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Girisa S, Aswani BS, Manickasamy MK, Hegde M, Alqahtani MS, Abbas M, Sethi G, Kunnumakkara AB. Restoring FXR expression as a novel treatment strategy in liver cancer and other liver disorders. Expert Opin Ther Targets 2025; 29:193-221. [PMID: 40169227 DOI: 10.1080/14728222.2025.2487465] [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: 12/08/2024] [Accepted: 03/28/2025] [Indexed: 04/03/2025]
Abstract
INTRODUCTION Liver cancer is a leading cause of cancer-associated mortality and is often linked to preexisting liver conditions. Emerging research demonstrates FXR dysregulation, particularly its reduced expression, in the pathogenesis of liver diseases, including inflammation, fibrosis, cholestatic disorders, metabolic dysregulation, and liver cancer. Therefore, this review explores the role of FXR and its agonists in mitigating these conditions. AREAS COVERED This article summarizes FXR's involvement in liver disorders, primarily emphasizing on hepatic neoplasms, and examines the potential of FXR agonists in restoring FXR activity in liver diseases, thereby preventing their progression to liver cancer. The information presented is drawn from existing preclinical and clinical studies specific to each liver disorder, sourced from PubMed. EXPERT OPINION It is well established that FXR expression is downregulated in liver disorders, contributing to disease progression. Notably, FXR agonists have demonstrated therapeutic potential in ameliorating liver diseases, including hepatocellular carcinoma. We believe that activating or restoring FXR expression with agonists offers significant promise for the treatment of liver cancer and other liver conditions. Therefore, FXR modulation by agonists, particularly in combination with other therapeutic agents, could lead to more targeted treatments, improving efficacy while reducing side effects.
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Affiliation(s)
- Sosmitha Girisa
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, India
| | - Babu Santha Aswani
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, India
| | - Mukesh Kumar Manickasamy
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, India
| | - Mangala Hegde
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, India
| | - Mohammed S Alqahtani
- Radiological Sciences Department, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia
- BioImaging Unit, Space Research Centre, University of Leicester, Leicester, UK
| | - Mohamed Abbas
- Electrical Engineering Department, College of Engineering, King Khalid University, Abha, Saudi Arabia
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Ajaikumar B Kunnumakkara
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, India
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Zhou F, Shang BH, Liu CW, Fang WW, Wen S, Zeng HZ, Huang JA, Liu ZH. Comparative study of the anti-obesity effects of white tea and dark tea: Insights from microbiome and metabolomics. Food Res Int 2025; 202:115666. [PMID: 39967141 DOI: 10.1016/j.foodres.2025.115666] [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: 09/30/2024] [Revised: 12/11/2024] [Accepted: 01/01/2025] [Indexed: 02/20/2025]
Abstract
The anti-obesity effects of tea and its functional components have been extensively studied. However, the protective effects of different types of tea against obesity induced by a high-fat diet (HFD) and the underlying mechanisms remain unclear. This study systematically compared the effects of white tea and dark tea on obese rats and explored their mechanisms. The results indicated that dark tea extracts (DT) higher concentrations of theabrownins and gallic acid, while white tea extracts (WT) contained abundant levels of polyphenols and amino acids. Moreover, both WT and DT effectively improved obesity-related symptoms, including weight loss, reduced fat accumulation, improved dyslipidemia, and alleviated liver and colon damage. Specifically, WT primarily functioned by inhibiting white fat accumulation and enhancing UCP1 expression in brown fat, leading to more significant weight loss. Conversely, DT increased both the quantity and uniform distribution of colonic goblet cells and elevated the expression levels of tight junction proteins in obese rats, thereby providing better protection for the intestinal barrier. Furthermore, 16S rRNA sequencing revealed that WT and DT regulated gut microbiota imbalances, restored microbiota diversity, inhibited the growth of potentially harmful bacteria, and promoted the proliferation of beneficial bacteria. Metabolomics analyses demonstrated that WT and DT increased the concentration of short-chain fatty acids in the feces of obese rats, regulated the biosynthesis of phenylalanine, tyrosine, and tryptophan, as well as the biosynthesis pathways of valine, leucine, and isoleucine, while decreasing the levels of these amino acids in feces. In conclusion, this study provides new evidence supporting the idea that tea can mitigate HFD-induced obesity through the regulation of gut microbiota and alteration of fecal metabolite profiles.
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Affiliation(s)
- Fang Zhou
- Key Laboratory of Tea Science of Ministry of Education, Hunan Agricultural University, Changsha, Hunan 410128, PR China; School of Chemistry and Environmental Sciences, Xiangnan University, Chenzhou, Hunan 423000, PR China; National Research Center of Engineering Technology for Utilization of Functional Ingredients from Botanicals, Hunan Agricultural University, Changsha, Hunan 410128, PR China; Co-Innovation Center of Education Ministry for Utilization of Botanical Functional Ingredients, Hunan Agricultural University, Hunan 410128, PR China; Key Laboratory for Evaluation and Utilization of Gene Resources of Horticultural Crops, Ministry of Agriculture and Rural Affairs of China, Hunan Agricultural University, Hunan 410128, PR China
| | - Bo-Hao Shang
- Key Laboratory of Tea Science of Ministry of Education, Hunan Agricultural University, Changsha, Hunan 410128, PR China; National Research Center of Engineering Technology for Utilization of Functional Ingredients from Botanicals, Hunan Agricultural University, Changsha, Hunan 410128, PR China; Co-Innovation Center of Education Ministry for Utilization of Botanical Functional Ingredients, Hunan Agricultural University, Hunan 410128, PR China; Key Laboratory for Evaluation and Utilization of Gene Resources of Horticultural Crops, Ministry of Agriculture and Rural Affairs of China, Hunan Agricultural University, Hunan 410128, PR China
| | - Chang-Wei Liu
- Key Laboratory of Tea Science of Ministry of Education, Hunan Agricultural University, Changsha, Hunan 410128, PR China; National Research Center of Engineering Technology for Utilization of Functional Ingredients from Botanicals, Hunan Agricultural University, Changsha, Hunan 410128, PR China; Co-Innovation Center of Education Ministry for Utilization of Botanical Functional Ingredients, Hunan Agricultural University, Hunan 410128, PR China; Key Laboratory for Evaluation and Utilization of Gene Resources of Horticultural Crops, Ministry of Agriculture and Rural Affairs of China, Hunan Agricultural University, Hunan 410128, PR China
| | - Wen-Wen Fang
- Key Laboratory of Tea Science of Ministry of Education, Hunan Agricultural University, Changsha, Hunan 410128, PR China; National Research Center of Engineering Technology for Utilization of Functional Ingredients from Botanicals, Hunan Agricultural University, Changsha, Hunan 410128, PR China; Co-Innovation Center of Education Ministry for Utilization of Botanical Functional Ingredients, Hunan Agricultural University, Hunan 410128, PR China; Key Laboratory for Evaluation and Utilization of Gene Resources of Horticultural Crops, Ministry of Agriculture and Rural Affairs of China, Hunan Agricultural University, Hunan 410128, PR China
| | - Shuai Wen
- Key Laboratory of Tea Science of Ministry of Education, Hunan Agricultural University, Changsha, Hunan 410128, PR China; National Research Center of Engineering Technology for Utilization of Functional Ingredients from Botanicals, Hunan Agricultural University, Changsha, Hunan 410128, PR China; Co-Innovation Center of Education Ministry for Utilization of Botanical Functional Ingredients, Hunan Agricultural University, Hunan 410128, PR China; Key Laboratory for Evaluation and Utilization of Gene Resources of Horticultural Crops, Ministry of Agriculture and Rural Affairs of China, Hunan Agricultural University, Hunan 410128, PR China
| | - Hong-Zhe Zeng
- Key Laboratory of Tea Science of Ministry of Education, Hunan Agricultural University, Changsha, Hunan 410128, PR China; National Research Center of Engineering Technology for Utilization of Functional Ingredients from Botanicals, Hunan Agricultural University, Changsha, Hunan 410128, PR China; Co-Innovation Center of Education Ministry for Utilization of Botanical Functional Ingredients, Hunan Agricultural University, Hunan 410128, PR China; Key Laboratory for Evaluation and Utilization of Gene Resources of Horticultural Crops, Ministry of Agriculture and Rural Affairs of China, Hunan Agricultural University, Hunan 410128, PR China
| | - Jian-An Huang
- Key Laboratory of Tea Science of Ministry of Education, Hunan Agricultural University, Changsha, Hunan 410128, PR China; National Research Center of Engineering Technology for Utilization of Functional Ingredients from Botanicals, Hunan Agricultural University, Changsha, Hunan 410128, PR China; Co-Innovation Center of Education Ministry for Utilization of Botanical Functional Ingredients, Hunan Agricultural University, Hunan 410128, PR China; Key Laboratory for Evaluation and Utilization of Gene Resources of Horticultural Crops, Ministry of Agriculture and Rural Affairs of China, Hunan Agricultural University, Hunan 410128, PR China.
| | - Zhong-Hua Liu
- Key Laboratory of Tea Science of Ministry of Education, Hunan Agricultural University, Changsha, Hunan 410128, PR China; National Research Center of Engineering Technology for Utilization of Functional Ingredients from Botanicals, Hunan Agricultural University, Changsha, Hunan 410128, PR China; Co-Innovation Center of Education Ministry for Utilization of Botanical Functional Ingredients, Hunan Agricultural University, Hunan 410128, PR China; Key Laboratory for Evaluation and Utilization of Gene Resources of Horticultural Crops, Ministry of Agriculture and Rural Affairs of China, Hunan Agricultural University, Hunan 410128, PR China.
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Zhang Y, Hao R, Chen J, Huang K, Li S, Cao H, Guan X. Gut-Derived Ursodeoxycholic Acid from Saponins of Quinoa Regulated Colitis via Inhibiting the TLR4/NF-κB Pathway. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2025; 73:2415-2429. [PMID: 39827465 DOI: 10.1021/acs.jafc.4c09151] [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: 01/22/2025]
Abstract
Alteration of the gut microbiota and its metabolites plays a key role in the development of inflammatory bowel disease (IBD). Here, we investigated the mechanism of saponins, a byproduct from quinoa (SQ) processing, in regulating IBD. SQ ameliorated gut microbiota dysbiosis revealed by 16S rRNA sequencing and improved colonic antioxidant activities and barrier integrity in dextran sulfate sodium (DSS)-treated mice. Broad-spectrum antibiotics further proved that the gut-protective effects of SQ were mediated by gut microbiota. Next, fecal microbiota transplantation (FMT) of SQ-induced gut microbiota/metabolites to inoculate DSS-treated mice alleviated colitis significantly. Untargeted metabolomics and lipidomics revealed that ursodeoxycholic acid (UDCA) was enriched as a microbial metabolite after SQ supplementation. UDCA was then found to attenuate DSS-induced colitis in vivo by targeting the TLR4/NF-κB pathway, which was also verified in a Caco-2 cell model treated with a TLR4 agonist/antagonist. Overall, our findings established that gut microbiota-UDCA-TLR4/NF-κB signaling plays a key role in mediating the protective effects of SQ.
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Affiliation(s)
- Yu Zhang
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China
- National Grain Industry (Urban Grain and Oil Security) Technology Innovation Center, Shanghai 200093, China
| | - Ruojie Hao
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China
| | - Junda Chen
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China
| | - Kai Huang
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China
- National Grain Industry (Urban Grain and Oil Security) Technology Innovation Center, Shanghai 200093, China
| | - Sen Li
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China
- National Grain Industry (Urban Grain and Oil Security) Technology Innovation Center, Shanghai 200093, China
| | - Hongwei Cao
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China
- National Grain Industry (Urban Grain and Oil Security) Technology Innovation Center, Shanghai 200093, China
| | - Xiao Guan
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China
- National Grain Industry (Urban Grain and Oil Security) Technology Innovation Center, Shanghai 200093, China
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Yang G, Wan YJY. Noninvasive biomarkers implicated in urea and TCA cycles for metabolic liver disease. Biomark Res 2024; 12:145. [PMID: 39578903 PMCID: PMC11583652 DOI: 10.1186/s40364-024-00694-7] [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: 09/18/2024] [Accepted: 11/17/2024] [Indexed: 11/24/2024] Open
Abstract
Bile acid (BA) and its receptor FXR play crucial roles in metabolism, and dysregulated BA synthesis regulated by hepatic and bacterial enzymes causes metabolic dysfunction-associated steatohepatitis (MASH) and hepatocellular carcinoma (HCC). Moreover, because ~ 75% of hepatic blood is from the gut, liver metabolism is influenced by intestinal bacteria and their metabolites. Thus, we used gut microbiota and metabolites from the urine and serum to uncover biomarkers for metabolic distress caused by Western diet (WD) intake, aging, and FXR inactivity. Hepatic transcriptomes were profiled to define liver phenotypes. There were 654 transcriptomes commonly altered by differential diet intake, ages, and FXR functional status, representing the signatures of liver dysfunction, and 76 of them were differentially expressed in healthy human livers and HCC. Machine learning approaches classified urine and serum metabolites for differential dietary intake and age difference. Additionally, the gut microbiota could predict FXR functional status. Furthermore, FXR was essential for differentiating dietary effects in colonizing age-related gut microbes. The integrated analysis established the relationships between the metabolites and gut microbiota correlated with hepatic transcripts commonly altered by diet, age, and FXR functionality. Remarkably, the changes in metabolites involved in the urea cycle, mitochondrial metabolism, and amino acid metabolism are associated with hepatic dysfunction (i.e. FXF deactivation). Taken together, noninvasive specimens and biomarkers are promising resources for identifying metabolic distress.
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Affiliation(s)
- Guiyan Yang
- College of Veterinary Medicine, China Agricultural University, Beijing, 100193, China
| | - Yu-Jui Yvonne Wan
- Department of Pathology and Laboratory Medicine, University of California, Davis, Davis Health. Room 3400B, Research Building III, 4645 2nd Ave, 95817, Sacramento, CA, USA.
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Le Corvec M, Farrugia MA, Nguyen-Khac E, Régimbeau JM, Dharhri A, Chatelain D, Khamphommala L, Gautier AL, Le Berre N, Frey S, Bronowicki JP, Brunaud L, Maréchal C, Blanchet MC, Frering V, Delwaide J, Kohnen L, Haumann A, Delvenne P, Sarfati-Lebreton M, Tariel H, Bernard J, Toullec A, Boursier J, Bedossa P, Gual P, Anty R, Iannelli A. Blood-based MASH diagnostic in candidates for bariatric surgery using mid-infrared spectroscopy: a European multicenter prospective study. Sci Rep 2024; 14:26452. [PMID: 39488538 PMCID: PMC11531585 DOI: 10.1038/s41598-024-72704-5] [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: 02/28/2024] [Accepted: 09/10/2024] [Indexed: 11/04/2024] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is common in individuals with obesity. Sexual dimorphism is present in MASLD. A noninvasive test to diagnose the severity of the disease, in particular the presence of Metabolic dysfunction-associated steatohepatitis (MASH), is lacking. This European multicenter prospective study uses a blood test based on mid-infrared (MIR) metabolic fingerprinting of individuals with severe or morbid obesity to diagnose MASH. Three hundred eighty-two individuals with severe or morbid obesity undergoing bariatric surgery were enrolled prospectively. Liver biopsies were obtained during surgery and assessed centrally. An algorithm was defined to calculate a score from the recorded MIR spectrum and to establish a diagnostic threshold to classify patients with MASH. Among the women (n = 217), MASH was diagnosed in 14.3% of cases. For women, the performance in terms of AUC were 0.83 and 0.82 in the calibration and validation groups, respectively. For a threshold of 0.1817, sensitivities were 86% and 70%, specificities were 81% and 75%, PPV were 43% and 32%, NPV were 97% and 94% and ACC were 82% and 74% for the calibration and validation groups, respectively. For men (n = 78; MASH: 33.3%), the performance of the spectral model was poor. The metabolic fingerprint obtained by MIR spectroscopy can rule out MASH in women with severe or morbid obesity. Its value in men needs new studies.Trial registration: ClinicalTrials.gov identifier: ClinicalTrials.gov identifier: NCT03978247 (04/06/2019).
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Affiliation(s)
| | - Marwin A Farrugia
- INSERM U1065, C3M, Nice Hospital, Université Cote d'Azur, Nice, France
| | - Eric Nguyen-Khac
- Department of Gastroenterology, Amiens University Hospital, Picardie University, Amiens, France
| | - Jean-Marc Régimbeau
- Department of Digestive Surgery, Amiens, France
- SSPC (Simplification des Soins des Patients Complexes) - UR7518, Unit of Clinical Research, University of Picardie Jules Verne, Amiens, France
| | - Abdennaceur Dharhri
- Department of Digestive Surgery, Amiens, France
- SSPC (Simplification des Soins des Patients Complexes) - UR7518, Unit of Clinical Research, University of Picardie Jules Verne, Amiens, France
| | - Denis Chatelain
- Department of Pathology, Amiens University and Hospital, Université de Picardie Jules Verne, Amiens, France
| | - Litavan Khamphommala
- Department of Digestive, Hepatobiliary Surgery, Centre Hospitalier Privé Saint-Grégoire, Saint-Gregoire, France
| | - Anne-Lise Gautier
- Biology Laboratory, Centre Hospitalier Privé Saint-Grégoire, Saint-Gregoire, France
| | | | - Sébastien Frey
- Digestive Surgery, University Hospital of Nice, Archet 2 Hospital, Nice, France
| | - Jean-Pierre Bronowicki
- Inserm U1254 and Department of Hepato-Gastroenterology, University Hospital of Nancy Brabois, Université de Lorraine, Vandoeuvre-les-Nancy, France
| | - Laurent Brunaud
- Department of Gastrointestinal, Visceral, Metabolic, and Cancer Surgery (CVMC), Faculté de Medicine, CHRU NANCY, Hopital Brabois adultes, INSERM U1256-NGERE, Université de Lorraine, 54511, Vandoeuvre-les-Nancy, France
| | - Chloé Maréchal
- Inserm U1254 and Department of Hepato-Gastroenterology, University Hospital of Nancy Brabois, Université de Lorraine, Vandoeuvre-les-Nancy, France
| | - Marie-Cécile Blanchet
- Department of General, Visceral and Endocrine Surgery, Clinique de la Sauvegarde, Lyon, France
| | - Vincent Frering
- Department of General, Visceral and Endocrine Surgery, Clinique de la Sauvegarde, Lyon, France
| | - Jean Delwaide
- Department of Hepatology and Gastroenterology, Centre Hospitalier Universitaire de Liège, Liège, Belgium
| | - Laurent Kohnen
- Department of Abdominal Surgery and Transplantation, Centre Hospitalier Universitaire de Liège, Liège, Belgium
| | - Alexandre Haumann
- Department of Abdominal Surgery and Transplantation, Centre Hospitalier Universitaire de Liège, Liège, Belgium
| | - Philippe Delvenne
- Department of Pathology, Clinique Hospitalo-Universitaire (CHU) University Hospital, Liege University, Liege, Belgium
| | - Marine Sarfati-Lebreton
- Department of Hepato-Gastroenterology and Digestive Oncology, Université, Angers University Hospital, Angers, France
| | | | | | | | - Jérôme Boursier
- Department of Hepato-Gastroenterology and Digestive Oncology, Université, Angers University Hospital, Angers, France
| | - Pierre Bedossa
- Department of Pathology, Beaujon Hospital Paris Diderot University, Paris, France
| | - Philippe Gual
- INSERM U1065, C3M, Nice Hospital, Université Cote d'Azur, Nice, France.
| | - Rodolphe Anty
- INSERM U1065, C3M, Nice Hospital, Université Cote d'Azur, Nice, France.
| | - Antonio Iannelli
- INSERM U1065, C3M, Nice Hospital, Université Cote d'Azur, Nice, France
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Cheng B, Wei W, Pan C, Liu L, Cheng S, Yang X, Meng P, Zhao B, Xia J, Liu H, Jia Y, Wen Y, Zhang F. Air pollutants and the risk of incident hepatobiliary diseases: A large prospective cohort study in the UK Biobank. THE SCIENCE OF THE TOTAL ENVIRONMENT 2024; 949:175047. [PMID: 39074751 DOI: 10.1016/j.scitotenv.2024.175047] [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: 04/03/2024] [Revised: 06/26/2024] [Accepted: 07/24/2024] [Indexed: 07/31/2024]
Abstract
The association between air pollutants and hepatobiliary pancreatic diseases remains inconclusive. This study analyzed up to 247,091 participants of White European ancestry (aged 37 to 73 years at recruitment) from the UK Biobank, a large-scale prospective cohort with open access. An air pollution score was utilized to assess the combined effect of PM2.5, PM2.5-10, PM10, NO2, and NOX on total hepatobiliary pancreatic diseases, liver diseases, cholecyst diseases, and pancreatic diseases. Cox proportional hazard models were employed to evaluate the relationships between air pollutants and the incidence of these diseases. Restricted cubic spline regressions were used to examine the dose-response association between air pollutants and the risk of hepatobiliary pancreatic diseases. We identified 4865 cases of total hepatobiliary pancreatic diseases, over a median follow-up of 10.86 years. The air pollution scores were moderately associated with increased liver disease risk (HR = 1.009, 95 % CI: 1.004, 1.014), but not with cholecyst and pancreatic diseases. Among the individual air pollutants, PM2.5 (HR = 1.069, 95 % CI: 1.025, 1.115) and PM10 (HR = 1.036, 95 % CI: 1.011, 1.061) significantly increased liver disease risk. Males showed a higher risk of liver diseases with PM2.5 (HR = 1.075, 95 % CI: 1.015, 1.139). Additionally, individuals with overweight (HR = 1.125, 95 % CI: 1.052, 1.203), age ≥ 60 and ≤73 (HR = 1.098, 95 % CI: 1.028, 1.172), and alcohol intake ≥ 14 unit/week (HR = 1.078, 95 % CI: 1.006, 1.155) had a higher risk of developing liver diseases at high expose to PM2.5. This study suggests that prolonged exposure to ambient air pollutants may elevate the risk of liver diseases.
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Affiliation(s)
- Bolun Cheng
- NHC Key Laboratory of Environment and Endemic Diseases (Xi'an Jiaotong University), Xi'an 710061, China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an 710061, China; Collaborative Innovation Center of Endemic Disease and Health Promotion for Silk Road Region, School of Public Health, Health Science Center, Xi'an Jiaotong University, 710061, China
| | - Wenming Wei
- NHC Key Laboratory of Environment and Endemic Diseases (Xi'an Jiaotong University), Xi'an 710061, China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an 710061, China; Collaborative Innovation Center of Endemic Disease and Health Promotion for Silk Road Region, School of Public Health, Health Science Center, Xi'an Jiaotong University, 710061, China
| | - Chuyu Pan
- NHC Key Laboratory of Environment and Endemic Diseases (Xi'an Jiaotong University), Xi'an 710061, China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an 710061, China; Collaborative Innovation Center of Endemic Disease and Health Promotion for Silk Road Region, School of Public Health, Health Science Center, Xi'an Jiaotong University, 710061, China
| | - Li Liu
- NHC Key Laboratory of Environment and Endemic Diseases (Xi'an Jiaotong University), Xi'an 710061, China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an 710061, China; Collaborative Innovation Center of Endemic Disease and Health Promotion for Silk Road Region, School of Public Health, Health Science Center, Xi'an Jiaotong University, 710061, China
| | - Shiqiang Cheng
- NHC Key Laboratory of Environment and Endemic Diseases (Xi'an Jiaotong University), Xi'an 710061, China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an 710061, China; Collaborative Innovation Center of Endemic Disease and Health Promotion for Silk Road Region, School of Public Health, Health Science Center, Xi'an Jiaotong University, 710061, China
| | - Xuena Yang
- NHC Key Laboratory of Environment and Endemic Diseases (Xi'an Jiaotong University), Xi'an 710061, China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an 710061, China; Collaborative Innovation Center of Endemic Disease and Health Promotion for Silk Road Region, School of Public Health, Health Science Center, Xi'an Jiaotong University, 710061, China
| | - Peilin Meng
- NHC Key Laboratory of Environment and Endemic Diseases (Xi'an Jiaotong University), Xi'an 710061, China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an 710061, China; Collaborative Innovation Center of Endemic Disease and Health Promotion for Silk Road Region, School of Public Health, Health Science Center, Xi'an Jiaotong University, 710061, China
| | - Boyue Zhao
- NHC Key Laboratory of Environment and Endemic Diseases (Xi'an Jiaotong University), Xi'an 710061, China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an 710061, China; Collaborative Innovation Center of Endemic Disease and Health Promotion for Silk Road Region, School of Public Health, Health Science Center, Xi'an Jiaotong University, 710061, China
| | - Jinyu Xia
- NHC Key Laboratory of Environment and Endemic Diseases (Xi'an Jiaotong University), Xi'an 710061, China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an 710061, China; Collaborative Innovation Center of Endemic Disease and Health Promotion for Silk Road Region, School of Public Health, Health Science Center, Xi'an Jiaotong University, 710061, China
| | - Huan Liu
- NHC Key Laboratory of Environment and Endemic Diseases (Xi'an Jiaotong University), Xi'an 710061, China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an 710061, China; Collaborative Innovation Center of Endemic Disease and Health Promotion for Silk Road Region, School of Public Health, Health Science Center, Xi'an Jiaotong University, 710061, China
| | - Yumeng Jia
- NHC Key Laboratory of Environment and Endemic Diseases (Xi'an Jiaotong University), Xi'an 710061, China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an 710061, China; Collaborative Innovation Center of Endemic Disease and Health Promotion for Silk Road Region, School of Public Health, Health Science Center, Xi'an Jiaotong University, 710061, China
| | - Yan Wen
- NHC Key Laboratory of Environment and Endemic Diseases (Xi'an Jiaotong University), Xi'an 710061, China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an 710061, China; Collaborative Innovation Center of Endemic Disease and Health Promotion for Silk Road Region, School of Public Health, Health Science Center, Xi'an Jiaotong University, 710061, China
| | - Feng Zhang
- NHC Key Laboratory of Environment and Endemic Diseases (Xi'an Jiaotong University), Xi'an 710061, China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an 710061, China; Collaborative Innovation Center of Endemic Disease and Health Promotion for Silk Road Region, School of Public Health, Health Science Center, Xi'an Jiaotong University, 710061, China.
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7
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Szudzik M, Hutsch T, Chabowski D, Zajdel M, Ufnal M. Normal caloric intake with high-fat diet induces metabolic dysfunction-associated steatotic liver disease and dyslipidemia without obesity in rats. Sci Rep 2024; 14:22796. [PMID: 39354056 PMCID: PMC11445425 DOI: 10.1038/s41598-024-74193-y] [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: 07/04/2024] [Accepted: 09/24/2024] [Indexed: 10/03/2024] Open
Abstract
Excessive caloric intake and obesity due to high-fat (HFD) and high-disaccharide (HDD) diets have been recognized as major contributing factors to dyslipidemia and metabolic dysfunction-associated steatotic liver disease (MASLD). However, the effect of HFD and HDD without excessive caloric intake is obscure. The aim of the study was to evaluate the effect of physiological caloric intake delivered through HFD and HDD on liver and lipid profiles. The study was performed on 6-week-old male and female (50/50%) Sprague Dawley rats, receiving either a standard (controls, n = 16), HFD (n = 14) or HDD (n = 14) chow. All groups received the same, standard daily calorie rations, titrated weekly to the age of growing rats, for 12 weeks. A panel of metabolic in vivo measurement were performed, followed by histological, biochemical and molecular biology assays on tissues harvested from sacrificed rats. There was no significant difference between the groups in body weight. In contrast to controls, HFD and HDD groups showed metabolic dysfunction-associated steatohepatitis (MASH) characterized by liver steatosis, inflammation, ballooning of hepatocytes and fibrosis. These changes were more pronounced in the HFD than in the HDD group. The HFD group showed significantly higher serum LDL than controls or HDD rats. Furthermore, the HFD group had higher liver protein levels of low-density lipoprotein receptor (LDLR) but lower plasma levels of proprotein convertase subtilisin/kexin type 9 (PCSK9) than the controls or HDD group. There were no differences between sexes in evaluated parameters. The excessive caloric intake and obesity are not prerequisites for the development of MASH and dyslipidemia in rats. The liver changes induced by the HFD and HDD diets exhibit differences in severity, as well as in the expression patterns of LDLR and PCSK9. Notably, these effects are independent of the sex of the rats.
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Affiliation(s)
- Mateusz Szudzik
- Laboratory of Centre for Preclinical Research, Department of Experimental Physiology and Pathophysiology, Medical University of Warsaw, Pawińskiego 3c Street, Warsaw, Poland.
| | - Tomasz Hutsch
- Department of Pathology and Veterinary Diagnostics, Institute of Veterinary Medicine, Warsaw University of Life Sciences (WULS-SGGW), Nowoursynowska 159c, Warsaw, Poland
- Veterinary Diagnostic Laboratory ALAB bioscience, 22/30 Stępińska Street, Warsaw, Poland
| | - Dawid Chabowski
- Laboratory of Centre for Preclinical Research, Department of Experimental Physiology and Pathophysiology, Medical University of Warsaw, Pawińskiego 3c Street, Warsaw, Poland
| | - Mikołaj Zajdel
- Laboratory of Centre for Preclinical Research, Department of Experimental Physiology and Pathophysiology, Medical University of Warsaw, Pawińskiego 3c Street, Warsaw, Poland
| | - Marcin Ufnal
- Laboratory of Centre for Preclinical Research, Department of Experimental Physiology and Pathophysiology, Medical University of Warsaw, Pawińskiego 3c Street, Warsaw, Poland.
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8
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Li XJ, Fang C, Zhao RH, Zou L, Miao H, Zhao YY. Bile acid metabolism in health and ageing-related diseases. Biochem Pharmacol 2024; 225:116313. [PMID: 38788963 DOI: 10.1016/j.bcp.2024.116313] [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: 02/18/2024] [Revised: 05/18/2024] [Accepted: 05/21/2024] [Indexed: 05/26/2024]
Abstract
Bile acids (BAs) have surpassed their traditional roles as lipid solubilizers and regulators of BA homeostasis to emerge as important signalling molecules. Recent research has revealed a connection between microbial dysbiosis and metabolism disruption of BAs, which in turn impacts ageing-related diseases. The human BAs pool is primarily composed of primary BAs and their conjugates, with a smaller proportion consisting of secondary BAs. These different BAs exert complex effects on health and ageing-related diseases through several key nuclear receptors, such as farnesoid X receptor and Takeda G protein-coupled receptor 5. However, the underlying molecular mechanisms of these effects are still debated. Therefore, the modulation of signalling pathways by regulating synthesis and composition of BAs represents an interesting and novel direction for potential therapies of ageing-related diseases. This review provides an overview of synthesis and transportion of BAs in the healthy body, emphasizing its dependence on microbial community metabolic capacity. Additionally, the review also explores how ageing and ageing-related diseases affect metabolism and composition of BAs. Understanding BA metabolism network and the impact of their nuclear receptors, such as farnesoid X receptor and G protein-coupled receptor 5 agonists, paves the way for developing therapeutic agents for targeting BA metabolism in various ageing-related diseases, such as metabolic disorder, hepatic injury, cardiovascular disease, renal damage and neurodegenerative disease.
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Affiliation(s)
- Xiao-Jun Li
- School of Pharmacy, Zhejiang Chinese Medical University, No. 548 Binwen Road, Hangzhou, Zhejiang 310053, China; Southern Medical University Hospital of Integrated Traditional Chinese and Western Medicine, Southern Medical University, No.13, Shi Liu Gang Road, Haizhu District, Guangzhou, Guangdong 510315, China
| | - Chu Fang
- School of Pharmacy, Zhejiang Chinese Medical University, No. 548 Binwen Road, Hangzhou, Zhejiang 310053, China
| | - Rui-Hua Zhao
- School of Pharmacy, Zhejiang Chinese Medical University, No. 548 Binwen Road, Hangzhou, Zhejiang 310053, China
| | - Liang Zou
- School of Food and Bioengineering, Chengdu University, No. 2025 Chengluo Avenue, Chengdu, Sichuan 610106, China
| | - Hua Miao
- School of Pharmacy, Zhejiang Chinese Medical University, No. 548 Binwen Road, Hangzhou, Zhejiang 310053, China.
| | - Ying-Yong Zhao
- School of Pharmacy, Zhejiang Chinese Medical University, No. 548 Binwen Road, Hangzhou, Zhejiang 310053, China; National Key Laboratory of Kidney Diseases, First Medical Center of Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing 100853, China.
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9
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Yang CW, Liu HM, Chang ZY, Liu GH, Chang HH, Huang PY, Lee TY. Puerarin Modulates Hepatic Farnesoid X Receptor and Gut Microbiota in High-Fat Diet-Induced Obese Mice. Int J Mol Sci 2024; 25:5274. [PMID: 38791314 PMCID: PMC11121391 DOI: 10.3390/ijms25105274] [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: 04/24/2024] [Revised: 05/04/2024] [Accepted: 05/06/2024] [Indexed: 05/26/2024] Open
Abstract
Obesity is associated with alterations in lipid metabolism and gut microbiota dysbiosis. This study investigated the effects of puerarin, a bioactive isoflavone, on lipid metabolism disorders and gut microbiota in high-fat diet (HFD)-induced obese mice. Supplementation with puerarin reduced plasma alanine aminotransferase, liver triglyceride, liver free fatty acid (FFA), and improved gut microbiota dysbiosis in obese mice. Puerarin's beneficial metabolic effects were attenuated when farnesoid X receptor (FXR) was antagonized, suggesting FXR-mediated mechanisms. In hepatocytes, puerarin ameliorated high FFA-induced sterol regulatory element-binding protein (SREBP) 1 signaling, inflammation, and mitochondrial dysfunction in an FXR-dependent manner. In obese mice, puerarin reduced liver damage, regulated hepatic lipogenesis, decreased inflammation, improved mitochondrial function, and modulated mitophagy and ubiquitin-proteasome pathways, but was less effective in FXR knockout mice. Puerarin upregulated hepatic expression of FXR, bile salt export pump (BSEP), and downregulated cytochrome P450 7A1 (CYP7A1) and sodium taurocholate transporter (NTCP), indicating modulation of bile acid synthesis and transport. Puerarin also restored gut microbial diversity, the Firmicutes/Bacteroidetes ratio, and the abundance of Clostridium celatum and Akkermansia muciniphila. This study demonstrates that puerarin effectively ameliorates metabolic disturbances and gut microbiota dysbiosis in obese mice, predominantly through FXR-dependent pathways. These findings underscore puerarin's potential as a therapeutic agent for managing obesity and enhancing gut health, highlighting its dual role in improving metabolic functions and modulating microbial communities.
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MESH Headings
- Animals
- Isoflavones/pharmacology
- Gastrointestinal Microbiome/drug effects
- Diet, High-Fat/adverse effects
- Receptors, Cytoplasmic and Nuclear/metabolism
- Mice
- Obesity/metabolism
- Obesity/drug therapy
- Liver/metabolism
- Liver/drug effects
- Male
- Dysbiosis
- Mice, Obese
- Mice, Inbred C57BL
- ATP Binding Cassette Transporter, Subfamily B, Member 11/metabolism
- ATP Binding Cassette Transporter, Subfamily B, Member 11/genetics
- Cholesterol 7-alpha-Hydroxylase/metabolism
- Cholesterol 7-alpha-Hydroxylase/genetics
- Mice, Knockout
- Organic Anion Transporters, Sodium-Dependent/metabolism
- Organic Anion Transporters, Sodium-Dependent/genetics
- Symporters/metabolism
- Symporters/genetics
- Lipid Metabolism/drug effects
- Hepatocytes/metabolism
- Hepatocytes/drug effects
- Akkermansia
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Affiliation(s)
- Ching-Wei Yang
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan;
- Division of Internal and Pediatric Chinese Medicine, Center for Traditional Chinese Medicine, Chang Gung Memorial Hospital, Linkou 333423, Taiwan
| | - Hsuan-Miao Liu
- Graduate Institute of Traditional Chinese Medicine, School of Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan;
| | - Zi-Yu Chang
- Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital, Keelung 20401, Taiwan;
| | - Geng-Hao Liu
- School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan 333323, Taiwan;
- Division of Acupuncture and Moxibustion, Center for Traditional Chinese Medicine, Chang Gung Memorial Hospital, Taoyuan 333423, Taiwan
- Sleep Center, Chang Gung Memorial Hospital, Taoyuan 333008, Taiwan
| | - Hen-Hong Chang
- Graduate Institute of Integrated Medicine, China Medical University, Taichung 40402, Taiwan;
| | - Po-Yu Huang
- Department of Chinese Medicine, Linsen Chinese Medicine and Kunming Branch, Taipei City Hospital, Taipei 10844, Taiwan
| | - Tzung-Yan Lee
- Graduate Institute of Traditional Chinese Medicine, School of Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan;
- School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan 333323, Taiwan;
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10
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Kuraji R, Ye C, Zhao C, Gao L, Martinez A, Miyashita Y, Radaic A, Kamarajan P, Le C, Zhan L, Range H, Sunohara M, Numabe Y, Kapila YL. Nisin lantibiotic prevents NAFLD liver steatosis and mitochondrial oxidative stress following periodontal disease by abrogating oral, gut and liver dysbiosis. NPJ Biofilms Microbiomes 2024; 10:3. [PMID: 38233485 PMCID: PMC10794237 DOI: 10.1038/s41522-024-00476-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: 04/17/2023] [Accepted: 01/02/2024] [Indexed: 01/19/2024] Open
Abstract
Oral microbiome dysbiosis mediates chronic periodontal disease, gut microbial dysbiosis, and mucosal barrier disfunction that leads to steatohepatitis via the enterohepatic circulation. Improving this dysbiosis towards health may improve liver disease. Treatment with antibiotics and probiotics have been used to modulate the microbial, immunological, and clinical landscape of periodontal disease with some success. The aim of the present investigation was to evaluate the potential for nisin, an antimicrobial peptide produced by Lactococcus lactis, to counteract the periodontitis-associated gut dysbiosis and to modulate the glycolipid-metabolism and inflammation in the liver. Periodontal pathogens, namely Porphyromonas gingivalis, Treponema denticola, Tannerella forsythia and Fusobacterium nucleatum, were administrated topically onto the oral cavity to establish polymicrobial periodontal disease in mice. In the context of disease, nisin treatment significantly shifted the microbiome towards a new composition, commensurate with health while preventing the harmful inflammation in the small intestine concomitant with decreased villi structural integrity, and heightened hepatic exposure to bacteria and lipid and malondialdehyde accumulation in the liver. Validation with RNA Seq analyses, confirmed the significant infection-related alteration of several genes involved in mitochondrial dysregulation, oxidative phosphorylation, and metal/iron binding and their restitution following nisin treatment. In support of these in vivo findings indicating that periodontopathogens induce gastrointestinal and liver distant organ lesions, human autopsy specimens demonstrated a correlation between tooth loss and severity of liver disease. Nisin's ability to shift the gut and liver microbiome towards a new state commensurate with health while mitigating enteritis, represents a novel approach to treating NAFLD-steatohepatitis-associated periodontal disease.
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Affiliation(s)
- Ryutaro Kuraji
- Orofacial Sciences Department, School of Dentistry, University of California, San Francisco, San Francisco, CA, USA
- Department of Periodontology, The Nippon Dental University School of Life Dentistry at Tokyo, Tokyo, Japan
| | - Changchang Ye
- Orofacial Sciences Department, School of Dentistry, University of California, San Francisco, San Francisco, CA, USA
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Periodontology, West China School of Stomatology, Sichuan University, Chengdu, China
| | - Chuanjiang Zhao
- Orofacial Sciences Department, School of Dentistry, University of California, San Francisco, San Francisco, CA, USA
- Department of Periodontology, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China
| | - Li Gao
- Orofacial Sciences Department, School of Dentistry, University of California, San Francisco, San Francisco, CA, USA
- Department of Periodontology, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China
| | - April Martinez
- Orofacial Sciences Department, School of Dentistry, University of California, San Francisco, San Francisco, CA, USA
| | - Yukihiro Miyashita
- Department of Periodontology, The Nippon Dental University School of Life Dentistry at Tokyo, Tokyo, Japan
| | - Allan Radaic
- Orofacial Sciences Department, School of Dentistry, University of California, San Francisco, San Francisco, CA, USA
- Sections of Biosystems and Function and Periodontics, School of Dentistry, University of California Los Angeles, Los Angeles, CA, USA
| | - Pachiyappan Kamarajan
- Orofacial Sciences Department, School of Dentistry, University of California, San Francisco, San Francisco, CA, USA
- Sections of Biosystems and Function and Periodontics, School of Dentistry, University of California Los Angeles, Los Angeles, CA, USA
| | - Charles Le
- Orofacial Sciences Department, School of Dentistry, University of California, San Francisco, San Francisco, CA, USA
| | - Ling Zhan
- Orofacial Sciences Department, School of Dentistry, University of California, San Francisco, San Francisco, CA, USA
| | - Helene Range
- Orofacial Sciences Department, School of Dentistry, University of California, San Francisco, San Francisco, CA, USA
- Department of Periodontology, University of Rennes, UFR of Odontology; Service d'Odontologie, CHU de Rennes, Rennes, France
- INSERM CHU Rennes, Institut NUMECAN (Nutrition Metabolisms and Cancer); CIC 1414, Rennes, France
| | - Masataka Sunohara
- Department of Anatomy, The Nippon Dental University School of Life Dentistry at Tokyo, Tokyo, Japan
| | - Yukihiro Numabe
- Department of Periodontology, The Nippon Dental University School of Life Dentistry at Tokyo, Tokyo, Japan
| | - Yvonne L Kapila
- Orofacial Sciences Department, School of Dentistry, University of California, San Francisco, San Francisco, CA, USA.
- Sections of Biosystems and Function and Periodontics, School of Dentistry, University of California Los Angeles, Los Angeles, CA, USA.
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11
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He X, Gao X, Hong Y, Zhong J, Li Y, Zhu W, Ma J, Huang W, Li Y, Li Y, Wang H, Liu Z, Bao Y, Pan L, Zheng N, Sheng L, Li H. High Fat Diet and High Sucrose Intake Divergently Induce Dysregulation of Glucose Homeostasis through Distinct Gut Microbiota-Derived Bile Acid Metabolism in Mice. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2024; 72:230-244. [PMID: 38079533 DOI: 10.1021/acs.jafc.3c02909] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/11/2024]
Abstract
A high calorie diet such as excessive fat and sucrose intake is always accompanied by impaired glucose homeostasis such as T2DM (type 2 diabetes mellitus). However, it remains unclear how fat and sucrose individually affect host glucose metabolism. In this study, mice were fed with high fat diet (HFD) or 30% sucrose in drinking water (HSD) for 24 weeks, and glucose metabolism, gut microbiota composition, as well as bile acid (BA) profile were investigated. In addition, the functional changes of HFD or HSD-induced gut microbiota were further verified by fecal microbiota transplantation (FMT) and ex vivo culture of gut bacteria with BAs. Our results showed that both HFD and HSD caused dysregulated lipid metabolism, while HFD feeding had a more severe effect on impaired glucose homeostasis, accompanied by reduced hyocholic acid (HCA) levels in all studied tissues. Meanwhile, HFD had a more dramatic influence on composition and function of gut microbiota based on α diversity indices, β diversity analysis, as well as the abundance of secondary BA producers than HSD. In addition, the phenotypes of impaired glucose homeostasis and less formation of HCA caused by HFD can be transferred to recipient mice by FMT. Ex vivo culture with gut bacteria and BAs revealed HFD-altered gut bacteria produced less HCA than HSD, which might closely associate with reduced relative abundance of C7 epimerase-coding bacteria g_norank/unclassified_f_Eggerthellaceae and bile salt hydrolase-producing bacteria Lactobacillus and Bifidobacterium in HFD group. Our findings revealed that the divergent effects of different high-calorie diets on glucose metabolism may be due to the gut microbiota-mediated generation and metabolism of BAs, highlighting the importance of dietary management in T2DM.
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Affiliation(s)
- Xiaofang He
- 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
| | - Ying Hong
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Jing Zhong
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
- Huzhou Key Laboratory of Molecular Medicine, Huzhou Central Hospital, Affiliated Central Hospital Huzhou University, Huzhou 313000, China
| | - Yue Li
- Department of Endocrinology, Shanghai Fifth People's Hospital, Shanghai Medical School, Fudan University, Shanghai 200032, China
| | - Weize Zhu
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Junli Ma
- 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
| | - Yifan Li
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yan Li
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Hao Wang
- 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
| | - Yiyang Bao
- 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
| | - Ningning Zheng
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, 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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12
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Smiriglia A, Lorito N, Serra M, Perra A, Morandi A, Kowalik MA. Sex difference in liver diseases: How preclinical models help to dissect the sex-related mechanisms sustaining NAFLD and hepatocellular carcinoma. iScience 2023; 26:108363. [PMID: 38034347 PMCID: PMC10682354 DOI: 10.1016/j.isci.2023.108363] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2023] Open
Abstract
Only a few preclinical findings are confirmed in the clinic, posing a critical issue for clinical development. Therefore, identifying the best preclinical models can help to dissect molecular and mechanistic insights into liver disease pathogenesis while being clinically relevant. In this context, the sex relevance of most preclinical models has been only partially considered. This is particularly significant in NAFLD and HCC, which have a higher prevalence in men when compared to pre-menopause women but not to those in post-menopausal status, suggesting a role for sex hormones in the pathogenesis of the diseases. This review gathers the sex-relevant findings and the available preclinical models focusing on both in vitro and in vivo studies and discusses the potential implications and perspectives of introducing the sex effect in the selection of the best preclinical model. This is a critical aspect that would help to tailor personalized therapies based on sex.
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Affiliation(s)
- Alfredo Smiriglia
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50134 Florence, Italy
| | - Nicla Lorito
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50134 Florence, Italy
| | - Marina Serra
- Department of Biomedical Sciences, University of Cagliari, 09042 Monserrato, Italy
| | - Andrea Perra
- Department of Biomedical Sciences, University of Cagliari, 09042 Monserrato, Italy
| | - Andrea Morandi
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50134 Florence, Italy
| | - Marta Anna Kowalik
- Department of Biomedical Sciences, University of Cagliari, 09042 Monserrato, Italy
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13
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Chen Z, Guan D, Wang Z, Li X, Dong S, Huang J, Zhou W. Microbiota in cancer: molecular mechanisms and therapeutic interventions. MedComm (Beijing) 2023; 4:e417. [PMID: 37937304 PMCID: PMC10626288 DOI: 10.1002/mco2.417] [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: 06/27/2023] [Revised: 10/04/2023] [Accepted: 10/12/2023] [Indexed: 11/09/2023] Open
Abstract
The diverse bacterial populations within the symbiotic microbiota play a pivotal role in both health and disease. Microbiota modulates critical aspects of tumor biology including cell proliferation, invasion, and metastasis. This regulation occurs through mechanisms like enhancing genomic damage, hindering gene repair, activating aberrant cell signaling pathways, influencing tumor cell metabolism, promoting revascularization, and remodeling the tumor immune microenvironment. These microbiota-mediated effects significantly impact overall survival and the recurrence of tumors after surgery by affecting the efficacy of chemoradiotherapy. Moreover, leveraging the microbiota for the development of biovectors, probiotics, prebiotics, and synbiotics, in addition to utilizing antibiotics, dietary adjustments, defensins, oncolytic virotherapy, and fecal microbiota transplantation, offers promising alternatives for cancer treatment. Nonetheless, due to the extensive and diverse nature of the microbiota, along with tumor heterogeneity, the molecular mechanisms underlying the role of microbiota in cancer remain a subject of intense debate. In this context, we refocus on various cancers, delving into the molecular signaling pathways associated with the microbiota and its derivatives, the reshaping of the tumor microenvironmental matrix, and the impact on tolerance to tumor treatments such as chemotherapy and radiotherapy. This exploration aims to shed light on novel perspectives and potential applications in the field.
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Affiliation(s)
- Zhou Chen
- The First Clinical Medical CollegeLanzhou UniversityLanzhouGansuChina
- The First Hospital of Lanzhou UniversityLanzhouGansuChina
| | - Defeng Guan
- The First Clinical Medical CollegeLanzhou UniversityLanzhouGansuChina
- The First Hospital of Lanzhou UniversityLanzhouGansuChina
| | - Zhengfeng Wang
- The First Clinical Medical CollegeLanzhou UniversityLanzhouGansuChina
- The First Hospital of Lanzhou UniversityLanzhouGansuChina
| | - Xin Li
- The Second Clinical Medical CollegeLanzhou UniversityLanzhouGansuChina
- The Department of General SurgeryLanzhou University Second HospitalLanzhouGansuChina
| | - Shi Dong
- The Second Clinical Medical CollegeLanzhou UniversityLanzhouGansuChina
- The Department of General SurgeryLanzhou University Second HospitalLanzhouGansuChina
| | - Junjun Huang
- The First Hospital of Lanzhou UniversityLanzhouGansuChina
| | - Wence Zhou
- The First Clinical Medical CollegeLanzhou UniversityLanzhouGansuChina
- The Department of General SurgeryLanzhou University Second HospitalLanzhouGansuChina
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14
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Gilbert MC, Setayesh T, Wan YJY. The contributions of bacteria metabolites to the development of hepatic encephalopathy. LIVER RESEARCH 2023; 7:296-303. [PMID: 38221945 PMCID: PMC10786625 DOI: 10.1016/j.livres.2022.11.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Over 20% of mortality during acute liver failure is associated with the development of hepatic encephalopathy (HE). Thus, HE is a complication of acute liver failure with a broad spectrum of neuropsychiatric abnormalities ranging from subclinical alterations to coma. HE is caused by the diversion of portal blood into systemic circulation through portosystemic collateral vessels. Thus, the brain is exposed to intestinal-derived toxic substances. Moreover, the strategies to prevent advancement and improve the prognosis of such a liver-brain disease rely on intestinal microbial modulation. This is supported by the findings that antibiotics such as rifaximin and laxative lactulose can alleviate hepatic cirrhosis and/or prevent HE. Together, the significance of the gut-liver-brain axis in human health warrants attention. This review paper focuses on the roles of bacteria metabolites, mainly ammonia and bile acids (BAs) as well as BA receptors in HE. The literature search conducted for this review included searches for phrases such as BA receptors, BAs, ammonia, farnesoid X receptor (FXR), G protein-coupled bile acid receptor 1 (GPBAR1 or TGR5), sphingosine-1-phosphate receptor 2 (S1PR2), and cirrhosis in conjunction with the phrase hepatic encephalopathy and portosystemic encephalopathy. PubMed, as well as Google Scholar, was the search engines used to find relevant publications.
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Affiliation(s)
- Miranda Claire Gilbert
- Department of Pathology and Laboratory Medicine, University of California, Davis, Sacramento, CA, USA
| | - Tahereh Setayesh
- Department of Pathology and Laboratory Medicine, University of California, Davis, Sacramento, CA, USA
| | - Yu-Jui Yvonne Wan
- Department of Pathology and Laboratory Medicine, University of California, Davis, Sacramento, CA, USA
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15
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Liu HM, Chang ZY, Yang CW, Chang HH, Lee TY. Farnesoid X Receptor Agonist GW4064 Protects Lipopolysaccharide-Induced Intestinal Epithelial Barrier Function and Colorectal Tumorigenesis Signaling through the αKlotho/βKlotho/FGFs Pathways in Mice. Int J Mol Sci 2023; 24:16932. [PMID: 38069256 PMCID: PMC10706872 DOI: 10.3390/ijms242316932] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 11/21/2023] [Accepted: 11/27/2023] [Indexed: 12/18/2023] Open
Abstract
The farnesoid X receptor (FXR)/βKlotho/fibroblast growth factors (FGFs) pathway is crucial for maintaining the intestinal barrier and preventing colorectal cancer (CRC). We used an FXR agonist, GW4064, and FXR-knockout (FXR-KO) mice to investigate the role of FXR/Klothos/FGFs pathways in lipopolysaccharide (LPS)-induced intestinal barrier dysfunction and colon carcinogenesis. The results showed that upregulation of FXR in enterocytes effectively ameliorated intestinal tight-junction markers (claudin1 and zonula occludens-1), inflammation, and bile acid levels, thereby protecting mice from intestinal barrier dysfunction and colon carcinogenesis. GW4064 treatment increased FXR, αKlotho, βKlotho, FGF19, FGF21, and FGF23 in wild-type mice exposed to LPS, while FXR-KO mice had decreased levels. FXR-KO mice exhibited elevated colon cancer markers (β-catenin, LGR5, CD44, CD34, and cyclin D1) under LPS, underscoring the pivotal role of FXR in inhibiting the development of colon tumorigenesis. The varying gut microbiota responses in FXR-KO mice versus wild-type mice post LPS exposure emphasize the pivotal role of FXR in preserving intestinal microbial health, involving Bacteroides thetaiotaomicron, Bacteroides acidifaciens, and Helicobacter hepaticus. Our study validates the effectiveness of GW4064 in alleviating LPS-induced disruptions to the intestinal barrier and colon carcinogenesis, emphasizing the importance of the FXR/αKlotho/βKlotho/FGFs pathway and the interplay between bile acids and gut microbiota.
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Affiliation(s)
- Hsuan-Miao Liu
- Graduate Institute of Traditional Chinese Medicine, School of Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan;
| | - Zi-Yu Chang
- Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital, Keelung 20401, Taiwan;
| | - Ching-Wei Yang
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan;
- Division of Internal and Pediatric Chinese Medicine, Center for Traditional Chinese Medicine, Chang Gung Memorial Hospital, Linkou 333423, Taiwan
| | - Hen-Hong Chang
- Graduate Institute of Integrated Medicine, China Medical University, Taichung 40402, Taiwan
| | - Tzung-Yan Lee
- Graduate Institute of Traditional Chinese Medicine, School of Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan;
- Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital, Keelung 20401, Taiwan;
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16
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Yang G, Liu R, Rezaei S, Liu X, Wan YJY. Uncovering the Gut-Liver Axis Biomarkers for Predicting Metabolic Burden in Mice. Nutrients 2023; 15:3406. [PMID: 37571345 PMCID: PMC10421148 DOI: 10.3390/nu15153406] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Revised: 07/28/2023] [Accepted: 07/28/2023] [Indexed: 08/13/2023] Open
Abstract
Western diet (WD) intake, aging, and inactivation of farnesoid X receptor (FXR) are risk factors for metabolic and chronic inflammation-related health issues ranging from metabolic dysfunction-associated steatotic liver disease (MASLD) to dementia. The progression of MASLD can be escalated when those risks are combined. Inactivation of FXR, the receptor for bile acid (BA), is cancer prone in both humans and mice. The current study used multi-omics including hepatic transcripts, liver, serum, and urine metabolites, hepatic BAs, as well as gut microbiota from mouse models to classify those risks using machine learning. A linear support vector machine with K-fold cross-validation was used for classification and feature selection. We have identified that increased urine sucrose alone achieved 91% accuracy in predicting WD intake. Hepatic lithocholic acid and serum pyruvate had 100% and 95% accuracy, respectively, to classify age. Urine metabolites (decreased creatinine and taurine as well as increased succinate) or increased gut bacteria (Dorea, Dehalobacterium, and Oscillospira) could predict FXR deactivation with greater than 90% accuracy. Human disease relevance is partly revealed using the metabolite-disease interaction network. Transcriptomics data were also compared with the human liver disease datasets. WD-reduced hepatic Cyp39a1 (cytochrome P450 family 39 subfamily a member 1) and increased Gramd1b (GRAM domain containing 1B) were also changed in human liver cancer and metabolic liver disease, respectively. Together, our data contribute to the identification of noninvasive biomarkers within the gut-liver axis to predict metabolic status.
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Affiliation(s)
- Guiyan Yang
- Department of Medical Pathology, Laboratory Medicine in Sacramento, University of California, Davis, CA 95817, USA;
| | - Rex Liu
- Department of Computer Science, University of California, Davis, CA 95616, USA; (R.L.); (S.R.); (X.L.)
| | - Shahbaz Rezaei
- Department of Computer Science, University of California, Davis, CA 95616, USA; (R.L.); (S.R.); (X.L.)
| | - Xin Liu
- Department of Computer Science, University of California, Davis, CA 95616, USA; (R.L.); (S.R.); (X.L.)
| | - Yu-Jui Yvonne Wan
- Department of Medical Pathology, Laboratory Medicine in Sacramento, University of California, Davis, CA 95817, USA;
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17
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Guo GJ, Yao F, Lu WP, Xu HM. Gut microbiome and metabolic-associated fatty liver disease: Current status and potential applications. World J Hepatol 2023; 15:867-882. [PMID: 37547030 PMCID: PMC10401411 DOI: 10.4254/wjh.v15.i7.867] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 06/11/2023] [Accepted: 06/30/2023] [Indexed: 07/21/2023] Open
Abstract
Metabolic-associated fatty liver disease (MAFLD) is one of the most common chronic liver diseases worldwide. In recent years, the occurrence rate of MAFLD has been on the rise, mainly due to lifestyle changes, high-calorie diets, and imbalanced dietary structures, thereby posing a threat to human health and creating heavy social and economic burdens. With the development of 16S sequencing and integrated multi-omics analysis, the role of the gut microbiota (GM) and its metabolites in MAFLD has been further recognized. The GM plays a role in digestion, energy metabolism, vitamin synthesis, the prevention of pathogenic bacteria colonisation, and immunoregulation. The gut-liver axis is one of the vital links between the GM and the liver. Toxic substances in the intestine can enter the liver through the portal vascular system when the intestinal barrier is severely damaged. The liver also influences the GM in various ways, such as bile acid circulation. The gut-liver axis is essential in maintaining the body's normal physiological state and plays a role in the onset and prognosis of many diseases, including MAFLD. This article reviews the status of the GM and MAFLD and summarizes the GM characteristics in MAFLD. The relationship between the GM and MAFLD is discussed in terms of bile acid circulation, energy metabolism, micronutrients, and signalling pathways. Current MAFLD treatments targeting the GM are also listed.
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Affiliation(s)
- Gong-Jing Guo
- Gastroenterology Department of The Second Affiliated Hospital, School of Medicine, The Chinese University of Hong Kong, Shenzhen & Longgang District People's Hospital of Shenzhen, Shenzhen 518172, Guangdong Province, China
| | - Fei Yao
- Department of Science and Education, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou 510370, Guangdong Province, China
| | - Wei-Peng Lu
- The First Clinical School, Guangzhou Medical University, Guangzhou 510120, Guangdong Province, China
| | - Hao-Ming Xu
- Department of Gastroenterology and Hepatology, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou 510180, Guangdong Province, China.
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18
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Ji J, Wu L, Wei J, Wu J, Guo C. The Gut Microbiome and Ferroptosis in MAFLD. J Clin Transl Hepatol 2023; 11:174-187. [PMID: 36406312 PMCID: PMC9647110 DOI: 10.14218/jcth.2022.00136] [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: 03/21/2022] [Revised: 05/22/2022] [Accepted: 06/12/2022] [Indexed: 12/04/2022] Open
Abstract
Metabolic-associated fatty liver disease (MAFLD) is a new disease definition, and is proposed to replace the previous name, nonalcoholic fatty liver disease (NAFLD). Globally, MAFLD/NAFLD is the most common liver disease, with an incidence rate ranging from 6% to 35% in adult populations. The pathogenesis of MAFLD/NAFLD is closely related to insulin resistance (IR), and the genetic susceptibility to acquired metabolic stress-associated liver injury. Similarly, the gut microbiota in MAFLD/NAFLD is being revaluated by scientists, as the gut and liver influence each other via the gut-liver axis. Ferroptosis is a novel form of programmed cell death caused by iron-dependent lipid peroxidation. Emerging evidence suggests that ferroptosis has a key role in the pathological progression of MAFLD/NAFLD, and inhibition of ferroptosis may become a novel therapeutic strategy for the treatment of NAFLD. This review focuses on the main mechanisms behind the promotion of MAFLD/NAFLD occurrence and development by the intestinal microbiota and ferroptosis. It outlines new strategies to target the intestinal microbiota and ferroptosis to facilitate future MAFLD/NAFLD therapies.
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Affiliation(s)
- Jie Ji
- Department of Gastroenterology, Putuo People’s Hospital, Tongji University, Shanghai, China
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
| | - Liwei Wu
- Department of Gastroenterology, Putuo People’s Hospital, Tongji University, Shanghai, China
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
| | - Jue Wei
- Department of Gastroenterology Shanghai Tongren Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Jianye Wu
- Department of Gastroenterology, Putuo People’s Hospital, Tongji University, Shanghai, China
- Correspondence to: Chuanyong Guo, Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, NO. 301, Middle Yanchang Road, Jing’an District, Shanghai 200072, China. ORCID: https://orcid.org/0000-0002-6527-4673. E-mail: ; Jianye Wu: Department of Gastroenterology, Putuo People’s Hospital, NO. 1291, Jiangning road, Putuo, Shanghai 200060, China. ORCID: https://orcid.org/0000-0003-2675-4241. E-mail:
| | - Chuanyong Guo
- Department of Gastroenterology, Putuo People’s Hospital, Tongji University, Shanghai, China
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
- Correspondence to: Chuanyong Guo, Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, NO. 301, Middle Yanchang Road, Jing’an District, Shanghai 200072, China. ORCID: https://orcid.org/0000-0002-6527-4673. E-mail: ; Jianye Wu: Department of Gastroenterology, Putuo People’s Hospital, NO. 1291, Jiangning road, Putuo, Shanghai 200060, China. ORCID: https://orcid.org/0000-0003-2675-4241. E-mail:
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19
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Yang G, Jena PK, Hu Y, Sheng L, Chen SY, Slupsky CM, Davis R, Tepper CG, Wan YJY. The essential roles of FXR in diet and age influenced metabolic changes and liver disease development: a multi-omics study. Biomark Res 2023; 11:20. [PMID: 36803569 PMCID: PMC9938992 DOI: 10.1186/s40364-023-00458-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Accepted: 01/24/2023] [Indexed: 02/20/2023] Open
Abstract
BACKGROUND Aging and diet are risks for metabolic diseases. Bile acid receptor farnesoid X receptor (FXR) knockout (KO) mice develop metabolic liver diseases that progress into cancer as they age, which is accelerated by Western diet (WD) intake. The current study uncovers the molecular signatures for diet and age-linked metabolic liver disease development in an FXR-dependent manner. METHODS Wild-type (WT) and FXR KO male mice, either on a healthy control diet (CD) or a WD, were euthanized at the ages of 5, 10, or 15 months. Hepatic transcriptomics, liver, serum, and urine metabolomics as well as microbiota were profiled. RESULTS WD intake facilitated hepatic aging in WT mice. In an FXR-dependent manner, increased inflammation and reduced oxidative phosphorylation were the primary pathways affected by WD and aging. FXR has a role in modulating inflammation and B cell-mediated humoral immunity which was enhanced by aging. Moreover, FXR dictated neuron differentiation, muscle contraction, and cytoskeleton organization in addition to metabolism. There were 654 transcripts commonly altered by diets, ages, and FXR KO, and 76 of them were differentially expressed in human hepatocellular carcinoma (HCC) and healthy livers. Urine metabolites differentiated dietary effects in both genotypes, and serum metabolites clearly separated ages irrespective of diets. Aging and FXR KO commonly affected amino acid metabolism and TCA cycle. Moreover, FXR is essential for colonization of age-related gut microbes. Integrated analyses uncovered metabolites and bacteria linked with hepatic transcripts affected by WD intake, aging, and FXR KO as well as related to HCC patient survival. CONCLUSION FXR is a target to prevent diet or age-associated metabolic disease. The uncovered metabolites and microbes can be diagnostic markers for metabolic disease.
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Affiliation(s)
- Guiyan Yang
- grid.27860.3b0000 0004 1936 9684Department of Pathology and Laboratory Medicine, University of California, Davis Health. Room 3400B, Research Building III, 4645 2nd Ave, Sacramento, CA 95817 USA
| | - Prasant K. Jena
- grid.27860.3b0000 0004 1936 9684Department of Pathology and Laboratory Medicine, University of California, Davis Health. Room 3400B, Research Building III, 4645 2nd Ave, Sacramento, CA 95817 USA
| | - Ying Hu
- grid.27860.3b0000 0004 1936 9684Department of Pathology and Laboratory Medicine, University of California, Davis Health. Room 3400B, Research Building III, 4645 2nd Ave, Sacramento, CA 95817 USA
| | - Lili Sheng
- grid.27860.3b0000 0004 1936 9684Department of Pathology and Laboratory Medicine, University of California, Davis Health. Room 3400B, Research Building III, 4645 2nd Ave, Sacramento, CA 95817 USA
| | - Shin-Yu Chen
- grid.27860.3b0000 0004 1936 9684Department of Nutrition, University of California, Davis, CA USA
| | - Carolyn M. Slupsky
- grid.27860.3b0000 0004 1936 9684Department of Nutrition, University of California, Davis, CA USA
| | - Ryan Davis
- grid.27860.3b0000 0004 1936 9684Department of Pathology and Laboratory Medicine, University of California, Davis Health. Room 3400B, Research Building III, 4645 2nd Ave, Sacramento, CA 95817 USA
| | - Clifford G. Tepper
- grid.27860.3b0000 0004 1936 9684Department of Biochemistry and Molecular Medicine, University of California, Davis, Sacramento, CA USA
| | - Yu-Jui Yvonne Wan
- Department of Pathology and Laboratory Medicine, University of California, Davis Health. Room 3400B, Research Building III, 4645 2nd Ave, Sacramento, CA, 95817, USA.
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20
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Kuraji R, Shiba T, Dong TS, Numabe Y, Kapila YL. Periodontal treatment and microbiome-targeted therapy in management of periodontitis-related nonalcoholic fatty liver disease with oral and gut dysbiosis. World J Gastroenterol 2023; 29:967-996. [PMID: 36844143 PMCID: PMC9950865 DOI: 10.3748/wjg.v29.i6.967] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2022] [Revised: 11/14/2022] [Accepted: 01/30/2023] [Indexed: 02/10/2023] Open
Abstract
A growing body of evidence from multiple areas proposes that periodontal disease, accompanied by oral inflammation and pathological changes in the microbiome, induces gut dysbiosis and is involved in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). A subgroup of NAFLD patients have a severely progressive form, namely nonalcoholic steatohepatitis (NASH), which is characterized by histological findings that include inflammatory cell infiltration and fibrosis. NASH has a high risk of further progression to cirrhosis and hepatocellular carcinoma. The oral microbiota may serve as an endogenous reservoir for gut microbiota, and transport of oral bacteria through the gastro-intestinal tract can set up a gut microbiome dysbiosis. Gut dysbiosis increases the production of potential hepatotoxins, including lipopolysaccharide, ethanol, and other volatile organic compounds such as acetone, phenol and cyclopentane. Moreover, gut dysbiosis increases intestinal permeability by disrupting tight junctions in the intestinal wall, leading to enhanced translocation of these hepatotoxins and enteric bacteria into the liver through the portal circulation. In particular, many animal studies support that oral administration of Porphyromonas gingivalis, a typical periodontopathic bacterium, induces disturbances in glycolipid metabolism and inflammation in the liver with gut dysbiosis. NAFLD, also known as the hepatic phenotype of metabolic syndrome, is strongly associated with metabolic complications, such as obesity and diabetes. Periodontal disease also has a bidirectional relationship with metabolic syndrome, and both diseases may induce oral and gut microbiome dysbiosis with insulin resistance and systemic chronic inflammation cooperatively. In this review, we will describe the link between periodontal disease and NAFLD with a focus on basic, epidemiological, and clinical studies, and discuss potential mechanisms linking the two diseases and possible therapeutic approaches focused on the microbiome. In conclusion, it is presumed that the pathogenesis of NAFLD involves a complex crosstalk between periodontal disease, gut microbiota, and metabolic syndrome. Thus, the conventional periodontal treatment and novel microbiome-targeted therapies that include probiotics, prebiotics and bacteriocins would hold great promise for preventing the onset and progression of NAFLD and subsequent complications in patients with periodontal disease.
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Affiliation(s)
- Ryutaro Kuraji
- Department of Periodontology, The Nippon Dental University School of Life Dentistry at Tokyo, Tokyo 102-0071, Japan
- Department of Orofacial Sciences, University of California San Francisco, San Francisco, CA 94143, United States
| | - Takahiko Shiba
- Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental Medicine, Boston, MA 02115, United States
- Department of Periodontology, Tokyo Medical and Dental University, Tokyo 113-8549, Japan
| | - Tien S Dong
- The Vatche and Tamar Manoukian Division of Digestive Diseases, University of California Los Angeles, Department of Medicine, University of California David Geffen School of Medicine, Los Angeles, CA 90095, United States
| | - Yukihiro Numabe
- Department of Periodontology, The Nippon Dental University School of Life Dentistry at Tokyo, Tokyo 102-8159, Japan
| | - Yvonne L Kapila
- Department of Orofacial Sciences, University of California San Francisco, San Francisco, CA 94143, United States
- Sections of Biosystems and Function and Periodontics, Professor and Associate Dean of Research, Felix and Mildred Yip Endowed Chair in Dentistry, University of California Los Angeles, Los Angeles, CA 90095, United States
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21
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Liu Y, Chen L, Liu L, Zhao SS, You JQ, Zhao XJ, Liu HX, Xu GW, Wen DL. Interplay between dietary intake, gut microbiota, and metabolic profile in obese adolescents: Sex-dependent differential patterns. Clin Nutr 2022; 41:2706-2719. [PMID: 36351362 DOI: 10.1016/j.clnu.2022.10.009] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2022] [Revised: 09/22/2022] [Accepted: 10/13/2022] [Indexed: 01/27/2023]
Abstract
BACKGROUND & AIMS The interplay among dietary intake, gut microbiota, gut metabolites and circulating metabolites in adolescents is barely known, not to mention sex-dependent pattern. We aimed to explore unique profiles of gut bacterial, gut metabolites and circulating metabolites from both genders of adolescents due to BMI and eating pattern. METHODS Clinical indices, fecal gut microbiota, fecal and plasma metabolites, and diet intake information were collected in case-control sample matched for normal and obesity in girls (normal = 12, obesity = 12) and boys (normal = 20, obesity = 20), respectively. 16S rRNA gene sequencing and untargeted metabolomics was performed to analysis the signature of gut microbiota and metabolites. Unique profiles of girls associated with BMI and eating pattern was revealed by Spearman's correlations analysis, co-occurrence network analysis, Kruskal-Wallis test, and Wilcoxon rank-sum test. RESULTS Gender difference was found between normal and obese adolescents in gut microbiota, fecal metabolites, and plasma metabolites. The Parabacteroides were only decreased in obese girls. And the characteristic of obese girls' and boys' cases in fecal and plasma was xanthine and glutamine, ornithine and LCA, respectively. Soy products intake was negatively associated with Parabacteroides. The predicted model has a higher accuracy based on the combined markers in obesity boys (AUC = 0.97) and girls (AUC = 0.97), respectively. CONCLUSIONS Reduced abundance of Phascolarctobacterium and Parabacteroides, as well as the increased fecal xanthine and ornithine, may provide a novel biomarker signature in obesity girls and boys. Soy products intake was positively and negatively associated with Romboutsia and Parabacteroides abundance, respectively. And the combined markers facilitate the accuracy of predicting obesity in girls and boys in advance.
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Affiliation(s)
- Yang Liu
- Health Sciences Institute, China Medical University, Shenyang 110122, Liaoning Province, PR China; Liaoning Key Laboratory of Obesity and Glucose/Lipid Associated Metabolic Diseases, China Medical University, Shenyang 110122, Liaoning Province, PR China
| | - Lei Chen
- Health Sciences Institute, China Medical University, Shenyang 110122, Liaoning Province, PR China; Liaoning Key Laboratory of Obesity and Glucose/Lipid Associated Metabolic Diseases, China Medical University, Shenyang 110122, Liaoning Province, PR China; Institute of Life Sciences, China Medical University, Shenyang 110122, Liaoning Province, PR China
| | - Lei Liu
- Health Sciences Institute, China Medical University, Shenyang 110122, Liaoning Province, PR China; Liaoning Key Laboratory of Obesity and Glucose/Lipid Associated Metabolic Diseases, China Medical University, Shenyang 110122, Liaoning Province, PR China
| | - Shan-Shan Zhao
- Health Sciences Institute, China Medical University, Shenyang 110122, Liaoning Province, PR China; Liaoning Key Laboratory of Obesity and Glucose/Lipid Associated Metabolic Diseases, China Medical University, Shenyang 110122, Liaoning Province, PR China; Institute of Life Sciences, China Medical University, Shenyang 110122, Liaoning Province, PR China
| | - Jun-Qiao You
- Health Sciences Institute, China Medical University, Shenyang 110122, Liaoning Province, PR China; Liaoning Key Laboratory of Obesity and Glucose/Lipid Associated Metabolic Diseases, China Medical University, Shenyang 110122, Liaoning Province, PR China
| | - Xin-Jie Zhao
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, The Chinese Academy of Sciences, Dalian 116023, Liaoning Province, PR China.
| | - Hui-Xin Liu
- Health Sciences Institute, China Medical University, Shenyang 110122, Liaoning Province, PR China; Liaoning Key Laboratory of Obesity and Glucose/Lipid Associated Metabolic Diseases, China Medical University, Shenyang 110122, Liaoning Province, PR China; Institute of Life Sciences, China Medical University, Shenyang 110122, Liaoning Province, PR China.
| | - Guo-Wang Xu
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, The Chinese Academy of Sciences, Dalian 116023, Liaoning Province, PR China
| | - De-Liang Wen
- Health Sciences Institute, China Medical University, Shenyang 110122, Liaoning Province, PR China; Liaoning Key Laboratory of Obesity and Glucose/Lipid Associated Metabolic Diseases, China Medical University, Shenyang 110122, Liaoning Province, PR China.
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22
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Mukhopadhyay S, Ray P, Aich P. A comparative analysis of gut microbial dysbiosis by select antibiotics and DSS to understand the effects of perturbation on the host immunity and metabolism. Life Sci 2022; 312:121212. [PMID: 36414091 DOI: 10.1016/j.lfs.2022.121212] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 11/09/2022] [Accepted: 11/17/2022] [Indexed: 11/21/2022]
Abstract
AIMS Balanced gut microbial composition of the host plays a crucial role in maintaining harmony among various physiological processes to maintain physiological homeostasis. Immunity and metabolism are the two physiologies mainly controlled by the gut microbiota. Reports suggested that gut microbial composition and diversity alteration are the leading causes of the host's healthy homeostasis alteration or a diseased state. The extent of gut perturbation depends on the perturbing agents' strength, chemical nature, and mode of action. In the current report, we have studied the effects of different perturbing agents on gut microbial dysbiosis and its impact on host immunity and metabolism. MATERIALS AND METHODS We studied the perturbation of gut microbial composition and diversity using next-generation sequencing and further investigated the changes in host immune and metabolic responses. KEY FINDINGS Enrichment or abolition of a particular phylum or genus depended on the perturbing agents. In the current study, treatment with neomycin yielded an increase in the Bacteroidetes phylum. Vancomycin treatment caused a significant rise in Verrucomicrobia and Proteobacteria phyla. The treatment with AVNM and DSS caused a substantial increase in the Proteobacteria phylum. The gut microbial diversity was also lowest in AVNM treated group. The altered gut microbial composition ultimately altered the immune responses at localized and systemic levels of the host. Gut dysbiosis also changed the systemic level of SCFAs. SIGNIFICANCE This study will help us understand how the enrichment of a particular phylum and genus maintains the host's immune responses and metabolism.
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Affiliation(s)
- Sohini Mukhopadhyay
- School of Biological Sciences, National Institute of Science Education and Research (NISER), P.O.-Bhimpur-Padanpur, Jatni-752050 District-Khurdha, Odisha, India; Homi Bhabha National Institute, Training School Complex, Anushaktinagar, Mumbai 400094, India
| | - Pratikshya Ray
- School of Biological Sciences, National Institute of Science Education and Research (NISER), P.O.-Bhimpur-Padanpur, Jatni-752050 District-Khurdha, Odisha, India; Homi Bhabha National Institute, Training School Complex, Anushaktinagar, Mumbai 400094, India
| | - Palok Aich
- School of Biological Sciences, National Institute of Science Education and Research (NISER), P.O.-Bhimpur-Padanpur, Jatni-752050 District-Khurdha, Odisha, India; Homi Bhabha National Institute, Training School Complex, Anushaktinagar, Mumbai 400094, India.
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23
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Yan S, Zhou J, Zhang H, Lin Z, Khambu B, Liu G, Ma M, Chen X, Chalasani N, Yin X. Promotion of diet-induced obesity and metabolic syndromes by BID is associated with gut microbiota. Hepatol Commun 2022; 6:3349-3362. [PMID: 36382356 PMCID: PMC9701492 DOI: 10.1002/hep4.2052] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 06/23/2022] [Accepted: 07/01/2022] [Indexed: 11/17/2022] Open
Abstract
A growing body of evidence has indicated an expanding functional network of B-cell lymphoma 2 (BCL-2) family proteins beyond regulation of cell death and survival. Here, we examined the role and mechanisms of BH3 interacting-domain death agonist (BID), a pro-death BCL-2 family member, in the development of diet-induced metabolic dysfunction. Mice deficient in bid (bid-/- ) were resistant to high-fat diet (HFD)-induced obesity, hepatic steatosis, and dyslipidemia with an increased insulin sensitivity. Indirect calorimetry analysis indicated that bid deficiency increased metabolic rate and decreased respiratory exchange ratio, suggesting a larger contribution of lipids to overall energy expenditure. While expression of several genes related to lipid accumulation was only increased in wild-type livers, metabolomics analysis revealed a consistent reduction in fatty acids but an increase in certain sugars and Krebs cycle intermediates in bid-/- livers. Gut microbiota (GM) analysis indicated that HFD induced gut dysbiosis with differential patterns in wild-type and in bid-/- mice. Notably, abrogation of GM by antibiotics during HFD feeding eliminated the beneficial effects against obesity and hepatic steatosis conferred by the bid deficiency. Conclusion: These results indicate that the protective role of bid-deficiency against diet-induced metabolic dysfunction interacts with the function of GM.
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Affiliation(s)
- Shengmin Yan
- Department of Pathology and Laboratory MedicineTulane University School of MedicineNew OrleansLouisianaUSA,Department of Pathology and Laboratory MedicineIndiana University School of MedicineIndianapolisIndianaUSA
| | - Jun Zhou
- Department of Pathology and Laboratory MedicineIndiana University School of MedicineIndianapolisIndianaUSA,Department of Emergency MedicineThe Second Xiangya HospitalCentral South UniversityChangshaChina
| | - Hao Zhang
- Department of Pathology and Laboratory MedicineIndiana University School of MedicineIndianapolisIndianaUSA,Digestive Health InstituteUniversity of IllinoisUrbanain IllinoisUSA
| | - Zhen Lin
- Department of Pathology and Laboratory MedicineTulane University School of MedicineNew OrleansLouisianaUSA
| | - Bilon Khambu
- Department of Pathology and Laboratory MedicineTulane University School of MedicineNew OrleansLouisianaUSA,Department of Pathology and Laboratory MedicineIndiana University School of MedicineIndianapolisIndianaUSA
| | - Gang Liu
- Department of Pathology and Laboratory MedicineTulane University School of MedicineNew OrleansLouisianaUSA
| | - Michelle Ma
- Department of Pathology and Laboratory MedicineTulane University School of MedicineNew OrleansLouisianaUSA
| | - Xiaoyun Chen
- Department of Pathology and Laboratory MedicineIndiana University School of MedicineIndianapolisIndianaUSA
| | - Naga Chalasani
- Department of MedicineIndiana University School of MedicineIndianapolisIndianaUSA
| | - Xiao‐Ming Yin
- Department of Pathology and Laboratory MedicineTulane University School of MedicineNew OrleansLouisianaUSA,Department of Pathology and Laboratory MedicineIndiana University School of MedicineIndianapolisIndianaUSA
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24
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Fu L, Qian Y, Shang Z, Sun X, Kong X, Gao Y. Antibiotics enhancing drug-induced liver injury assessed for causality using Roussel Uclaf Causality Assessment Method: Emerging role of gut microbiota dysbiosis. Front Med (Lausanne) 2022; 9:972518. [PMID: 36160154 PMCID: PMC9500153 DOI: 10.3389/fmed.2022.972518] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2022] [Accepted: 08/22/2022] [Indexed: 11/13/2022] Open
Abstract
Drug-induced liver injury (DILI) is a disease that remains difficult to predict and prevent from a clinical perspective, as its occurrence is hard to fully explain by the traditional mechanisms. In recent years, the risk of the DILI for microbiota dysbiosis has been recognized as a multifactorial process. Amoxicillin-clavulanate is the most commonly implicated drug in DILI worldwide with high causality gradings based on the use of RUCAM in different populations. Antibiotics directly affect the structure and diversity of gut microbiota (GM) and changes in metabolites. The depletion of probiotics after antibiotics interference can reduce the efficacy of hepatoprotective agents, also manifesting as liver injury. Follow-up with liver function examination is essential during the administration of drugs that affect intestinal microorganisms and their metabolic activities, such as antibiotics, especially in patients on a high-fat diet. In the meantime, altering the GM to reconstruct the hepatotoxicity of drugs by exhausting harmful bacteria and supplementing with probiotics/prebiotics are potential therapeutic approaches. This review will provide an overview of the current evidence between gut microbiota and DILI events, and discuss the potential mechanisms of gut microbiota-mediated drug interactions. Finally, this review also provides insights into the "double-edged sword" effect of antibiotics treatment against DILI and the potential prevention and therapeutic strategies.
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Affiliation(s)
- Lihong Fu
- Central Laboratory, Department of Liver Diseases, ShuGuang Hospital, Affiliated to Shanghai University of Chinese Traditional Medicine, Shanghai, China
- Institute of Infection Diseases, Shanghai University of Chinese Traditional Medicine, Shanghai, China
| | - Yihan Qian
- Central Laboratory, Department of Liver Diseases, ShuGuang Hospital, Affiliated to Shanghai University of Chinese Traditional Medicine, Shanghai, China
| | - Zhi Shang
- Central Laboratory, Department of Liver Diseases, ShuGuang Hospital, Affiliated to Shanghai University of Chinese Traditional Medicine, Shanghai, China
| | - Xuehua Sun
- Central Laboratory, Department of Liver Diseases, ShuGuang Hospital, Affiliated to Shanghai University of Chinese Traditional Medicine, Shanghai, China
| | - Xiaoni Kong
- Central Laboratory, Department of Liver Diseases, ShuGuang Hospital, Affiliated to Shanghai University of Chinese Traditional Medicine, Shanghai, China
| | - Yueqiu Gao
- Central Laboratory, Department of Liver Diseases, ShuGuang Hospital, Affiliated to Shanghai University of Chinese Traditional Medicine, Shanghai, China
- Institute of Infection Diseases, Shanghai University of Chinese Traditional Medicine, Shanghai, China
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25
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Kuraji R, Kapila Y, Numabe Y. Periodontal Disease and Nonalcoholic Fatty Liver Disease: New Microbiome-Targeted Therapy Based on the Oral–Gut–Liver Axis Concept. CURRENT ORAL HEALTH REPORTS 2022; 9:89-102. [DOI: 10.1007/s40496-022-00312-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 04/26/2022] [Indexed: 01/03/2025]
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Liu J, Wu A, Cai J, She ZG, Li H. The contribution of the gut-liver axis to the immune signaling pathway of NAFLD. Front Immunol 2022; 13:968799. [PMID: 36119048 PMCID: PMC9471422 DOI: 10.3389/fimmu.2022.968799] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Accepted: 08/12/2022] [Indexed: 11/24/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the liver manifestation of metabolic syndrome and is the most common chronic liver disease in the world. The pathogenesis of NAFLD has not been fully clarified; it involves metabolic disturbances, inflammation, oxidative stress, and various forms of cell death. The "intestinal-liver axis" theory, developed in recent years, holds that there is a certain relationship between liver disease and the intestinal tract, and changes in intestinal flora are closely involved in the development of NAFLD. Many studies have found that the intestinal flora regulates the pathogenesis of NAFLD by affecting energy metabolism, inducing endotoxemia, producing endogenous ethanol, and regulating bile acid and choline metabolism. In this review, we highlighted the updated discoveries in intestinal flora dysregulation and their link to the pathogenesis mechanism of NAFLD and summarized potential treatments of NAFLD related to the gut microbiome.
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Affiliation(s)
- Jiayi Liu
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Institute of Model Animal of Wuhan University, Wuhan, China
| | - Anding Wu
- Department of general surgery, Huanggang Central Hospital, Huanggang, China
- Huanggang Institute of Translation Medicine, Huanggang, China
| | - Jingjing Cai
- Department of Cardiology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Zhi-Gang She
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Institute of Model Animal of Wuhan University, Wuhan, China
| | - Hongliang Li
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Institute of Model Animal of Wuhan University, Wuhan, China
- School of Basic Medical Sciences, Wuhan University, Wuhan, China
- Medical Science Research Center, Zhongnan Hospital of Wuhan University, Wuhan, China
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27
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Wu ZH, Yang J, Chen L, Du C, Zhang Q, Zhao SS, Wang XY, Yang J, Liu Y, Cai D, Du J, Liu HX. Short-Term High-Fat Diet Fuels Colitis Progression in Mice Associated With Changes in Blood Metabolome and Intestinal Gene Expression. Front Nutr 2022; 9:899829. [PMID: 35747264 PMCID: PMC9209758 DOI: 10.3389/fnut.2022.899829] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2022] [Accepted: 04/29/2022] [Indexed: 12/16/2022] Open
Abstract
Clinical cases and animal experiments show that high-fat (HF) diet is involved in inflammatory bowel disease (IBD), but the specific mechanism is not fully clear. A close association between long-term HF-induced obesity and IBD has been well-documented. However, there has been limited evaluation of the impact of short-term HF feeding on the risk of intestinal inflammation, particularly on the risk of disrupted metabolic homeostasis. In this study, we analyzed the metabolic profile and tested the vulnerability of 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis after short-term HF feeding in mice. The results showed that compared with the control diet (CD), the fatty acid (FA), amino acid (AA), and bile acid (BA) metabolisms of mice in the HF group were significantly changed. HF-fed mice showed an increase in the content of saturated and unsaturated FAs and a decrease in the content of tryptophan (Trp). Furthermore, the disturbed spatial distribution of taurocholic acid (TCA) in the ileum and colon was identified in the HF group using matrix-assisted laser desorption/ionization-mass spectrometry imaging (MALDI-MSI). After HF priming, mice on TNBS induction were subjected to more severe colonic ulceration and histological damage compared with their CD counterparts. In addition, TNBS enema induced higher gene expressions of mucosal pro-inflammatory cytokines under HF priming conditions. Overall, our results show that HF may promote colitis by disturbing lipid, AA, and BA metabolic homeostasis and inflammatory gene expressions.
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Affiliation(s)
- Zhen-Hua Wu
- Health Sciences Institute, China Medical University, Shenyang, China
- Institute of Life Sciences, China Medical University, Shenyang, China
- Liaoning Key Laboratory of Obesity and Glucose/Lipid Associated Metabolic Diseases, China Medical University, Shenyang, China
| | - Jing Yang
- Department of Endocrinology, The Fourth Affiliated Hospital, China Medical University, Shenyang, China
| | - Lei Chen
- Health Sciences Institute, China Medical University, Shenyang, China
- Institute of Life Sciences, China Medical University, Shenyang, China
- Liaoning Key Laboratory of Obesity and Glucose/Lipid Associated Metabolic Diseases, China Medical University, Shenyang, China
| | - Chuang Du
- Health Sciences Institute, China Medical University, Shenyang, China
- Institute of Life Sciences, China Medical University, Shenyang, China
- Liaoning Key Laboratory of Obesity and Glucose/Lipid Associated Metabolic Diseases, China Medical University, Shenyang, China
| | - Qi Zhang
- Health Sciences Institute, China Medical University, Shenyang, China
| | - Shan-Shan Zhao
- Health Sciences Institute, China Medical University, Shenyang, China
- Institute of Life Sciences, China Medical University, Shenyang, China
- Liaoning Key Laboratory of Obesity and Glucose/Lipid Associated Metabolic Diseases, China Medical University, Shenyang, China
| | - Xiao-Yu Wang
- Health Sciences Institute, China Medical University, Shenyang, China
- Institute of Life Sciences, China Medical University, Shenyang, China
- Liaoning Key Laboratory of Obesity and Glucose/Lipid Associated Metabolic Diseases, China Medical University, Shenyang, China
| | - Jing Yang
- Health Sciences Institute, China Medical University, Shenyang, China
- Institute of Life Sciences, China Medical University, Shenyang, China
- Liaoning Key Laboratory of Obesity and Glucose/Lipid Associated Metabolic Diseases, China Medical University, Shenyang, China
| | - Yang Liu
- Health Sciences Institute, China Medical University, Shenyang, China
- Liaoning Key Laboratory of Obesity and Glucose/Lipid Associated Metabolic Diseases, China Medical University, Shenyang, China
| | - Demin Cai
- Laboratory of Animal Physiology and Molecular Nutrition, College of Animal Science and Technology, Yangzhou University, Yangzhou, China
| | - Jian Du
- Department of Endocrinology, The Fourth Affiliated Hospital, China Medical University, Shenyang, China
- *Correspondence: Jian Du,
| | - Hui-Xin Liu
- Health Sciences Institute, China Medical University, Shenyang, China
- Institute of Life Sciences, China Medical University, Shenyang, China
- Liaoning Key Laboratory of Obesity and Glucose/Lipid Associated Metabolic Diseases, China Medical University, Shenyang, China
- Hui-Xin Liu,
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Zhang Q, Wu ZH, Zhao SS, Yang J, Chen L, Wang XY, Wang ZY, Liu HX. Identification and Spatial Visualization of Dysregulated Bile Acid Metabolism in High-Fat Diet-Fed Mice by Mass Spectral Imaging. Front Nutr 2022; 9:858603. [PMID: 35433798 PMCID: PMC9007086 DOI: 10.3389/fnut.2022.858603] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Accepted: 02/15/2022] [Indexed: 12/12/2022] Open
Abstract
Changes in overall bile acid (BA) levels and specific BA metabolites are involved in metabolic diseases, gastrointestinal, and liver cancer. BAs have become established as important signaling molecules that enable fine-tuned inter-tissue communication within the enterohepatic circulation. The liver, BAs site of production, displayed physiological and functional zonal differences in the periportal zone versus the centrilobular zone. In addition, BA metabolism shows regional differences in the intestinal tract. However, there is no available method to detect the spatial distribution and molecular profiling of BAs within the enterohepatic circulation. Herein, we demonstrated the application in mass spectrometry imaging (MSI) with a high spatial resolution (3 μm) plus mass accuracy matrix-assisted laser desorption ionization (MALDI) to imaging BAs and N-1-naphthylphthalamic acid (NPA). Our results could clearly determine the zonation patterns and regional difference characteristics of BAs on mouse liver, ileum, and colon tissue sections, and the relative content of BAs based on NPA could also be ascertained. In conclusion, our method promoted the accessibility of spatial localization and quantitative study of BAs on gastrointestinal tissue sections and demonstrated that MALDI-MSI was a valuable tool to investigate and locate several BA molecules in different tissue types leading to a better understanding of the role of BAs behind the gastrointestinal diseases.
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Affiliation(s)
- Qi Zhang
- Health Sciences Institute, China Medical University, Shenyang, China.,Institute of Life Sciences, China Medical University, Shenyang, China
| | - Zhen-Hua Wu
- Health Sciences Institute, China Medical University, Shenyang, China.,Institute of Life Sciences, China Medical University, Shenyang, China.,Liaoning Key Laboratory of Obesity and Glucose/Lipid Associated Metabolic Diseases, China Medical University, Shenyang, China
| | - Shan-Shan Zhao
- Health Sciences Institute, China Medical University, Shenyang, China.,Institute of Life Sciences, China Medical University, Shenyang, China.,Liaoning Key Laboratory of Obesity and Glucose/Lipid Associated Metabolic Diseases, China Medical University, Shenyang, China
| | - Jing Yang
- Health Sciences Institute, China Medical University, Shenyang, China.,Institute of Life Sciences, China Medical University, Shenyang, China.,Liaoning Key Laboratory of Obesity and Glucose/Lipid Associated Metabolic Diseases, China Medical University, Shenyang, China
| | - Lei Chen
- Health Sciences Institute, China Medical University, Shenyang, China.,Institute of Life Sciences, China Medical University, Shenyang, China.,Liaoning Key Laboratory of Obesity and Glucose/Lipid Associated Metabolic Diseases, China Medical University, Shenyang, China
| | - Xiao-Yu Wang
- Health Sciences Institute, China Medical University, Shenyang, China.,Institute of Life Sciences, China Medical University, Shenyang, China.,Liaoning Key Laboratory of Obesity and Glucose/Lipid Associated Metabolic Diseases, China Medical University, Shenyang, China
| | - Zhan-You Wang
- Health Sciences Institute, China Medical University, Shenyang, China
| | - Hui-Xin Liu
- Health Sciences Institute, China Medical University, Shenyang, China.,Institute of Life Sciences, China Medical University, Shenyang, China.,Liaoning Key Laboratory of Obesity and Glucose/Lipid Associated Metabolic Diseases, China Medical University, Shenyang, China
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29
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Yeo E, Brubaker PL, Sloboda DM. The intestine and the microbiota in maternal glucose homeostasis during pregnancy. J Endocrinol 2022; 253:R1-R19. [PMID: 35099411 PMCID: PMC8942339 DOI: 10.1530/joe-21-0354] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Accepted: 01/31/2022] [Indexed: 11/23/2022]
Abstract
It is now well established that, beyond its role in nutrient processing and absorption, the intestine and its accompanying gut microbiome constitute a major site of immunological and endocrine regulation that mediates whole-body metabolism. Despite the growing field of host-microbe research, few studies explore what mechanisms govern this relationship in the context of pregnancy. During pregnancy, significant maternal metabolic adaptations are made to accommodate the additional energy demands of the developing fetus and to prevent adverse pregnancy outcomes. Recent data suggest that the maternal gut microbiota may play a role in these adaptations, but changes to maternal gut physiology and the underlying intestinal mechanisms remain unclear. In this review, we discuss selective aspects of intestinal physiology including the role of the incretin hormone, glucagon-like peptide 1 (GLP-1), and the role of the maternal gut microbiome in the maternal metabolic adaptations to pregnancy. Specifically, we discuss how bacterial components and metabolites could mediate the effects of the microbiota on host physiology, including nutrient absorption and GLP-1 secretion and action, and whether these mechanisms may change maternal insulin sensitivity and secretion during pregnancy. Finally, we discuss how these pathways could be altered in disease states during pregnancy including maternal obesity and diabetes.
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Affiliation(s)
- Erica Yeo
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada
| | - Patricia L Brubaker
- Department of Physiology, University of Toronto, Toronto, ON, Canada
- Department of Medicine, University of Toronto, Toronto, ON, Canada
| | - Deborah M Sloboda
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada
- Department of Obstetrics, Gynecology and Pediatrics, McMaster University, Hamilton, ON, Canada
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30
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Jena PK, Setayesh T, Sheng L, Di Lucente J, Jin LW, Wan YJY. Intestinal Microbiota Remodeling Protects Mice from Western Diet-Induced Brain Inflammation and Cognitive Decline. Cells 2022; 11:cells11030504. [PMID: 35159313 PMCID: PMC8834507 DOI: 10.3390/cells11030504] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 01/25/2022] [Accepted: 01/29/2022] [Indexed: 01/27/2023] Open
Abstract
It has been shown that the Western diet (WD) induces systemic inflammation and cognitive decline. Moreover, probiotic supplementation and antibiotic treatment reduce diet-induced hepatic inflammation. The current study examines whether shaping the gut microbes by Bifidobacterium infantis (B. infantis) supplementation and antibiotic treatment reduce diet-induced brain inflammation and improve neuroplasticity. Furthermore, the significance of bile acid (BA) signaling in regulating brain inflammation was studied. Mice were fed a control diet (CD) or WD for seven months. B. infantis was supplemented to WD-fed mice to study brain inflammation, lipid, metabolomes, and neuroplasticity measured by long-term potentiation (LTP). Broad-spectrum coverage antibiotics and cholestyramine treatments were performed to study the impact of WD-associated gut microbes and BA in brain inflammation. Probiotic B. infantis supplementation inhibited diet-induced brain inflammation by reducing IL6, TNFα, and CD11b levels. B. infantis improved LTP and increased brain PSD95 and BDNF levels, which were reduced due to WD intake. Additionally, B. infantis reduced cecal cholesterol, brain ceramide and enhanced saturated fatty acids. Moreover, antibiotic treatment, as well as cholestyramine, diminished WD-induced brain inflammatory signaling. Our findings support the theory that intestinal microbiota remodeling by B. infantis reduces brain inflammation, activates BA receptor signaling, and improves neuroplasticity.
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Affiliation(s)
- Prasant Kumar Jena
- Department of Medical Pathology and Laboratory Medicine, University of California, Davis, Sacramento, CA 95817, USA; (P.K.J.); (T.S.); (L.S.); (J.D.L.); (L.W.J.)
- Department of Pediatrics, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Tahereh Setayesh
- Department of Medical Pathology and Laboratory Medicine, University of California, Davis, Sacramento, CA 95817, USA; (P.K.J.); (T.S.); (L.S.); (J.D.L.); (L.W.J.)
| | - Lili Sheng
- Department of Medical Pathology and Laboratory Medicine, University of California, Davis, Sacramento, CA 95817, USA; (P.K.J.); (T.S.); (L.S.); (J.D.L.); (L.W.J.)
| | - Jacopo Di Lucente
- Department of Medical Pathology and Laboratory Medicine, University of California, Davis, Sacramento, CA 95817, USA; (P.K.J.); (T.S.); (L.S.); (J.D.L.); (L.W.J.)
| | - Lee Way Jin
- Department of Medical Pathology and Laboratory Medicine, University of California, Davis, Sacramento, CA 95817, USA; (P.K.J.); (T.S.); (L.S.); (J.D.L.); (L.W.J.)
| | - Yu-Jui Yvonne Wan
- Department of Medical Pathology and Laboratory Medicine, University of California, Davis, Sacramento, CA 95817, USA; (P.K.J.); (T.S.); (L.S.); (J.D.L.); (L.W.J.)
- Correspondence: ; Tel.: +1-916-734-4293; Fax: +1-916-734-3787
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31
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Little M, Dutta M, Li H, Matson A, Shi X, Mascarinas G, Molla B, Weigel K, Gu H, Mani S, Cui JY. Understanding the physiological functions of the host xenobiotic-sensing nuclear receptors PXR and CAR on the gut microbiome using genetically modified mice. Acta Pharm Sin B 2022; 12:801-820. [PMID: 35256948 PMCID: PMC8897037 DOI: 10.1016/j.apsb.2021.07.022] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 05/29/2021] [Accepted: 07/09/2021] [Indexed: 12/12/2022] Open
Abstract
Pharmacological activation of the xenobiotic-sensing nuclear receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR) is well-known to increase drug metabolism and reduce inflammation. Little is known regarding their physiological functions on the gut microbiome. In this study, we discovered bivalent hormetic functions of PXR/CAR modulating the richness of the gut microbiome using genetically engineered mice. The absence of PXR or CAR increased microbial richness, and absence of both receptors synergistically increased microbial richness. PXR and CAR deficiency increased the pro-inflammatory bacteria Helicobacteraceae and Helicobacter. Deficiency in both PXR and CAR increased the relative abundance of Lactobacillus, which has bile salt hydrolase activity, corresponding to decreased primary taurine-conjugated bile acids (BAs) in feces, which may lead to higher internal burden of taurine and unconjugated BAs, both of which are linked to inflammation, oxidative stress, and cytotoxicity. The basal effect of PXR/CAR on the gut microbiome was distinct from pharmacological and toxicological activation of these receptors. Common PXR/CAR-targeted bacteria were identified, the majority of which were suppressed by these receptors. hPXR-TG mice had a distinct microbial profile as compared to wild-type mice. This study is the first to unveil the basal functions of PXR and CAR on the gut microbiome.
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Key Words
- BA, bile acid
- BSH, bile salt hydrolase
- Bile acids
- CA, cholic acid
- CAR
- CAR, constitutive androstane receptor
- CDCA, chenodeoxycholic acid
- CITCO, 6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime
- CV, conventional
- CYP, cytochrome P450
- DCA, deoxycholic acid
- EGF, epidermal growth factor
- Feces
- GF, germ free
- GLP-1, glucagon-like peptide-1
- GM-CSF, granulocyte-macrophage colony-stimulating factor
- Gut microbiome
- HDCA, hyodeoxycholic acid
- IBD, inflammatory bowel disease
- IFNγ, interferon-gamma
- IL, interleukin
- IS, internal standards
- Inflammation
- LCA, lithocholic acid
- LC–MS/MS, liquid chromatography–tandem mass spectrometry
- MCA, muricholic acid
- MCP-1, monocyte chemoattractant protein-1
- Mice
- NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells
- NSAID, non-steroidal anti-inflammatory drug
- Nuclear receptor
- OH, hydroxylated
- OTUs, operational taxonomy units
- PA, indole-3 propionic acid
- PBDEs, polybrominated diphenyl ethers
- PCBs, polychlorinated biphenyls
- PCoA, Principle Coordinate Analysis
- PXR
- PXR, pregnane X receptor
- PiCRUSt, Phylogenetic Investigation of Communities by Reconstruction of Observed States
- QIIME, Quantitative Insights Into Microbial Ecology
- SCFAs, short-chain fatty acids
- SNP, single-nucleotide polymorphism
- SPF, specific-pathogen-free
- T, wild type
- T-, taurine conjugated
- TCPOBOP, 1,4-bis-[2-(3,5-dichloropyridyloxy)]benzene, 3,3′,5,5′-Tetrachloro-1,4-bis(pyridyloxy)benzene
- TGR-5, Takeda G-protein-coupled receptor 5
- TLR4, toll-like receptor 4
- TNF, tumor necrosis factor
- UDCA, ursodeoxycholic acid
- YAP, yes-associated protein
- hPXR-TG, humanized PXR transgenic
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Affiliation(s)
- Mallory Little
- Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98105, USA
| | - Moumita Dutta
- Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98105, USA
| | - Hao Li
- Department of Medicine, Molecular Pharmacology and Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Adam Matson
- University of Connecticut, Hartford, CT 06106, USA
| | - Xiaojian Shi
- Arizona Metabolomics Laboratory, College of Health Solutions, Arizona State University, Phoenix, AZ 85004, USA
| | - Gabby Mascarinas
- Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98105, USA
| | - Bruk Molla
- Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98105, USA
| | - Kris Weigel
- Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98105, USA
| | - Haiwei Gu
- Arizona Metabolomics Laboratory, College of Health Solutions, Arizona State University, Phoenix, AZ 85004, USA
| | - Sridhar Mani
- Department of Medicine, Molecular Pharmacology and Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Julia Yue Cui
- Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98105, USA
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Simas AM, Kramer CD, Genco CA. Diet-Induced Non-alcoholic Fatty Liver Disease and Associated Gut Dysbiosis Are Exacerbated by Oral Infection. FRONTIERS IN ORAL HEALTH 2022; 2:784448. [PMID: 35141703 PMCID: PMC8820505 DOI: 10.3389/froh.2021.784448] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 12/29/2021] [Indexed: 11/13/2022] Open
Abstract
Increasing evidence indicates that chronic inflammation due to periodontal disease is associated with progression of non-alcoholic fatty liver disease (NAFLD) caused by a Western diet. NAFLD has also been associated with oral infection with the etiological agent of periodontal disease, Porphyromonas gingivalis. P. gingivalis oral infection has been shown to induce cardiometabolic disease features including hepatic lipid accumulation while also leading to dysbiosis of the gut microbiome. However, the impact of P. gingivalis infection on the gut microbiota of mice with diet-induced NAFLD and the potential for those changes to mediate NAFLD progression has yet to be determined. In the current study, we have demonstrated that P. gingivalis infection induced sustained alterations of the gut microbiota composition and predicted functions, which was associated with the promotion of NAFLD in steatotic mice. Reduced abundance of short-chain fatty acid-producing microbiota was observed after both acute and chronic P. gingivalis infection. Collectively, our findings demonstrate that P. gingivalis infection produces a persistent change in the gut microbiota composition and predicted functions that promotes steatosis and metabolic disease.
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Affiliation(s)
- Alexandra M. Simas
- Gerald J. and Dorothy R. Friedman School of Nutrition and Science Policy, Graduate Program in Biochemical and Molecular Nutrition, Tufts University, Boston, MA, United States
- Department of Immunology, Tufts University School of Medicine, Boston, MA, United States
| | - Carolyn D. Kramer
- Department of Immunology, Tufts University School of Medicine, Boston, MA, United States
| | - Caroline A. Genco
- Department of Immunology, Tufts University School of Medicine, Boston, MA, United States
- Graduate Program in Immunology, Graduate School of Biomedical Sciences, Tufts University, Boston, MA, United States
- Graduate Program in Molecular Microbiology, Graduate School of Biomedical Sciences, Tufts University, Boston, MA, United States
- *Correspondence: Caroline A. Genco
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Swaminathan G, Citron M, Xiao J, Norton JE, Reens AL, Topçuoğlu BD, Maritz JM, Lee KJ, Freed DC, Weber TM, White CH, Kadam M, Spofford E, Bryant-Hall E, Salituro G, Kommineni S, Liang X, Danilchanka O, Fontenot JA, Woelk CH, Gutierrez DA, Hazuda DJ, Hannigan GD. Vaccine Hyporesponse Induced by Individual Antibiotic Treatment in Mice and Non-Human Primates Is Diminished upon Recovery of the Gut Microbiome. Vaccines (Basel) 2021; 9:vaccines9111340. [PMID: 34835271 PMCID: PMC8619314 DOI: 10.3390/vaccines9111340] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 10/19/2021] [Accepted: 10/29/2021] [Indexed: 11/16/2022] Open
Abstract
Emerging evidence demonstrates a connection between microbiome composition and suboptimal response to vaccines (vaccine hyporesponse). Harnessing the interaction between microbes and the immune system could provide novel therapeutic strategies for improving vaccine response. Currently we do not fully understand the mechanisms and dynamics by which the microbiome influences vaccine response. Using both mouse and non-human primate models, we report that short-term oral treatment with a single antibiotic (vancomycin) results in the disruption of the gut microbiome and this correlates with a decrease in systemic levels of antigen-specific IgG upon subsequent parenteral vaccination. We further show that recovery of microbial diversity before vaccination prevents antibiotic-induced vaccine hyporesponse, and that the antigen specific IgG response correlates with the recovery of microbiome diversity. RNA sequencing analysis of small intestine, spleen, whole blood, and secondary lymphoid organs from antibiotic treated mice revealed a dramatic impact on the immune system, and a muted inflammatory signature is correlated with loss of bacteria from Lachnospiraceae, Ruminococcaceae, and Clostridiaceae. These results suggest that microbially modulated immune pathways may be leveraged to promote vaccine response and will inform future vaccine design and development strategies.
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Affiliation(s)
- Gokul Swaminathan
- Exploratory Science Center, Merck & Co., Inc., Cambridge, MA 02141, USA; (J.E.N.J.); (A.L.R.); (B.D.T.); (J.M.M.); (C.H.W.); (M.K.); (S.K.); (X.L.); (O.D.); (C.H.W.); (D.A.G.); (D.J.H.)
- Correspondence: (G.S.); (G.D.H.)
| | - Michael Citron
- Infectious Diseases and Vaccine Research, MRL, Merck & Co., Inc., West Point, PA 19486, USA; (M.C.); (J.X.); (D.C.F.); (T.M.W.)
| | - Jianying Xiao
- Infectious Diseases and Vaccine Research, MRL, Merck & Co., Inc., West Point, PA 19486, USA; (M.C.); (J.X.); (D.C.F.); (T.M.W.)
| | - James E. Norton
- Exploratory Science Center, Merck & Co., Inc., Cambridge, MA 02141, USA; (J.E.N.J.); (A.L.R.); (B.D.T.); (J.M.M.); (C.H.W.); (M.K.); (S.K.); (X.L.); (O.D.); (C.H.W.); (D.A.G.); (D.J.H.)
| | - Abigail L. Reens
- Exploratory Science Center, Merck & Co., Inc., Cambridge, MA 02141, USA; (J.E.N.J.); (A.L.R.); (B.D.T.); (J.M.M.); (C.H.W.); (M.K.); (S.K.); (X.L.); (O.D.); (C.H.W.); (D.A.G.); (D.J.H.)
| | - Begüm D. Topçuoğlu
- Exploratory Science Center, Merck & Co., Inc., Cambridge, MA 02141, USA; (J.E.N.J.); (A.L.R.); (B.D.T.); (J.M.M.); (C.H.W.); (M.K.); (S.K.); (X.L.); (O.D.); (C.H.W.); (D.A.G.); (D.J.H.)
| | - Julia M. Maritz
- Exploratory Science Center, Merck & Co., Inc., Cambridge, MA 02141, USA; (J.E.N.J.); (A.L.R.); (B.D.T.); (J.M.M.); (C.H.W.); (M.K.); (S.K.); (X.L.); (O.D.); (C.H.W.); (D.A.G.); (D.J.H.)
| | - Keun-Joong Lee
- Pharmacokinetics, Pharmacodynamics & Drug Metabolism, MRL, Merck & Co. Inc., Rahway, NJ 07065, USA; (K.-J.L.); (G.S.)
| | - Daniel C. Freed
- Infectious Diseases and Vaccine Research, MRL, Merck & Co., Inc., West Point, PA 19486, USA; (M.C.); (J.X.); (D.C.F.); (T.M.W.)
| | - Teresa M. Weber
- Infectious Diseases and Vaccine Research, MRL, Merck & Co., Inc., West Point, PA 19486, USA; (M.C.); (J.X.); (D.C.F.); (T.M.W.)
| | - Cory H. White
- Exploratory Science Center, Merck & Co., Inc., Cambridge, MA 02141, USA; (J.E.N.J.); (A.L.R.); (B.D.T.); (J.M.M.); (C.H.W.); (M.K.); (S.K.); (X.L.); (O.D.); (C.H.W.); (D.A.G.); (D.J.H.)
| | - Mahika Kadam
- Exploratory Science Center, Merck & Co., Inc., Cambridge, MA 02141, USA; (J.E.N.J.); (A.L.R.); (B.D.T.); (J.M.M.); (C.H.W.); (M.K.); (S.K.); (X.L.); (O.D.); (C.H.W.); (D.A.G.); (D.J.H.)
| | - Erin Spofford
- Safety Assessment and Laboratory Animal Research, MRL, Merck & Co. Inc., Boston, MA 02115, USA; (E.S.); (E.B.-H.)
| | - Erin Bryant-Hall
- Safety Assessment and Laboratory Animal Research, MRL, Merck & Co. Inc., Boston, MA 02115, USA; (E.S.); (E.B.-H.)
| | - Gino Salituro
- Pharmacokinetics, Pharmacodynamics & Drug Metabolism, MRL, Merck & Co. Inc., Rahway, NJ 07065, USA; (K.-J.L.); (G.S.)
| | - Sushma Kommineni
- Exploratory Science Center, Merck & Co., Inc., Cambridge, MA 02141, USA; (J.E.N.J.); (A.L.R.); (B.D.T.); (J.M.M.); (C.H.W.); (M.K.); (S.K.); (X.L.); (O.D.); (C.H.W.); (D.A.G.); (D.J.H.)
| | - Xue Liang
- Exploratory Science Center, Merck & Co., Inc., Cambridge, MA 02141, USA; (J.E.N.J.); (A.L.R.); (B.D.T.); (J.M.M.); (C.H.W.); (M.K.); (S.K.); (X.L.); (O.D.); (C.H.W.); (D.A.G.); (D.J.H.)
| | - Olga Danilchanka
- Exploratory Science Center, Merck & Co., Inc., Cambridge, MA 02141, USA; (J.E.N.J.); (A.L.R.); (B.D.T.); (J.M.M.); (C.H.W.); (M.K.); (S.K.); (X.L.); (O.D.); (C.H.W.); (D.A.G.); (D.J.H.)
| | - Jane A. Fontenot
- New Iberia Research Center, University of Louisiana at Lafayette, Lafayette, LA 70503, USA;
| | - Christopher H. Woelk
- Exploratory Science Center, Merck & Co., Inc., Cambridge, MA 02141, USA; (J.E.N.J.); (A.L.R.); (B.D.T.); (J.M.M.); (C.H.W.); (M.K.); (S.K.); (X.L.); (O.D.); (C.H.W.); (D.A.G.); (D.J.H.)
| | - Dario A. Gutierrez
- Exploratory Science Center, Merck & Co., Inc., Cambridge, MA 02141, USA; (J.E.N.J.); (A.L.R.); (B.D.T.); (J.M.M.); (C.H.W.); (M.K.); (S.K.); (X.L.); (O.D.); (C.H.W.); (D.A.G.); (D.J.H.)
| | - Daria J. Hazuda
- Exploratory Science Center, Merck & Co., Inc., Cambridge, MA 02141, USA; (J.E.N.J.); (A.L.R.); (B.D.T.); (J.M.M.); (C.H.W.); (M.K.); (S.K.); (X.L.); (O.D.); (C.H.W.); (D.A.G.); (D.J.H.)
- Infectious Diseases and Vaccine Research, MRL, Merck & Co., Inc., West Point, PA 19486, USA; (M.C.); (J.X.); (D.C.F.); (T.M.W.)
| | - Geoffrey D. Hannigan
- Exploratory Science Center, Merck & Co., Inc., Cambridge, MA 02141, USA; (J.E.N.J.); (A.L.R.); (B.D.T.); (J.M.M.); (C.H.W.); (M.K.); (S.K.); (X.L.); (O.D.); (C.H.W.); (D.A.G.); (D.J.H.)
- Correspondence: (G.S.); (G.D.H.)
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Lefebvre P, Staels B. Hepatic sexual dimorphism - implications for non-alcoholic fatty liver disease. Nat Rev Endocrinol 2021; 17:662-670. [PMID: 34417588 DOI: 10.1038/s41574-021-00538-6] [Citation(s) in RCA: 63] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/06/2021] [Indexed: 12/14/2022]
Abstract
The liver is often thought of as a single functional unit, but both its structural and functional architecture make it highly multivalent and adaptable. In any given physiological situation, the liver can maintain metabolic homeostasis, conduct appropriate inflammatory responses, carry out endobiotic and xenobiotic transformation and synthesis reactions, as well as store and release multiple bioactive molecules. Moreover, the liver is a very resilient organ. This resilience means that chronic liver diseases can go unnoticed for decades, yet culminate in life-threatening clinical complications once the adaptive capacity of the liver is overwhelmed. Non-alcoholic fatty liver disease (NAFLD) predisposes individuals to cirrhosis and increases liver-related and cardiovascular disease-related mortality. This Review discusses the accumulating evidence of sexual dimorphism in NAFLD, which is currently rarely considered in preclinical and clinical studies. Increased awareness of the mechanistic causes of hepatic sexual dimorphism could lead to improved understanding of the biological processes that are dysregulated in NAFLD, to the identification of relevant therapeutic targets and to improved risk stratification of patients with NAFLD undergoing therapeutic intervention.
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Affiliation(s)
- Philippe Lefebvre
- Université Lille, INSERM, CHU Lille, Institut Pasteur de Lille, Lille, France.
| | - Bart Staels
- Université Lille, INSERM, CHU Lille, Institut Pasteur de Lille, Lille, France
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Kuraji R, Sekino S, Kapila Y, Numabe Y. Periodontal disease-related nonalcoholic fatty liver disease and nonalcoholic steatohepatitis: An emerging concept of oral-liver axis. Periodontol 2000 2021; 87:204-240. [PMID: 34463983 PMCID: PMC8456799 DOI: 10.1111/prd.12387] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Periodontal disease, a chronic inflammatory disease of the periodontal tissues, is not only a major cause of tooth loss, but it is also known to exacerbate/be associated with various metabolic disorders, such as obesity, diabetes, dyslipidemia, and cardiovascular disease. Recently, growing evidence has suggested that periodontal disease has adverse effects on the pathophysiology of liver disease. In particular, nonalcoholic fatty liver disease, a hepatic manifestation of metabolic syndrome, has been associated with periodontal disease. Nonalcoholic fatty liver disease is characterized by hepatic fat deposition in the absence of a habitual drinking history, viral infections, or autoimmune diseases. A subset of nonalcoholic fatty liver diseases can develop into more severe and progressive forms, namely nonalcoholic steatohepatitis. The latter can lead to cirrhosis and hepatocellular carcinoma, which are end‐stage liver diseases. Extensive research has provided plausible mechanisms to explain how periodontal disease can negatively affect nonalcoholic fatty liver disease and nonalcoholic steatohepatitis, namely via hematogenous or enteral routes. During periodontitis, the liver is under constant exposure to various pathogenic factors that diffuse systemically from the oral cavity, such as bacteria and their by‐products, inflammatory cytokines, and reactive oxygen species, and these can be involved in disease promotion of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Also, gut microbiome dysbiosis induced by enteral translocation of periodontopathic bacteria may impair gut wall barrier function and promote the transfer of hepatotoxins and enterobacteria to the liver through the enterohepatic circulation. Moreover, in a population with metabolic syndrome, the interaction between periodontitis and systemic conditions related to insulin resistance further strengthens the association with nonalcoholic fatty liver disease. However, most of the pathologic links between periodontitis and nonalcoholic fatty liver disease in humans are provided by epidemiologic observational studies, with the causal relationship not yet being established. Several systematic and meta‐analysis studies also show conflicting results. In addition, the effect of periodontal treatment on nonalcoholic fatty liver disease has hardly been studied. Despite these limitations, the global burden of periodontal disease combined with the recent nonalcoholic fatty liver disease epidemic has important clinical and public health implications. Emerging evidence suggests an association between periodontal disease and liver diseases, and thus we propose the term periodontal disease–related nonalcoholic fatty liver disease or periodontal disease–related nonalcoholic steatohepatitis. Continued efforts in this area will pave the way for new diagnostic and therapeutic approaches based on a periodontologic viewpoint to address this life‐threatening liver disease.
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Affiliation(s)
- Ryutaro Kuraji
- Department of Life Science Dentistry, The Nippon Dental University, Tokyo, Japan.,Department of Periodontology, The Nippon Dental University School of Life Dentistry at Tokyo, Tokyo, Japan.,Department of Orofacial Sciences, University of California San Francisco School of Dentistry, San Francisco, California, USA
| | - Satoshi Sekino
- Department of Periodontology, The Nippon Dental University School of Life Dentistry at Tokyo, Tokyo, Japan
| | - Yvonne Kapila
- Department of Orofacial Sciences, University of California San Francisco School of Dentistry, San Francisco, California, USA
| | - Yukihiro Numabe
- Department of Periodontology, The Nippon Dental University School of Life Dentistry at Tokyo, Tokyo, Japan
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Hyun CK. Molecular and Pathophysiological Links between Metabolic Disorders and Inflammatory Bowel Diseases. Int J Mol Sci 2021; 22:ijms22179139. [PMID: 34502047 PMCID: PMC8430512 DOI: 10.3390/ijms22179139] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Revised: 08/21/2021] [Accepted: 08/22/2021] [Indexed: 02/07/2023] Open
Abstract
Despite considerable epidemiological evidence indicating comorbidity between metabolic disorders, such as obesity, type 2 diabetes, and non-alcoholic fatty liver disease, and inflammatory bowel diseases (IBD), such as Crohn’s disease and ulcerative colitis, as well as common pathophysiological features shared by these two categories of diseases, the relationship between their pathogenesis at molecular levels are not well described. Intestinal barrier dysfunction is a characteristic pathological feature of IBD, which also plays causal roles in the pathogenesis of chronic inflammatory metabolic disorders. Increased intestinal permeability is associated with a pro-inflammatory response of the intestinal immune system, possibly leading to the development of both diseases. In addition, dysregulated interactions between the gut microbiota and the host immunity have been found to contribute to immune-mediated disorders including the two diseases. In connection with disrupted gut microbial composition, alterations in gut microbiota-derived metabolites have also been shown to be closely related to the pathogeneses of both diseases. Focusing on these prominent pathophysiological features observed in both metabolic disorders and IBD, this review highlights and summarizes the molecular risk factors that may link between the pathogeneses of the two diseases, which is aimed at providing a comprehensive understanding of molecular mechanisms underlying their comorbidity.
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Affiliation(s)
- Chang-Kee Hyun
- School of Life Science, Handong Global University, Pohang 37554, Gyungbuk, Korea
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Guo Q, Tang Y, Li Y, Xu Z, Zhang D, Liu J, Wang X, Xia W, Xu S. Perinatal High-Salt Diet Induces Gut Microbiota Dysbiosis, Bile Acid Homeostasis Disbalance, and NAFLD in Weanling Mice Offspring. Nutrients 2021; 13:nu13072135. [PMID: 34206629 PMCID: PMC8308454 DOI: 10.3390/nu13072135] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 06/13/2021] [Accepted: 06/16/2021] [Indexed: 01/14/2023] Open
Abstract
A perinatal high-salt (HS) diet was reported to elevate plasma triglycerides. This study aimed to investigate the hypothesis that a perinatal HS diet predisposed offspring to non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of abnormal lipid metabolism, and the possible mechanism. Female C57BL/6 mice were fed a control diet (0.5% NaCl) or HS diet (4% NaCl) during pregnancy and lactation and their offspring were sacrificed at weaning. The perinatal HS diet induced greater variation in fecal microbial beta-diversity (β-diversity) and increased bacteria abundance of Proteobacteria and Bacteroides. The gut microbiota dysbiosis promoted bile acid homeostasis disbalance, characterized by the accumulation of lithocholic acid (LCA) and deoxycholic acid (DCA) in feces. These alterations disturbed gut barrier by increasing the expression of tight junction protein (Tjp) and occludin (Ocln), and increased systemic lipopolysaccharide (LPS) levels and hepatic inflammatory cytokine secretion (TNF-α and IL-6) in the liver. The perinatal HS diet also inhibited hepatic expression of hepatic FXR signaling (CYP7A1 and FXR), thus triggering increased hepatic expression of pro-inflammatory cytokines (TNF-α and IL-6) and hepatic lipid metabolism-associated genes (SREBP-1c, FAS, ACC), leading to unique characteristics of NAFLD. In conclusion, a perinatal HS diet induced NAFLD in weanling mice offspring; the possible mechanism was related to increased bacteria abundance of Proteobacteria and Bacteroides, increased levels of LCA and DCA in feces, and increased expressions of hepatic FXR signaling.
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Affiliation(s)
| | | | | | | | | | | | | | - Wei Xia
- Correspondence: ; Tel.: +86-27-83693417
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Rajeev R, Seethalakshmi PS, Jena PK, Prathiviraj R, Kiran GS, Selvin J. Gut microbiome responses in the metabolism of human dietary components: Implications in health and homeostasis. Crit Rev Food Sci Nutr 2021; 62:7615-7631. [PMID: 34016000 DOI: 10.1080/10408398.2021.1916429] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The gut microbiome and its link with human health and disease have gained a lot of attention recently. The microbiome executes its functions in the host by carrying out the transformation of dietary components and/or de novo synthesis of various essential nutrients. The presence of complex microbial communities makes it difficult to understand the host-microbiome interplay in the metabolism of dietary components. This review attempts to uncover the incredible role of the gut microbiome in the metabolism of dietary components, diet-microbiome interplay, and restoration of the microbiome. The in silico analysis performed in this study elucidates the functional description of essential/hub genes involved in the amino acid degradation pathway, which are mutually present in the host and its gut microbiome. Hence, the computational model helps comprehend the inter-and intracellular molecular networks between humans and their microbial partners.
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Affiliation(s)
- Riya Rajeev
- Department of Microbiology, Pondicherry University, Puducherry, India
| | - P S Seethalakshmi
- Department of Microbiology, Pondicherry University, Puducherry, India
| | - Prasant Kumar Jena
- Immunology and infectious disease research, Department of Pediatrics, Cedars Sinai Medical Center, Los Angeles, California, USA
| | - R Prathiviraj
- Department of Microbiology, Pondicherry University, Puducherry, India
| | - George Seghal Kiran
- Department of Food Science and Technology, Pondicherry University, Puducherry, India
| | - Joseph Selvin
- Department of Microbiology, Pondicherry University, Puducherry, India
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Oral Microbiota of Children Is Conserved across Han, Tibetan and Hui Groups and Is Correlated with Diet and Gut Microbiota. Microorganisms 2021; 9:microorganisms9051030. [PMID: 34064692 PMCID: PMC8151815 DOI: 10.3390/microorganisms9051030] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 05/05/2021] [Accepted: 05/06/2021] [Indexed: 01/12/2023] Open
Abstract
The oral microbiota can be affected by several factors; however, little is known about the relationship between diet, ethnicity and commensal oral microbiota among school children living in close geographic proximity. In addition, the relationship between the oral and gut microbiota remains unclear. We collected saliva from 60 school children from the Tibetan, Han and Hui ethnicities for a 16S rRNA gene sequencing analysis and comparison with previously collected fecal samples. The study revealed that Bacteroidetes and Proteobacteria were the dominant phyla in the oral microbiota. The Shannon diversity was lowest in the Tibetan group. A PCA showed a substantial overlap in the distribution of the taxa, indicating a high degree of conservation among the oral microbiota across ethnic groups while the enrichment of a few specific taxa was observed across different ethnic groups. The consumption of seafood, poultry, sweets and vegetables was significantly correlated with multiple oral microbiotas. Furthermore, 123 oral genera were significantly associated with 191 gut genera. A principal coordinate analysis revealed that the oral microbiota clustered separately from the gut microbiota. This work extends the findings of previous studies comparing microbiota from human populations and provides a basis for the exploration of the interactions governing the tri-partite relationship between diet, oral microbiota and gut microbiota.
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Yang L, Li Y, Wang S, Bian X, Jiang X, Wu J, Wang K, Wang Q, Xia J, Jiang S, Zhuge A, Yuan Y, Li S, Li L. Western Diet Aggravated Carbon Tetrachloride-Induced Chronic Liver Injury by Disturbing Gut Microbiota and Bile Acid Metabolism. Mol Nutr Food Res 2021; 65:e2000811. [PMID: 33458949 DOI: 10.1002/mnfr.202000811] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2020] [Revised: 11/17/2020] [Indexed: 12/13/2022]
Abstract
SCOPE The high-fat, high-sucrose, and low-fiber Western diet (WD) is popular in many countries and affects the onset and progression of many diseases. This study is aimed to explore the influence of the WD on chronic liver disease (CLD) and its possible mechanism. METHODS AND RESULTS C57BL/6 mice are given a control diet (CD) or WD and CLD is induced by intraperitoneally injecting carbon tetrachloride (CCL4 ) twice a week for 8 weeks. The WD aggravated CCL4 -induced chronic liver injury, as evidenced by increased serum transaminase levels, worsened hepatic inflammatory response, and fibrosis. Gut microbiota is disturbed in mice treated with CCL4 +WD (WC group), manifested as the accumulation of Fusobacteria, Streptococcaceae, Streptococcus, Fusobacterium, and Prevotella and the depletion of Firmicutes, Lachnospiraceae, and Roseburia. Additionally, increased hepatic taurocholic acid in the WC group activated sphingosine-1-phosphate receptor 2, which is positively correlated with hepatic fibrosis and inflammation parameters. Mice in the WC group have higher fecal primary bile acid (BA) levels and lower fecal secondary/primary BA ratios. Serum FGF15 levels are also elevated in the WC group, which is positively correlated with hepatic inflammation. CONCLUSION WD accelerates the progression of CLD which is associated with changes in the gut microbiota and BA metabolism.
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Affiliation(s)
- Liya Yang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, P. R. China
| | - Yating Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, P. R. China
| | - Shuting Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, P. R. China
| | - Xiaoyuan Bian
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, P. R. China
| | - Xianwan Jiang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, P. R. China
| | - Jingjing Wu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, P. R. China
| | - Kaicen Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, P. R. China
| | - Qiangqiang Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, P. R. China
| | - Jiafeng Xia
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, P. R. China
| | - Shiman Jiang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, P. R. China
| | - Aoxiang Zhuge
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, P. R. China
| | - Yin Yuan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, P. R. China
| | - Shenjie Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, P. R. China
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, P. R. China
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Xu J, Xu HM, Peng Y, Zhao C, Zhao HL, Huang W, Huang HL, He J, Du YL, Zhou YJ, Zhou YL, Nie YQ. The effect of different combinations of antibiotic cocktails on mice and selection of animal models for further microbiota research. Appl Microbiol Biotechnol 2021; 105:1669-1681. [PMID: 33511441 DOI: 10.1007/s00253-021-11131-2] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Revised: 01/01/2021] [Accepted: 01/20/2021] [Indexed: 12/20/2022]
Abstract
The gut microbiota is closely related to host health and disease. However, there are no suitable animal models available at present for exploring its functions. We analyzed the effect of 3 different antibiotic cocktails (ABx) via two administration routes on the composition of murine gut microbiota, as well as on the general physiological and metabolic indices. High-throughput 16S rRNA sequencing showed that ABx treatment altered the gut microbiota community structure, and also caused low-degree inflammation in the colon. In addition, ad libitum administration of antibiotics depleted the gut microbiota more effectively compared to direct oral gavage, especially with 3ABx. The ABx treatment also had a significant impact on renal and liver functions, as indicated by the altered serum levels of creatinine, urea, total triglycerides, and total cholesterol. Finally, Spearman's correlation analysis showed that the predominant bacterial genera resulting from ABx intervention, including Lactobacillus, Roseburia, and Candidatus-Saccharimonas, were negatively correlated with renal function indices. Taken together, different antibiotic combinations and interventions deplete the gut microbiota and induce physiological changes in the host. Our findings provide the basis for developing an adaptive animal model for studying gut microbiota. KEY POINTS: • Ad libitum administration of 3ABx can effectively deplete intestinal microbiota. • ABx treatment may have slight effect on renal and liver function. • The levels of urea and creatinine correlated with the growth of Roseburia.
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Affiliation(s)
- Jing Xu
- Department of Gastroenterology and Hepatology, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, No. 1 Panfu Road, Guangzhou, 510180, Guangdong, China
| | - Hao-Ming Xu
- Department of Gastroenterology and Hepatology, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, No. 1 Panfu Road, Guangzhou, 510180, Guangdong, China
| | - Yao Peng
- Department of Gastroenterology and Hepatology, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, No. 1 Panfu Road, Guangzhou, 510180, Guangdong, China
| | - Chong Zhao
- Department of Gastroenterology and Hepatology, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, No. 1 Panfu Road, Guangzhou, 510180, Guangdong, China
| | - Hai-Lan Zhao
- Department of Gastroenterology and Hepatology, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, No. 1 Panfu Road, Guangzhou, 510180, Guangdong, China
| | - Wenqi Huang
- Department of Gastroenterology and Hepatology, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, No. 1 Panfu Road, Guangzhou, 510180, Guangdong, China
| | - Hong-Li Huang
- Department of Gastroenterology and Hepatology, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, No. 1 Panfu Road, Guangzhou, 510180, Guangdong, China
| | - Jie He
- Department of Gastroenterology and Hepatology, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, No. 1 Panfu Road, Guangzhou, 510180, Guangdong, China
| | - Yan-Lei Du
- Department of Gastroenterology and Hepatology, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, No. 1 Panfu Road, Guangzhou, 510180, Guangdong, China
| | - Yong-Jian Zhou
- Department of Gastroenterology and Hepatology, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, No. 1 Panfu Road, Guangzhou, 510180, Guangdong, China
| | - You-Lian Zhou
- Department of Gastroenterology and Hepatology, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, No. 1 Panfu Road, Guangzhou, 510180, Guangdong, China.
| | - Yu-Qiang Nie
- Department of Gastroenterology and Hepatology, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, No. 1 Panfu Road, Guangzhou, 510180, Guangdong, China.
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Sheng L, Jena PK, Hu Y, Wan YJY. Age-specific microbiota in altering host inflammatory and metabolic signaling as well as metabolome based on the sex. Hepatobiliary Surg Nutr 2021; 10:31-48. [PMID: 33575288 DOI: 10.21037/hbsn-20-671] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Accepted: 11/25/2020] [Indexed: 12/19/2022]
Abstract
Background Metabolism is sex-different, and the direct link between gut microbiota and aging-associated metabolic changes needs to be established in both sexes. Methods Gene expression, metabolic and inflammatory signaling, gut microbiota profile, and metabolome were studied during aging and after fecal microbiota transplantation (FMT) in mice of both sexes. Results Our data revealed young female mice and aged male mice were the most insulin sensitive and resistant group, respectively. In addition, aging reduced sex difference in insulin sensitivity. Such age- and sex-dependent metabolic phenotypes were accompanied by shifted gut microbiota profile and altered abundance of bacterial genes that produce butyrate, propionate, and bile acids. After receiving feces from the aged males (AFMT), the most insulin-resistant group, recipients of both sexes had increased hepatic inflammation and serum endotoxin. However, AFMT only increased insulin resistance in female mice and abolished sex difference in insulin sensitivity. Additionally, such changes were accompanied by narrowed sex difference in metabolome. Metabolomics data revealed that age-associated insulin resistance in males was accompanied by increased sugar alcohols and dicarboxylic acids as well as reduced aromatic and branched-chain amino acids. Further, receiving feces from the young females (YFMT), the most insulin-sensitive group, reduced body weight and fasting blood glucose in male recipients and improved insulin sensitivity in females, leading to enhanced sex differences in insulin sensitivity and metabolome. Conclusions Aging systemically affected inflammatory and metabolic signaling based on the sex. Gut microbiome is age and sex-specific, which affects inflammation and metabolism in a sex-dependent manner.
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Affiliation(s)
- Lili Sheng
- Department of Pathology and Laboratory Medicine, Davis Health, University of California, Sacramento, CA, USA.,Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Prasant Kumar Jena
- Department of Pathology and Laboratory Medicine, Davis Health, University of California, Sacramento, CA, USA.,Department of Pediatrics, Cedars Sinai Medical Center, Los Angeles, CA, USA
| | - Ying Hu
- Department of Pathology and Laboratory Medicine, Davis Health, University of California, Sacramento, CA, USA
| | - Yu-Jui Yvonne Wan
- Department of Pathology and Laboratory Medicine, Davis Health, University of California, Sacramento, CA, USA
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Shi Z, Wu X, Santos Rocha C, Rolston M, Garcia-Melchor E, Huynh M, Nguyen M, Law T, Haas KN, Yamada D, Millar NL, Wan YJY, Dandekar S, Hwang ST. Short-Term Western Diet Intake Promotes IL-23‒Mediated Skin and Joint Inflammation Accompanied by Changes to the Gut Microbiota in Mice. J Invest Dermatol 2021; 141:1780-1791. [PMID: 33485880 DOI: 10.1016/j.jid.2020.11.032] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2020] [Revised: 11/26/2020] [Accepted: 11/27/2020] [Indexed: 02/08/2023]
Abstract
We previously showed that exposure to a high-sugar and moderate-fat diet (i.e., Western diet [WD]) in mice induces appreciable skin inflammation and enhances the susceptibility to imiquimod-induced psoriasiform dermatitis, suggesting that dietary components may render the skin susceptible to psoriatic inflammation. In this study, utilizing an IL-23 minicircle-based model with features of both psoriasiform dermatitis and psoriatic arthritis, we showed that intake of WD for 10 weeks predisposed mice not only to skin but also to joint inflammation. Both WD-induced skin and joint injuries were associated with an expansion of IL-17A‒producing γδ T cells and increased expression of T helper type 17 cytokines. After IL-23 minicircle delivery, WD-fed mice had reduced microbial diversity and pronounced dysbiosis. Treatment with broad-spectrum antibiotics suppressed IL-23‒mediated skin and joint inflammation in the WD-fed mice. Strikingly, reduced skin and joint inflammation with a partial reversion of the gut microbiota were noted when mice switched from a WD to a standard diet after IL-23 minicircle delivery. These findings reveal that a short-term WD intake‒induced dysbiosis is accompanied by enhanced psoriasis-like skin and joint inflammation. Modifications toward a healthier dietary pattern should be considered in patients with psoriatic skin and/or joint disease.
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Affiliation(s)
- Zhenrui Shi
- Department of Dermatology, University of California Davis School of Medicine, Sacramento, California, USA; Department of Dermatology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xuesong Wu
- Department of Dermatology, University of California Davis School of Medicine, Sacramento, California, USA
| | - Clarissa Santos Rocha
- Department of Medical Microbiology and Immunology, University of California Davis School of Medicine, Sacramento, California, USA
| | - Matthew Rolston
- Department of Medical Microbiology and Immunology, University of California Davis School of Medicine, Sacramento, California, USA
| | - Emma Garcia-Melchor
- Institute of Infection, Immunity & Inflammation, College of Medicine, Veterinary & Life Sciences, University of Glasgow, Glasgow, United Kingdom
| | - Mindy Huynh
- Department of Dermatology, University of California Davis School of Medicine, Sacramento, California, USA
| | - Mimi Nguyen
- Department of Dermatology, University of California Davis School of Medicine, Sacramento, California, USA
| | - Timothy Law
- Department of Dermatology, University of California Davis School of Medicine, Sacramento, California, USA
| | - Kelly N Haas
- Biology Department, University of Massachusetts Amherst, Amherst, Massachusetts, USA
| | - Daisuke Yamada
- Department of Dermatology, University of California Davis School of Medicine, Sacramento, California, USA
| | - Neal L Millar
- Institute of Infection, Immunity & Inflammation, College of Medicine, Veterinary & Life Sciences, University of Glasgow, Glasgow, United Kingdom
| | - Yu-Jui Yvonne Wan
- Department of Medical Pathology and Laboratory Medicine, University of California Davis School of Medicine, Sacramento, California, USA
| | - Satya Dandekar
- Department of Medical Microbiology and Immunology, University of California Davis School of Medicine, Sacramento, California, USA
| | - Samuel T Hwang
- Department of Dermatology, University of California Davis School of Medicine, Sacramento, California, USA.
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Khaliq A, Ravindran R, Afzal S, Jena PK, Akhtar MW, Ambreen A, Wan YJY, Malik KA, Irfan M, Khan IH. Gut microbiome dysbiosis and correlation with blood biomarkers in active-tuberculosis in endemic setting. PLoS One 2021; 16:e0245534. [PMID: 33481833 PMCID: PMC7822526 DOI: 10.1371/journal.pone.0245534] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Accepted: 01/02/2021] [Indexed: 12/11/2022] Open
Abstract
Tuberculosis (TB) is the largest infectious disease with 10 million new active-TB patients and1.7 million deaths per year. Active-TB is an inflammatory disease and is increasingly viewed as an imbalance of immune responses to M. tb. infection. The mechanisms of a switch from latent infection to active disease is not well worked out but a shift in the immune responses is thought to be responsible. Increasingly, the role of gut microbiota has been described as a major influencer of the immune system. And because the gut is the largest immune organ, we aimed to analyze the gut microbiome in active-TB patients in a TB-endemic country, Pakistan. The study revealed that Ruminococcacea, Enetrobactericeae, Erysipelotrichaceae, Bifidobacterium, etc. were the major genera associated with active-TB, also associated with chronic inflammatory disease. Plasma antibody profiles against several M. tb. antigens, as specific biomarkers for active-TB, correlated closely with the patient gut microbial profiles. Besides, bcoA gene copy number, indicative of the level of butyrate production by the gut microbiome was five-fold lower in TB patients compared to healthy individuals. These findings suggest that gut health in TB patients is compromised, with implications for disease morbidity (e.g., severe weight loss) as well as immune impairment.
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Affiliation(s)
- Aasia Khaliq
- School of Biological Sciences, University of the Punjab, Lahore, Pakistan
| | - Resmi Ravindran
- Department of Pathology and Laboratory Medicine, University of California, Davis, California, United States of America
| | - Samia Afzal
- Kauser Abdulla Malik School of Life Sciences, Forman Christian College, Lahore, Pakistan
| | - Prasant Kumar Jena
- Department of Pathology and Laboratory Medicine, University of California, Davis, California, United States of America
| | | | - Atiqa Ambreen
- Department of Microbiology, Gulab Devi Hospital, Lahore, Pakistan
| | - Yu-Jui Yvonne Wan
- Department of Pathology and Laboratory Medicine, University of California, Davis, California, United States of America
| | - Kauser Abdulla Malik
- Kauser Abdulla Malik School of Life Sciences, Forman Christian College, Lahore, Pakistan
| | - Muhammad Irfan
- Kauser Abdulla Malik School of Life Sciences, Forman Christian College, Lahore, Pakistan
| | - Imran H. Khan
- Department of Pathology and Laboratory Medicine, University of California, Davis, California, United States of America
- * E-mail:
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Ma C, Guo Y, Klaassen CD. Effect of Gender and Various Diets on Bile Acid Profile and Related Genes in Mice. Drug Metab Dispos 2021; 49:62-71. [PMID: 33093018 PMCID: PMC7804885 DOI: 10.1124/dmd.120.000166] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Accepted: 10/02/2020] [Indexed: 12/12/2022] Open
Abstract
Diet is an important factor for many diseases. Previous studies have demonstrated that several diets had remarkable effects on bile acid (BA) homeostasis, but no comprehensive information for both genders has been reported. Therefore, the current study characterized the nine most used laboratory animal diets fed to both genders of mice for a comparable evaluation of the topic. The results revealed that marked gender difference of BA homeostasis is ubiquitous in mice fed the various diets, and of the nine diets fed to mice, the atherogenic and calorie-restricted diets had the most marked effects on BA homeostasis, followed by the laboratory chow and essential fatty acid-deficient diets. More specifically, females had higher concentrations of total BAs in serum when fed six of the nine diets compared with male mice, and 26 of the 35 BA-related genes had marked gender difference in mice fed at least one diet. Although mice fed the calorie-restricted and atherogenic diets had increased BA, which was more pronounced in serum than liver, the intestinal farnesoid X nuclear receptor-fibroblast growth factor 15 axis changed in the opposite direction and resulted in different hepatic expression patterns of Cyp7a1 Compared with AIN-93M purified diet, higher hepatic expression of multidrug resistance-associated protein 3 was the only alteration in mice fed the laboratory chow diet. The other diets had little or no effect on BA concentrations in the liver and plasma or in the expression of BA-related genes. This study indicates that gender, the atherogenic diet, and the calorie-restricted diet have the most marked effects on BA homeostasis. SIGNIFICANCE STATEMENT: Previous evidence suggested that various diets have effect on bile acid (BA) homeostasis; however, it is not possible to directly compare these findings, as they are all from different studies. The current study was the first to systematically investigate the influence of the nine most used experimental mouse diets on BA homeostasis and potential mechanism in both genders of mice and indicates that gender, the atherogenic diet, and the calorie-restricted diet have the most marked effects on BA homeostasis, which will aid future investigations.
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Affiliation(s)
- Chong Ma
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, P. R. China (C.M., Y.G.); Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, P. R. China (C.M., Y.G.); Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, P. R. China (C.M., Y.G.); National Clinical Research Center for Geriatric Disorders,Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China (C.M., Y.G.); and Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas (C.D.K.)
| | - Ying Guo
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, P. R. China (C.M., Y.G.); Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, P. R. China (C.M., Y.G.); Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, P. R. China (C.M., Y.G.); National Clinical Research Center for Geriatric Disorders,Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China (C.M., Y.G.); and Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas (C.D.K.)
| | - Curtis D Klaassen
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, P. R. China (C.M., Y.G.); Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, P. R. China (C.M., Y.G.); Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, P. R. China (C.M., Y.G.); National Clinical Research Center for Geriatric Disorders,Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China (C.M., Y.G.); and Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas (C.D.K.)
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Wu L, Feng J, Li J, Yu Q, Ji J, Wu J, Dai W, Guo C. The gut microbiome-bile acid axis in hepatocarcinogenesis. Biomed Pharmacother 2021; 133:111036. [PMID: 33378947 DOI: 10.1016/j.biopha.2020.111036] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2020] [Revised: 11/01/2020] [Accepted: 11/15/2020] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and is a leading cause of cancer-related deaths globally, with few effective therapeutic options. Bile acids (BAs) are synthesized from cholesterol in the liver and can be modulated by farnesoid X receptor (FXR) and G-protein coupled BA receptor 1 (GPBAR1/TGR5). Alterations in BAs can affect hepatic metabolic homeostasis and contribute to the pathogenesis of liver cancer. Increasing evidence points to the key role of bacterial microbiota in the promotion and development of liver cancer. They are also involved in the regulation of BA synthesis and metabolism. The purpose of this review is to integrate related articles involving gut microbiota, BAs and HCC, and review how the gut microbiota-BA signaling axis can possibly influence the development of HCC.
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Affiliation(s)
- Liwei Wu
- Department of Gastroenterology, Putuo People's Hospital, Tongji University School of Medicine, Shanghai 200060, China; Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Jiao Feng
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Jingjing Li
- Department of Gastroenterology, Putuo People's Hospital, Tongji University School of Medicine, Shanghai 200060, China; Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Qiang Yu
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Jie Ji
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Jianye Wu
- Department of Gastroenterology, Putuo People's Hospital, Tongji University School of Medicine, Shanghai 200060, China.
| | - Weiqi Dai
- Department of Gastroenterology, Putuo People's Hospital, Tongji University School of Medicine, Shanghai 200060, China; Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China; Department of Gastroenterology, Zhongshan Hospital of Fudan University, Shanghai 200032, China; Shanghai Institute of Liver Diseases, Zhongshan Hospital of Fudan University, Shanghai 200032, China; Shanghai Tongren Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200336, China.
| | - Chuanyong Guo
- Department of Gastroenterology, Putuo People's Hospital, Tongji University School of Medicine, Shanghai 200060, China; Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
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Zhang S, Zhong R, Han H, Yi B, Yin J, Chen L, Zhang H. Short-Term Lincomycin Exposure Depletion of Murine Microbiota Affects Short-Chain Fatty Acids and Intestinal Morphology and Immunity. Antibiotics (Basel) 2020; 9:antibiotics9120907. [PMID: 33327537 PMCID: PMC7765009 DOI: 10.3390/antibiotics9120907] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 12/07/2020] [Accepted: 12/11/2020] [Indexed: 12/17/2022] Open
Abstract
Lincomycin, as one of the most commonly used antibiotics, may cause intestinal injury, enteritis and other side effects, but it remains unknown whether these effects are associated with microbial changes and the effects of different doses of lincomycin on infants. Here, 21-day old mice were exposed to 1 and 5 g/L lincomycin to explore the effects of lincomycin on the gut microbiota, metabolites and inflammation. Compared to the control mice, 1 g/L lincomycin exposure decreased the body weight gain of mice (p < 0.05). Both 1 and 5 g/L lincomycin exposure reduced the diversity and microbial composition of mice (p < 0.05). Furthermore, 1 and 5 g/L lincomycin reduced the relative concentrations of acetate, propionate, butyrate, valerate, isobutyric acid and isovaleric acid in the colon chyme of mice (p < 0.05). In addition, 5 g/L lincomycin exposure reduced the villus height, crypt depth, and relative expression of TLR2, TLR3, TLR4, IL-18, TNF-α, and p65 in the jejunum of mice (p < 0.05), while 1 g/L lincomycin exposure reduced the relative expression of TLR2, TLR3, TNF-α, and p65 (p < 0.05). Collectively, these results highlight the depletion effect of short-term lincomycin exposure on microbiota and the further regulatory effect on intestinal morphology and immunosuppression in infant mice.
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Affiliation(s)
- Shunfen Zhang
- State Key Laboratory of Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China; (S.Z.); (R.Z.); (H.H.); (B.Y.); (H.Z.)
| | - Ruqing Zhong
- State Key Laboratory of Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China; (S.Z.); (R.Z.); (H.H.); (B.Y.); (H.Z.)
| | - Hui Han
- State Key Laboratory of Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China; (S.Z.); (R.Z.); (H.H.); (B.Y.); (H.Z.)
| | - Bao Yi
- State Key Laboratory of Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China; (S.Z.); (R.Z.); (H.H.); (B.Y.); (H.Z.)
| | - Jie Yin
- College of Animal Science and Technology, Hunan Agricultural University, Changsha 410128, China
- Correspondence: (J.Y.); (L.C.); Tel.: +86-10-62819432 (L.C.)
| | - Liang Chen
- State Key Laboratory of Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China; (S.Z.); (R.Z.); (H.H.); (B.Y.); (H.Z.)
- Correspondence: (J.Y.); (L.C.); Tel.: +86-10-62819432 (L.C.)
| | - Hongfu Zhang
- State Key Laboratory of Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China; (S.Z.); (R.Z.); (H.H.); (B.Y.); (H.Z.)
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Jennison E, Byrne CD. The role of the gut microbiome and diet in the pathogenesis of non-alcoholic fatty liver disease. Clin Mol Hepatol 2020; 27:22-43. [PMID: 33291863 PMCID: PMC7820212 DOI: 10.3350/cmh.2020.0129] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Accepted: 08/12/2020] [Indexed: 02/07/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease, with a prevalence that is increasing in parallel with the global rise in obesity and type 2 diabetes mellitus. The pathogenesis of NAFLD is complex and multifactorial, involving environmental, genetic and metabolic factors. The role of the diet and the gut microbiome is gaining interest as a significant factor in NAFLD pathogenesis. Dietary factors induce alterations in the composition of the gut microbiome (dysbiosis), commonly reflected by a reduction of the beneficial species and an increase in pathogenic microbiota. Due to the close relationship between the gut and liver, altering the gut microbiome can affect liver functions; promoting hepatic steatosis and inflammation. This review summarises the current evidence supporting an association between NAFLD and the gut microbiome and dietary factors. The review also explores potential underlying mechanisms underpinning these associations and whether manipulation of the gut microbiome is a potential therapeutic strategy to prevent or treat NAFLD.
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Affiliation(s)
- Erica Jennison
- Department of Chemical Pathology, Southampton General Hospital, University Hospital Southampton, Southampton, UK
| | - Christopher D Byrne
- Department of Nutrition and Metabolism, Faculty of Medicine, University of Southampton, Southampton, UK.,Southampton National Institute for Health Research Biomedical Research Centre, Southampton General Hospital, University Hospital Southampton, Southampton, UK
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Jena PK, Sheng L, Nguyen M, Di Lucente J, Hu Y, Li Y, Maezawa I, Jin LW, Wan YJY. Dysregulated bile acid receptor-mediated signaling and IL-17A induction are implicated in diet-associated hepatic health and cognitive function. Biomark Res 2020; 8:59. [PMID: 33292701 PMCID: PMC7648397 DOI: 10.1186/s40364-020-00239-8] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Accepted: 10/21/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Chronic consumption of high sugar and high fat diet associated with liver inflammation and cognitive decline. This paper tests a hypothesis that the development and resolution of diet-induced nonalcoholic fatty liver disease (NAFLD) has an impact on neuroplasticity and cognition. METHODS C57BL/6 wild-type mice were fed with either a healthy control diet (CD) or a fructose, palmitate, and cholesterol (FPC)-enriched diet since weaning. When mice were 3-months old, FPC diet-fed mice were randomly assigned to receive either FPC-enriched diet with or without 6% inulin supplementation. At 8 months of age, all three groups of mice were euthanized followed by analysis of inflammatory signaling in the liver and brain, gut microbiota, and cecal metabolites. RESULTS Our data showed that FPC diet intake induced hepatic steatosis and inflammation in the liver and brain along with elevated RORγ and IL-17A signaling. Accompanied by microglia activation and reduced hippocampal long-term potentiation, FPC diet intake also reduced postsynaptic density-95 and brain derived neurotrophic factor, whereas inulin supplementation prevented diet-reduced neuroplasticity and the development of NAFLD. In the gut, FPC diet increased Coriobacteriaceae and Erysipelotrichaceae, which are implicated in cholesterol metabolism, and the genus Allobaculum, and inulin supplementation reduced them. Furthermore, FPC diet reduced FXR and TGR5 signaling, and inulin supplementation reversed these changes. Untargeted cecal metabolomics profiling uncovered 273 metabolites, and 104 had significant changes due to FPC diet intake or inulin supplementation. Among the top 10 most affected metabolites, FPC-fed mice had marked increase of zymosterol, a cholesterol biosynthesis metabolite, and reduced 2,8-dihydroxyquinoline, which has known benefits in reducing glucose intolerance; these changes were reversible by inulin supplementation. Additionally, the abundance of Barnesiella, Coprobacter, Clostridium XIVa, and Butyrivibrio were negatively correlated with FPC diet intake and the concentration of cecal zymosterol but positively associated with inulin supplementation, suggesting their benefits. CONCLUSION Taken together, the presented data suggest that diet alters the gut microbiota and their metabolites, including bile acids. This will subsequently affect IL-17A signaling, resulting in systemic impacts on both hepatic metabolism and cognitive function.
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Affiliation(s)
- Prasant Kumar Jena
- Department of Medical Pathology and Laboratory Medicine, University of California, Davis Health, Room 3400B, Research Building III, 4645 2nd Ave, Sacramento, CA, 95817, USA
- Department of Pediatrics, Cedars Sinai Medical Center, Los Angeles, CA, 90048, USA
| | - Lili Sheng
- Department of Medical Pathology and Laboratory Medicine, University of California, Davis Health, Room 3400B, Research Building III, 4645 2nd Ave, Sacramento, CA, 95817, USA
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Michelle Nguyen
- Department of Medical Pathology and Laboratory Medicine, University of California, Davis Health, Room 3400B, Research Building III, 4645 2nd Ave, Sacramento, CA, 95817, USA
| | - Jacopo Di Lucente
- Department of Medical Pathology and Laboratory Medicine, University of California, Davis Health, Room 3400B, Research Building III, 4645 2nd Ave, Sacramento, CA, 95817, USA
| | - Ying Hu
- Department of Medical Pathology and Laboratory Medicine, University of California, Davis Health, Room 3400B, Research Building III, 4645 2nd Ave, Sacramento, CA, 95817, USA
| | - Yongchun Li
- Department of Medical Pathology and Laboratory Medicine, University of California, Davis Health, Room 3400B, Research Building III, 4645 2nd Ave, Sacramento, CA, 95817, USA
- Department of Gastroenterology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China
- Department of Infectious Diseases, Nanhai Hospital, Southern Medical University, Foshan, 528200, China
| | - Izumi Maezawa
- Department of Medical Pathology and Laboratory Medicine, University of California, Davis Health, Room 3400B, Research Building III, 4645 2nd Ave, Sacramento, CA, 95817, USA
| | - Lee-Way Jin
- Department of Medical Pathology and Laboratory Medicine, University of California, Davis Health, Room 3400B, Research Building III, 4645 2nd Ave, Sacramento, CA, 95817, USA
| | - Yu-Jui Yvonne Wan
- Department of Medical Pathology and Laboratory Medicine, University of California, Davis Health, Room 3400B, Research Building III, 4645 2nd Ave, Sacramento, CA, 95817, USA.
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Yan S, Khambu B, Chen X, Dong Z, Guo G, Yin XM. Hepatic Autophagy Deficiency Remodels Gut Microbiota for Adaptive Protection via FGF15-FGFR4 Signaling. Cell Mol Gastroenterol Hepatol 2020; 11:973-997. [PMID: 33127558 PMCID: PMC7898036 DOI: 10.1016/j.jcmgh.2020.10.011] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 09/28/2020] [Accepted: 10/13/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS The functions of the liver and the intestine are closely tied in both physiological and pathologic conditions. The gut microbiota (GM) often cause deleterious effects during hepatic pathogenesis. Autophagy is essential for liver homeostasis, but the impact of hepatic autophagy function on liver-gut interaction remains unknown. Here we investigated the effect of hepatic autophagy deficiency (Atg5Δhep) on GM and in turn the effect of GM on the liver pathology. METHODS Fecal microbiota were analyzed by 16S sequencing. Antibiotics were used to modulate GM. Cholestyramine was used to reduce the enterohepatic bile acid (BA) level. The functional role of fibroblast growth factor 15 (FGF15) and ileal farnesoid X receptor (FXR) was examined in mice overexpressing FGF15 gene or in mice given a fibroblast growth factor receptor-4 (FGFR4) inhibitor. RESULTS Atg5Δhep causes liver injury and alterations of intestinal BA composition, with a lower proportion of tauro-conjugated BAs and a higher proportion of unconjugated BAs. The composition of GM is significantly changed with an increase in BA-metabolizing bacteria, leading to an increased expression of ileal FGF15 driven by FXR that has a higher affinity to unconjugated BAs. Notably, antibiotics or cholestyramine treatment decreased FGF15 expression and exacerbated liver injury. Consistently, inhibition of FGF15 signaling in the liver enhances liver injury. CONCLUSIONS Deficiency of autophagy function in the liver can affect intestinal environment, leading to gut dysbiosis. Surprisingly, such changes provide an adaptive protection against the liver injury through the FGF15-FGFR4 signaling. Antibiotics use in the condition of liver injury may thus have unexpected adverse consequences via the gut-liver axis.
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Affiliation(s)
- Shengmin Yan
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana
| | - Bilon Khambu
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana
| | - Xiaoyun Chen
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Zheng Dong
- Department of Cell Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, Georgia; Charlie Norwood VA Medical Center, Augusta, Georgia
| | - Grace Guo
- Department of Pharmacology and Toxicology, Rutgers University, Piscataway, New Jersey
| | - Xiao-Ming Yin
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana.
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