii, and systematically investigated the functions of gut microbiota and its functional metabolites. The study achieved this by monitoring phenotypic indicators, conducting 16S rDNA sequencing, targeted metabolomics, and in vitro anaerobic fermentation of intestinal contents. Feeding prawns with control and high-fat diets for 8 weeks, the lipid level of 7 % in the CON diet and 12 % in the HF diet. Results showed that high-fat intake impaired the intestinal epithelial cells, intestinal barrier structure, and permeability of M. rosenbergii, activated the tight junction signaling pathway inhibiting factor NF-κB transcription factor Relish/myosin light chain kinase (MLCK), and suppressed the expression of downstream tight junction proteins zona occludens protein 1 (ZO-1) and Claudin. High-fat intake resulted in a significant increase in abundance of Aeromonas, Enterobacter, and Clostridium sensu stricto 3 genera, while Lactobacillus, Lactococcus, Bacteroides, and Ruminococcaceae UCG-010 genera were significantly decreased. Targeted metabolomics results of bile acids and short-chain fatty acids in intestinal contents and in vitro anaerobic fermentation products showed a marked rise in the abundance of DCA, 12-KetoLCA, 7,12-diketoLCA, and Isovaleric acid, and a significant reduction in the abundance of HDCA, CDCA, and Acetate in the HF group. Pearson correlation analysis revealed a substantial correlation between various genera (Clostridium sensu stricto 3, Lactobacillus, Bacteroides) and secondary metabolites (DCA, HDCA, 12-KetoLCA, Acetate), and the latter was significantly correlated with intestinal barrier function related genes (Relish, ZO-1, MLCK, vitamin D receptor, and ecdysone receptor). These findings indicate that gut microorganisms and their specific bile acids and short-chain fatty acid secondary metabolites play a crucial role in the process of high-fat-induced intestinal barrier damage of M. rosenbergii. Moreover, identifying and targeting these factors could facilitate precise regulation of high-fat nutrition for crustaceans.
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Affiliation(s)
- Xiaochuan Zheng
- Key Laboratory for Genetic Breeding of Aquatic Animals and Aquaculture Biology, Freshwater Fisheries Research Center (FFRC), Chinese Academy of Fishery Sciences (CAFS), Wuxi, China; Wuxi Fisheries College, Nanjing Agricultural University, Wuxi, China
| | - Xiaodi Xu
- Wuxi Fisheries College, Nanjing Agricultural University, Wuxi, China
| | - Mingyang Liu
- Wuxi Fisheries College, Nanjing Agricultural University, Wuxi, China
| | - Jie Yang
- Wuxi Fisheries College, Nanjing Agricultural University, Wuxi, China
| | - Meng Yuan
- Wuxi Fisheries College, Nanjing Agricultural University, Wuxi, China
| | - Cunxin Sun
- Key Laboratory for Genetic Breeding of Aquatic Animals and Aquaculture Biology, Freshwater Fisheries Research Center (FFRC), Chinese Academy of Fishery Sciences (CAFS), Wuxi, China; Wuxi Fisheries College, Nanjing Agricultural University, Wuxi, China
| | - Qunlan Zhou
- Key Laboratory for Genetic Breeding of Aquatic Animals and Aquaculture Biology, Freshwater Fisheries Research Center (FFRC), Chinese Academy of Fishery Sciences (CAFS), Wuxi, China; Wuxi Fisheries College, Nanjing Agricultural University, Wuxi, China
| | - Jianming Chen
- Key Laboratory of Healthy Freshwater Aquaculture, Ministry of Agriculture and Rural Affairs, Key Laboratory of Fish Health and Nutrition of Zhejiang Province, Zhejiang Institute of Freshwater Fisheries, Huzhou, China.
| | - Bo Liu
- Key Laboratory for Genetic Breeding of Aquatic Animals and Aquaculture Biology, Freshwater Fisheries Research Center (FFRC), Chinese Academy of Fishery Sciences (CAFS), Wuxi, China; Wuxi Fisheries College, Nanjing Agricultural University, Wuxi, China.
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Yan M, Zhao Y, Man S, Dai Y, Ma L, Gao W. Diosgenin as a substitute for cholesterol alleviates NAFLD by affecting CYP7A1 and NPC1L1-related pathway. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 125:155299. [PMID: 38301301 DOI: 10.1016/j.phymed.2023.155299] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Revised: 12/08/2023] [Accepted: 12/17/2023] [Indexed: 02/03/2024]
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) rapidly becomes the leading cause of end-stage liver disease or liver transplantation. Nowadays, there has no approved drug for NAFLD treatment. Diosgenin as the structural analogue of cholesterol attenuates hypercholesterolemia by inhibiting cholesterol metabolism, which is an important pathogenesis in NAFLD progression. However, there has been no few report concerning its effects on NAFLD so far. METHODS Using a high-fat diet & 10% fructose-feeding mice, we evaluated the anti-NAFLD effects of diosgenin. Transcriptome sequencing, LC/MS analysis, molecular docking simulation, molecular dynamics simulations and Luci fluorescent reporter gene analysis were used to evaluate pathways related to cholesterol metabolism. RESULTS Diosgenin treatment ameliorated hepatic dysfunction and inhibited NAFLD formation including lipid accumulation, inflammation aggregation and fibrosis formation through regulating cholesterol metabolism. For the first time, diosgenin was structurally similar to cholesterol, down-regulated expression of CYP7A1 and regulated cholesterol metabolism in the liver (p < 0.01) and further affecting bile acids like CDCA, CA and TCA in the liver and feces. Besides, diosgenin decreased expression of NPC1L1 and suppressed cholesterol transport (p < 0.05). Molecular docking and molecular dynamics further proved that diosgenin was more strongly bound to CYP7A1. Luci fluorescent reporter gene analysis revealed that diosgenin concentration-dependently inhibited the enzymes activity of CYP7A1. CONCLUSION Our findings demonstrated that diosgenin was identified as a specific regulator of cholesterol metabolism, which pave way for the design of novel clinical therapeutic strategies.
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Affiliation(s)
- Mengyao Yan
- State Key Laboratory of Food Nutrition and Safety, Key Laboratory of Industrial Microbiology, Ministry of Education, Tianjin Key Laboratory of Industry Microbiology, National and Local United Engineering Lab of Metabolic Control Fermentation Technology, China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, College of Biotechnology, Tianjin University of Science & Technology, Tianjin, 300457, China.
| | - Yixin Zhao
- State Key Laboratory of Food Nutrition and Safety, Key Laboratory of Industrial Microbiology, Ministry of Education, Tianjin Key Laboratory of Industry Microbiology, National and Local United Engineering Lab of Metabolic Control Fermentation Technology, China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, College of Biotechnology, Tianjin University of Science & Technology, Tianjin, 300457, China
| | - Shuli Man
- State Key Laboratory of Food Nutrition and Safety, Key Laboratory of Industrial Microbiology, Ministry of Education, Tianjin Key Laboratory of Industry Microbiology, National and Local United Engineering Lab of Metabolic Control Fermentation Technology, China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, College of Biotechnology, Tianjin University of Science & Technology, Tianjin, 300457, China.
| | - Yujie Dai
- State Key Laboratory of Food Nutrition and Safety, Key Laboratory of Industrial Microbiology, Ministry of Education, Tianjin Key Laboratory of Industry Microbiology, National and Local United Engineering Lab of Metabolic Control Fermentation Technology, China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, College of Biotechnology, Tianjin University of Science & Technology, Tianjin, 300457, China
| | - Long Ma
- State Key Laboratory of Food Nutrition and Safety, Key Laboratory of Industrial Microbiology, Ministry of Education, Tianjin Key Laboratory of Industry Microbiology, National and Local United Engineering Lab of Metabolic Control Fermentation Technology, China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, College of Biotechnology, Tianjin University of Science & Technology, Tianjin, 300457, China
| | - Wenyuan Gao
- Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, Weijin Road, Tianjin 300072, China
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Rodrigues SG, van der Merwe S, Krag A, Wiest R. Gut-liver axis: Pathophysiological concepts and medical perspective in chronic liver diseases. Semin Immunol 2024; 71:101859. [PMID: 38219459 DOI: 10.1016/j.smim.2023.101859] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 10/11/2023] [Accepted: 12/04/2023] [Indexed: 01/16/2024]
Affiliation(s)
- Susana G Rodrigues
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland
| | - Schalk van der Merwe
- Department of Gastroenterology and Hepatology, University hospital Gasthuisberg, University of Leuven, Belgium
| | - Aleksander Krag
- Institute of Clinical Research, University of Southern Denmark, Odense, Denmark; Centre for Liver Research, Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark, University of Southern Denmark, Odense, Denmark
| | - Reiner Wiest
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland.
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Li Y, Peng X, Wang G, Zan B, Wang Y, Zou J, Tian T, Meng Q, Shi R, Wang T, Wu J, Ma Y. Identifying hepatoprotective mechanism and effective components of Yinchenzhufu decoction in chronic cholestatic liver injury using a comprehensive strategy based on metabolomics, molecular biology, pharmacokinetics, and cytology. JOURNAL OF ETHNOPHARMACOLOGY 2024; 319:117060. [PMID: 37598769 DOI: 10.1016/j.jep.2023.117060] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/08/2023] [Revised: 08/11/2023] [Accepted: 08/16/2023] [Indexed: 08/22/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE In Traditional Chinese Medicine (TCM), cholestasis liver disease belongs to jaundice. Yinchenzhufu decoction (YCZFD) is a classic formula used for treating jaundice. AIM OF THE STUDY This study was aimed to investigate the potential mechanism and effective components of YCZFD in chronic cholestatic liver injury (CCLI). MATERIALS AND METHODS A chronic cholestatic mouse model induced by 3, 5-diethoxycarbonyl-1, 4-dihydroxychollidine was used to investigate the effect of YCZFD. Then, metabolomics was used to investigate the metabolites influenced by YCZFD. Serum and liver bile acid (BA) levels were measured using liquid chromatography coupled with triple quadruple mass spectrometry (LC-MS/MS), and the gene and protein expressions of BA transporters and metabolic enzymes were detected. Additionally, the pharmacokinetics of multiple components of YCZFD was explored to clarify the potential effective components. The effects of absorbed components of YCZFD on BA metabolism and transporter function, inflammation, and farnesoid X receptor (FXR) and pregnane X receptor (PXR) activation were analyzed using sandwich cultured rat hepatocytes, AML12 cells, and dual-luciferase receptor systems, respectively. RESULTS YCZFD decreased the liver damage in chronic cholestatic mice. Serum metabolomics results indicated that the main pathways influenced by YCZFD involved primary BA biosynthesis and arachidonic acid metabolism. YCZFD upregulated the expression of FXR, PXR, and BA efflux transporters and the metabolic enzymes of liver tissues, promoting BA excretion and metabolism in cholestatic mice. Additionally, YCZFD downregulated the expression of genes and proteins of the toll-like receptor 4 (TLR4)/nuclear factor kappa-B (NF-κB) pathway and decreased liver inflammation. The pharmacokinetic study indicated that multiple components showed different pharmacokinetic properties. Among the absorbed components of YCZFD, multiple components activated the transcription of FXR and PXR, regulated BA transporters and metabolic enzyme function, and reduced the gene expression of TLR4 and NF-κB1. CONCLUSION YCZFD can ameliorate CCLI by promoting the excretion and metabolism of BAs and inhibiting inflammation via the TLR4/NF-κB signaling pathway. The multiple components of YCZFD could act on BA homeostasis regulation and anti-inflammation, exhibiting a combined effect against CCLI.
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Affiliation(s)
- Yuanyuan Li
- Department of Pharmacology, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, 201203, China
| | - Xiaotian Peng
- Department of Pharmacology, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, 201203, China
| | - Guofeng Wang
- Department of Pharmacology, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, 201203, China
| | - Bin Zan
- Department of Pharmacology, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, 201203, China
| | - Yahang Wang
- Department of Pharmacology, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, 201203, China
| | - Juan Zou
- Department of Pharmacology, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, 201203, China
| | - Tian Tian
- Department of Pharmacology, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, 201203, China
| | - Qian Meng
- Department of Pharmacology, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, 201203, China
| | - Rong Shi
- Department of Pharmacology, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, 201203, China
| | - Tianming Wang
- Department of Pharmacology, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, 201203, China
| | - Jiasheng Wu
- Department of Pharmacology, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, 201203, China.
| | - Yueming Ma
- Department of Pharmacology, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, 201203, China; Shanghai Key Laboratory of Compound Chinese Medicines, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, 201203, China.
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Lu H, Zhang H, Wu Z, Li L. Microbiota-gut-liver-brain axis and hepatic encephalopathy. MICROBIOME RESEARCH REPORTS 2024; 3:17. [PMID: 38841407 PMCID: PMC11149093 DOI: 10.20517/mrr.2023.44] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Revised: 01/16/2024] [Accepted: 01/19/2024] [Indexed: 06/07/2024]
Abstract
Hepatic encephalopathy (HE) is a clinical manifestation of neurological and psychiatric abnormalities that are caused by complications of liver dysfunction including hyperammonemia, hyperuricemia, and portal hypertension. Accumulating evidence suggests that HE could be reversed through therapeutic modifications of gut microbiota. Multiple preclinical and clinical studies have indicated that gut microbiome affects the physiological function of the liver, such as the regulation of metabolism, secretion, and immunity, through the gut-liver crosstalk. In addition, gut microbiota also influences the brain through the gut-brain crosstalk, altering its physiological functions including the regulation of the immune, neuroendocrine, and vagal pathways. Thus, key molecules that are involved in the microbiota-gut-liver-brain axis might be able to serve as clinical biomarkers for early diagnosis of HE, and could be effective therapeutic targets for clinical interventions. In this review, we summarize the pathophysiology of HE and further propose approaches modulating the microbiota-gut-liver-brain axis in order to provide a comprehensive understanding of the prevention and potential clinical treatment for HE with a microbiota-targeted therapy.
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Affiliation(s)
| | | | | | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang, China
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Yu J, Zhu P, Shi L, Gao N, Li Y, Shu C, Xu Y, Yu Y, He J, Guo D, Zhang X, Wang X, Shao S, Dong W, Wang Y, Zhang W, Zhang W, Chen WH, Chen X, Liu Z, Yang X, Zhang B. Bifidobacterium longum promotes postoperative liver function recovery in patients with hepatocellular carcinoma. Cell Host Microbe 2024; 32:131-144.e6. [PMID: 38091982 DOI: 10.1016/j.chom.2023.11.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Revised: 09/02/2023] [Accepted: 11/14/2023] [Indexed: 01/13/2024]
Abstract
Timely liver function recovery (LFR) is crucial for postoperative hepatocellular carcinoma (HCC) patients. Here, we established the significance of LFR on patient long-term survival through retrospective and prospective cohorts and identified a key gut microbe, Bifidobacterium longum, depleted in patients with delayed recovery. Fecal microbiota transfer from HCC patients with delayed recovery to mice similarly impacted recovery time post hepatectomy. However, oral gavage of B. longum improved liver function and repair in these mice. In a clinical trial of HCC patients, orally administering a probiotic bacteria cocktail containing B. longum reduced the rates of delayed recovery, shortened hospital stays, and improved overall 1-year survival. These benefits, attributed to diminished liver inflammation, reduced liver fibrosis, and hepatocyte proliferation, were associated with changes in key metabolic pathways, including 5-hydroxytryptamine, secondary bile acids, and short-chain fatty acids. Our findings propose that gut microbiota modulation can enhance LFR, thereby improving postoperative outcomes for HCC patients.
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Affiliation(s)
- Jingjing Yu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China; Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Peng Zhu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Linlin Shi
- National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China; Henan Key Laboratory of Microbiome and Esophageal Cancer Prevention and Treatment, State Key Laboratory of Esophageal Cancer Prevention & Treatment, Henan Key Laboratory of Cancer Epigenetics, Cancer Hospital, The First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang 471003, China
| | - Na Gao
- Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China
| | - Yani Li
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Chang Shu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Ying Xu
- Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074, China
| | - Ying Yu
- Henan Key Laboratory of Microbiome and Esophageal Cancer Prevention and Treatment, State Key Laboratory of Esophageal Cancer Prevention & Treatment, Henan Key Laboratory of Cancer Epigenetics, Cancer Hospital, The First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang 471003, China
| | - Junqing He
- Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074, China
| | - Dingming Guo
- Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074, China
| | - Xiaoman Zhang
- Henan Key Laboratory of Microbiome and Esophageal Cancer Prevention and Treatment, State Key Laboratory of Esophageal Cancer Prevention & Treatment, Henan Key Laboratory of Cancer Epigenetics, Cancer Hospital, The First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang 471003, China
| | - Xiangfeng Wang
- Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074, China
| | - Sirui Shao
- Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074, China
| | - Wei Dong
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Yuwei Wang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Wei Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Wanguang Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Wei-Hua Chen
- Key Laboratory of Molecular Biophysics of the Ministry of Education, Hubei Key Laboratory of Bioinformatics and Molecular-Imaging, Center for Artificial Biology, Department of Bioinformatics and Systems Biology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China; Institution of Medical Artificial Intelligence, Binzhou Medical University, Yantai 264003, China.
| | - Xiaoping Chen
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
| | - Zhi Liu
- Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074, China; Department of Biotechnology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074, China.
| | - Xiangliang Yang
- National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China; Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medica, Huazhong University of Science and Technology, Wuhan 430074, China; Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074, China.
| | - Bixiang Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
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Tenge V, Vijayalakshmi Ayyar B, Ettayebi K, Crawford SE, Shen YT, Neill FH, Atmar RL, Estes MK. Bile acid-sensitive human norovirus strains are susceptible to sphingosine-1-phosphate receptor 2 inhibition. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.01.02.573926. [PMID: 38260626 PMCID: PMC10802320 DOI: 10.1101/2024.01.02.573926] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/24/2024]
Abstract
Human noroviruses (HuNoVs) are a diverse group of RNA viruses that cause both endemic and pandemic acute viral gastroenteritis. Previously we reported that many strains of HuNoV require bile or bile acid (BA) to infect human jejunal intestinal enteroid cultures. Of note, BA was not essential for replication of a pandemic-causing GII.4 HuNoV strain. Using the BA-requiring strain GII.3, we found that the hydrophobic BA GCDCA induces multiple cellular responses that promote replication in jejunal enteroids. Further, we found that chemical inhibition of the G-protein coupled receptor, sphingosine-1- phosphate receptor 2 (S1PR2), by JTE-013 reduced both GII.3 infection in a dose- dependent manner and cellular uptake in enteroids. Herein, we sought to determine if S1PR2 is required by other BA-dependent HuNoV strains and BA-independent GII.4, and if S1PR2 is required for BA-dependent HuNoV infection in other segments of the small intestine. We found JTE-013 inhibition of S1PR2 in jejunal HIEs reduces GI.1, GII.3, and GII.17 (BA-dependent) but not the GII.4 Sydney variant (BA-independent) infection, providing additional evidence of strain-specific differences in HuNoV infection. GII.3 infection of duodenal, jejunal and ileal lines derived from the same individual was also reduced with S1PR2 inhibition, indicating a common mechanism of BA-dependent infection among multiple segments of the small intestine. Our results support a model where BA-dependent HuNoV exploit the activation of S1PR2 by BA to infect the entire small intestine. Importance Human noroviruses (HuNoVs) are important viral human pathogens that cause both outbreaks and sporadic gastroenteritis. These viruses are diverse, and many strains are capable of infecting humans. Our previous studies have identified strain-specific requirements for hydrophobic bile acids (BAs) to infect intestinal epithelial cells. Moreover, we identified a BA receptor, sphingosine-1-phosphate receptor 2 (S1PR2), required for infection by a BA-dependent strain. To better understand how various HuNoV strains enter and infect the small intestine and the role of S1PR2 in HuNoV infection, we evaluated infection by additional HuNoV strains using an expanded repertoire of intestinal enteroid cell lines. We found that multiple BA-dependent strains, but not a BA- independent strain, all required S1PR2 for infection. Additionally, BA-dependent infection required S1PR2 in multiple segments of the small intestine. Together these results indicate S1PR2 has value as a potential therapeutic target for BA-dependent HuNoV infection.
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