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Shi J, Cui J, Zheng T, Han X, Wang B, Wang W, Zhu C, Fang C, Zhou X, Cong N, Yin X, Yang Q. Comparative effects of aerobic and resistance exercise on bile acid profiles and liver function in patients with non-alcoholic fatty liver disease. BMC Gastroenterol 2025; 25:239. [PMID: 40211236 PMCID: PMC11983906 DOI: 10.1186/s12876-025-03826-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Accepted: 03/28/2025] [Indexed: 04/12/2025] Open
Abstract
OBJECTIVE Our research aims to explore the effects of different exercise on liver function and bile acid in patients with non-alcoholic fatty liver disease (NAFLD), to identify the most beneficial exercise modalities for patients with NAFLD. DESIGN Participants were randomly divided into four groups: control group, aerobic training group, resistance training group, and aerobic training combined with resistance training group. Participants underwent assessments of body shape, blood lipid, glucose levels and liver function biochemical parameters. Their bile acid levels were measured using the LC-MS/MS system. Changes in these parameters before and after the intervention and differences between groups were analyzed. RESULTS Participants in the AT group showed significant improvements in liver function parameters. Additionally, levels of total bile acids and ursodeoxycholic acid significantly increased. The RT group and AT + RT group also showed improvements in body shape and liver function parameters, but the improvements in these groups were not as pronounced as those in the AT group. CONCLUSIONS Aerobic exercise is the most beneficial modality for young patients with NAFLD, as it significantly improves body shape and liver function while also reducing blood lipid and glucose levels. TRIAL REGISTRATION Clinical trial number NCT06338449, registered on March 22, 2024.
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Affiliation(s)
- Jiasen Shi
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, No.209, Tongshan Road, Xuzhou, Jiangsu, 221004, China
| | - Junchao Cui
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, No.209, Tongshan Road, Xuzhou, Jiangsu, 221004, China
| | - Tianlei Zheng
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, No.209, Tongshan Road, Xuzhou, Jiangsu, 221004, China
| | - Xiaoping Han
- Department of Campus Hospital, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Bin Wang
- Department of Laboratory Medicine, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Wenjing Wang
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, No.209, Tongshan Road, Xuzhou, Jiangsu, 221004, China
| | - Chenggang Zhu
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, No.209, Tongshan Road, Xuzhou, Jiangsu, 221004, China
| | - Chenle Fang
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, No.209, Tongshan Road, Xuzhou, Jiangsu, 221004, China
| | - Xueyan Zhou
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, No.209, Tongshan Road, Xuzhou, Jiangsu, 221004, China
| | - Ning Cong
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, No.209, Tongshan Road, Xuzhou, Jiangsu, 221004, China
| | - Xiaoxing Yin
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, No.209, Tongshan Road, Xuzhou, Jiangsu, 221004, China.
| | - Qiang Yang
- Department of Physical Education, Xuzhou Medical University, Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, No.209, Tongshan Road, Xuzhou, Jiangsu, 221004, China.
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Schnabl B, Damman CJ, Carr RM. Metabolic dysfunction-associated steatotic liver disease and the gut microbiome: pathogenic insights and therapeutic innovations. J Clin Invest 2025; 135:e186423. [PMID: 40166938 PMCID: PMC11957707 DOI: 10.1172/jci186423] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/02/2025] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major cause of liver disease worldwide, and our understanding of its pathogenesis continues to evolve. MASLD progresses from steatosis to steatohepatitis, fibrosis, and cirrhosis, and this Review explores how the gut microbiome and their metabolites contribute to MASLD pathogenesis. We explore the complexity and importance of the intestinal barrier function and how disruptions of the intestinal barrier and dysbiosis work in concert to promote the onset and progression of MASLD. The Review focuses on specific bacterial, viral, and fungal communities that impact the trajectory of MASLD and how specific metabolites (including ethanol, bile acids, short chain fatty acids, and other metabolites) contribute to disease pathogenesis. Finally, we underscore how knowledge of the interaction between gut microbes and the intestinal barrier may be leveraged for MASLD microbial-based therapeutics. Here, we include a discussion of the therapeutic potential of prebiotics, probiotics, postbiotics, and microbial-derived metabolites.
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Affiliation(s)
- Bernd Schnabl
- Department of Medicine, Division of Gastroenterology, UCSD, San Diego, California, USA
- Department of Medicine, VA San Diego Healthcare System, San Diego, California, USA
| | - Christopher J. Damman
- Department of Medicine, Division of Gastroenterology, University of Washington, Seattle, Washington, USA
| | - Rotonya M. Carr
- Department of Medicine, Division of Gastroenterology, University of Washington, Seattle, Washington, USA
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Asselah T, Lampertico P, Aleman S, Bourlière M, Streinu‐Cercel A, Bogomolov P, Morozov V, Stepanova T, Lazar S, Manuilov D, Mercier R, Tseng S, Ye L, Flaherty JF, Osinusi A, Da BL, Chee GM, Lau AH, Brunetto MR, Wedemeyer H. Bulevirtide Monotherapy Is Safe and Well Tolerated in Chronic Hepatitis Delta: An Integrated Safety Analysis of Bulevirtide Clinical Trials at Week 48. Liver Int 2025; 45:e16174. [PMID: 39648559 PMCID: PMC11907224 DOI: 10.1111/liv.16174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Revised: 10/17/2024] [Accepted: 11/04/2024] [Indexed: 12/10/2024]
Abstract
BACKGROUND AND AIMS The safety and tolerability of bulevirtide (BLV), a novel entry inhibitor of hepatitis delta virus, were evaluated in an integrated analysis of clinical trial results from patients with chronic hepatitis delta (CHD). METHODS Week 48 on-treatment clinical and laboratory results from two Phase 2 trials (MYR203 [NCT02888106] and MYR204 [NCT03852433]) and one Phase 3 trial (MYR301 [NCT03852719]) were pooled (N = 269). Patients were grouped as follows: BLV 2 mg (n = 64), BLV 10 mg (n = 115), pegylated interferon-alfa (n = 39) and control (n = 51). The control group consisted of patients assigned to the delayed treatment group in Study MYR301. RESULTS Adverse events (AEs) that occurred more frequently with BLV 2 mg and BLV 10 mg versus control included increased total bile acid levels (20% and 17% vs. 0%), injection-site reactions (16% and 20% vs. 0%), headache (16% and 17% vs. 0%), pruritus (11% and 10% vs. 0%) and eosinophilia (9% and 4% vs. 0%). Increases in total bile acid levels were observed with BLV without clear correlation with AEs, such as pruritus, eosinophilia or vitamin D deficiency. Grade 3 or 4 study drug-related AEs occurred in a higher proportion of patients receiving pegylated interferon-alfa (51%) than with BLV 2 or 10 mg (3% and 4%, respectively). There were no serious AEs related to BLV, and no patients discontinued BLV due to an AE. Neither hepatic decompensation nor death occurred. CONCLUSIONS BLV monotherapy was safe and well tolerated through 48 weeks of treatment in patients with CHD. TRIAL REGISTRATION NCT02888106, NCT03852433 and NCT03852719.
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Affiliation(s)
- Tarik Asselah
- Department of Hepatology, Hôpital Beaujon, Université de Paris‐Cité, INSERM UMR1149ClichyFrance
| | - Pietro Lampertico
- Division of Gastroenterology and HepatologyFoundation IRCCS Ca' Granda Ospedale Maggiore PoliclinicoMilanItaly
- CRC ‘A. M. And A. Migliavacca’ Center for Liver Disease, Department of Pathophysiology and TransplantationUniversity of MilanMilanItaly
| | - Soo Aleman
- Department of Infectious DiseasesKarolinska University Hospital/Karolinska InstitutetStockholmSweden
| | | | - Adrian Streinu‐Cercel
- National Institute for Infectious Diseases ‘Prof. Dr. Matei Bals’BucharestRomania
- Carol Davila Medicine and Pharmacy UniversityBucharestRomania
| | - Pavel Bogomolov
- M.F. Vladimirsky Moscow Regional Research and Clinical InstituteMoscowRussian Federation
| | | | - Tatiana Stepanova
- Limited Liability Company ‘Clinic of Modern Medicine’MoscowRussian Federation
| | | | | | | | - Steve Tseng
- Gilead Sciences Inc.Foster CityCaliforniaUSA
| | - Lei Ye
- Gilead Sciences Inc.Foster CityCaliforniaUSA
| | | | - Anu Osinusi
- Gilead Sciences Inc.Foster CityCaliforniaUSA
| | - Ben L. Da
- Gilead Sciences Inc.Foster CityCaliforniaUSA
| | | | | | - Maurizia R. Brunetto
- Hepatology Unit, Reference Center of the Tuscany Region for Chronic Liver Disease and CancerUniversity Hospital of PisaPisaItaly
- Department of Clinical and Experimental MedicineUniversity of PisaPisaItaly
| | - Heiner Wedemeyer
- Clinic for Gastroenterology, Hepatology, Infectious Diseases, and EndocrinologyHannover Medical SchoolHannoverGermany
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Shukla A, Sharma C, Malik MZ, Singh AK, Aditya AK, Mago P, Shalimar, Ray AK. Deciphering the tripartite interaction of urbanized environment, gut microbiome and cardio-metabolic disease. JOURNAL OF ENVIRONMENTAL MANAGEMENT 2025; 377:124693. [PMID: 40022791 DOI: 10.1016/j.jenvman.2025.124693] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Revised: 02/13/2025] [Accepted: 02/21/2025] [Indexed: 03/04/2025]
Abstract
The world is experiencing a sudden surge in urban population, especially in developing Asian and African countries. Consequently, the global burden of cardio-metabolic disease (CMD) is also rising owing to gut microbiome dysbiosis due to urbanization factors such as mode of birth, breastfeeding, diet, environmental pollutants, and soil exposure. Dysbiotic gut microbiome indicated by altered Firmicutes to Bacteroides ratio and loss of beneficial short-chain fatty acids-producing bacteria such as Prevotella, and Ruminococcus may disrupt host-intestinal homeostasis by altering host immune response, gut barrier integrity, and microbial metabolism through altered T-regulatory cells/T-helper cells balance, activation of pattern recognition receptors and toll-like receptors, decreased mucus production, elevated level of trimethylamine-oxide and primary bile acids. This leads to a pro-inflammatory gut characterized by increased pro-inflammatory cytokines such as tumour necrosis factor-α, interleukin-2, Interferon-ϒ and elevated levels of metabolites or metabolic endotoxemia due to leaky gut formation. These pathophysiological characteristics are associated with an increased risk of cardio-metabolic disease. This review aims to comprehensively elucidate the effect of urbanization on gut microbiome-driven cardio-metabolic disease. Additionally, it discusses targeting the gut microbiome and its associated pathways via strategies such as diet and lifestyle modulation, probiotics, prebiotics intake, etc., for the prevention and treatment of disease which can potentially be integrated into clinical and professional healthcare settings.
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Affiliation(s)
- Avaneesh Shukla
- Department of Environmental Studies, University of Delhi, New Delhi, India
| | - Chanchal Sharma
- Department of Environmental Studies, University of Delhi, New Delhi, India
| | - Md Zubbair Malik
- Department of Translational Medicine, Dasman Diabetes Institute, Kuwait City, Kuwait
| | - Alok Kumar Singh
- Department of Zoology, Ramjas College, University of Delhi, New Delhi, India
| | - Abhishek Kumar Aditya
- Department of Medicine, K.D. Medical College, Hospital and Research Center, Mathura, India
| | - Payal Mago
- Shaheed Rajguru College of Applied Sciences for Women, University of Delhi, New Delhi, India; Campus of Open Learning, University of Delhi, New Delhi, India
| | - Shalimar
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India
| | - Ashwini Kumar Ray
- Department of Environmental Studies, University of Delhi, New Delhi, India.
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Bintee B, Banerjee R, Hegde M, Vishwa R, Alqahtani MS, Abbas M, Alqahtani A, Rangan L, Sethi G, Kunnumakkara AB. Exploring bile acid transporters as key players in cancer development and treatment: Evidence from preclinical and clinical studies. Cancer Lett 2025; 609:217324. [PMID: 39571783 DOI: 10.1016/j.canlet.2024.217324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Revised: 11/09/2024] [Accepted: 11/11/2024] [Indexed: 12/01/2024]
Abstract
Bile acid transporters (BATs) are integral membrane proteins belonging to various families, such as solute carriers, organic anion transporters, and ATP-binding cassette families. These transporters play a crucial role in bile acid transportation within the portal and systemic circulations, with expression observed in tissues, including the liver, kidney, and small intestine. Bile acids serve as signaling molecules facilitating the absorption and reabsorption of fats and lipids. Dysregulation of bile acid concentration has been implicated in tumorigenesis, yet the role of BATs in this process remains underexplored. Emerging evidence suggests that BATs may modulate various stages of cancer progression, including initiation, development, proliferation, metastasis, and tumor microenvironment regulation. Targeting BATs using siRNAs, miRNAs, and small compound inhibitors in preclinical models and their polymorphisms are well-studied for transporters like BSEP, MDR1, MRP2, OATP1A2, etc., and have shed light on their involvement in tumorigenesis, particularly in cancers such as those affecting the liver and gastrointestinal tract. While BATs' role in diseases like Alagille syndrome, biliary atresia, and cirrhosis have been extensively studied, their implications in cancer warrant further investigation. This review highlights the expression and function of BATs in cancer development and emphasizes the potential of targeting these transporters as a novel therapeutic strategy for various malignancies.
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Affiliation(s)
- Bintee Bintee
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, 781039, Assam, India
| | - Ruchira Banerjee
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, 781039, Assam, India; Applied Biodiversity Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, 781039, Assam, India
| | - Mangala Hegde
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, 781039, Assam, India
| | - Ravichandran Vishwa
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, 781039, Assam, India
| | - Mohammed S Alqahtani
- Radiological Sciences Department, College of Applied Medical Sciences, King Khalid University, Abha, 61421, Saudi Arabia; BioImaging Unit, Space Research Centre, Michael Atiyah Building, University of Leicester, Leicester, LE1 7RH, United Kingdom
| | - Mohamed Abbas
- Electrical Engineering Department, College of Engineering, King Khalid University, Abha, 61421, Saudi Arabia
| | - Athba Alqahtani
- Research Centre, King Fahad Medical City, P.O. Box: 59046, Riyadh, 11525, Saudi Arabia
| | - Latha Rangan
- Applied Biodiversity Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, 781039, Assam, India
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore; NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117699, Singapore.
| | - Ajaikumar B Kunnumakkara
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, 781039, Assam, India.
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Liu Z, You C. The bile acid profile. Clin Chim Acta 2025; 565:120004. [PMID: 39419312 DOI: 10.1016/j.cca.2024.120004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Revised: 10/13/2024] [Accepted: 10/14/2024] [Indexed: 10/19/2024]
Abstract
As a large and structurally diverse family of small molecules, bile acids play a crucial role in regulating lipid, glucose, and energy metabolism. In the human body, bile acids share a similar chemical structure with many isomers, exhibit little difference in polarity, and possess various physiological activities. The types and contents of bile acids present in different diseases vary significantly. Therefore, comprehensive and accurate detection of the content of various types of bile acids in different biological samples can not only provide new insights into the pathogenesis of diseases but also facilitate the exploration of novel strategies for disease diagnosis, treatment, and prognosis. The detection of disease-induced changes in bile acid profiles has emerged as a prominent research focus in recent years. Concurrently, targeted metabolomics methods utilizing high-performance liquid chromatography-mass spectrometry (HPLC-MS) have progressively established themselves as the predominant technology for the separation and detection of bile acids. Bile acid profiles will increasingly play an important role in diagnosis and guidance in the future as the relationship between disease and changes in bile acid profiles becomes clearer. This highlights the growing diagnostic value of bile acid profiles and their potential to guide clinical decision-making. This review aims to explore the significance of bile acid profiles in clinical diagnosis from four perspectives: the synthesis and metabolism of bile acids, techniques for detecting bile acid profiles, changes in bile acid profiles associated with diseases, and the challenges and future prospects of applying bile acid profiles in clinical settings.
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Affiliation(s)
- Zhenhua Liu
- Laboratory Medicine Center, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou 730030, China
| | - Chongge You
- Laboratory Medicine Center, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou 730030, China.
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Chen L, Ye Z, Li J, Wang L, Chen Y, Yu M, Han J, Huang J, Li D, Lv Y, Xiong K, Tian D, Liao J, Seidler U, Xiao F. Gut bacteria Prevotellaceae related lithocholic acid metabolism promotes colonic inflammation. J Transl Med 2025; 23:55. [PMID: 39806416 PMCID: PMC11727794 DOI: 10.1186/s12967-024-05873-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Accepted: 11/11/2024] [Indexed: 01/16/2025] Open
Abstract
BACKGROUND The conversion of primary bile acids to secondary bile acids by the gut microbiota has been implicated in colonic inflammation. This study investigated the role of gut microbiota related bile acid metabolism in colonic inflammation in both patients with inflammatory bowel disease (IBD) and a murine model of dextran sulfate sodium (DSS)-induced colitis. METHODS Bile acids in fecal samples from patients with IBD and DSS-induced colitis mice, with and without antibiotic treatment, were analyzed using ultraperformance liquid chromatography-mass spectrometry (UPLC-MS). The composition of the microbiota in fecal samples from IBD patients and DSS-colitis mice was characterized via Illumina MiSeq sequencing of the bacterial 16S rRNA gene V3-V4 region. Metagenomic profiling further identified metabolism-related gene signatures in stool samples from DSS-colitis mice. Histological analysis, quantitative PCR (qPCR) and Western Blotting were conducted on colonic samples from DSS-induced colitis mice to assess colonic inflammation, mucosal barrier integrity, and associated signaling pathways. The multivariate analysis of bile acids was conducted using Soft Independent Modelling of Class Analogy (SIMCA, Umetrics, Sweden). The relation between the relative abundance of specific phyla/genera and bile acid concentration was assess through Spearman's correlation analyses. Finally, lithocholic acid (LCA), the key bile acid, was administered via gavage to evaluate its effect on colonic inflammation and mucosal barrier integrity. RESULTS In patients with IBD, the composition of colonic bile acids and gut microbiota was altered. Moreover, changes in the gut microbiota further modulate the composition of bile acids in the intestine. As the gut microbiota continues to shift, the bile acid profile undergoes additional alterations. The aforementioned alterations were also observed in mice with DSS-induced colitis. The study revealed a correlation between dysbiosis of the gut microbiota and modifications in the profile of colonic bile acids, notably LCA observed in both patients with IBD and mice with DSS-induced colitis. Through multivariate analysis, LCA was identified as the key bile acid that significantly affects colonic inflammation and the integrity of mucosal barrier. Subsequent experiments confirmed that LCA supplementation effectively mitigated the inhibitory effects of gut microbiota on colitis progression in mice, primarily through the activation of the sphingosine-1-phosphate receptor 2 (S1PR2)/NF-κB p65 signaling pathway. Analysis of the microbiome and metagenomic data revealed changes in the gut microbiota, notably an increased abundance of an unclassified genus within the family Prevotellaceae in DSS-induced colitis mice. Furthermore, a positive correlation was observed between the relative abundance of Prevotellaceae and bile acid biosynthesis pathways, as well as colonic LCA level. CONCLUSIONS These findings suggest that LCA and its positively correlated gut bacteria, Prevotellaceae, are closely associated with intestinal inflammation. Targeting colonic inflammation may involve inhibiting LCA and members of the Prevotellaceae family as potential therapeutic strategies.
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Affiliation(s)
- Liping Chen
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, People's Republic of China
| | - Zhenghao Ye
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, People's Republic of China
- Department of Gastroenterology, Hannover Medical School, Hannover, Germany
| | - Junhua Li
- Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Lijia Wang
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, People's Republic of China
| | - Yu Chen
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, People's Republic of China
| | - Meiping Yu
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, People's Republic of China
| | - Jian Han
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, People's Republic of China
| | - Jiangeng Huang
- Department of Pharmaceutics, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Dongyan Li
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yongling Lv
- Meiyitian Biopharmaceutical (Wuhan) Ltd., Wuhan, China
| | - Kai Xiong
- Meiyitian Biopharmaceutical (Wuhan) Ltd., Wuhan, China
| | - De'an Tian
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, People's Republic of China
| | - Jiazhi Liao
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, People's Republic of China
| | - Ursula Seidler
- Department of Gastroenterology, Hannover Medical School, Hannover, Germany
| | - Fang Xiao
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, People's Republic of China.
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Popov J, Despot T, Avelar Rodriguez D, Khan I, Mech E, Khan M, Bojadzija M, Pai N. Implications of Microbiota and Immune System in Development and Progression of Metabolic Dysfunction-Associated Steatotic Liver Disease. Nutrients 2024; 16:1668. [PMID: 38892602 PMCID: PMC11175128 DOI: 10.3390/nu16111668] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Revised: 05/23/2024] [Accepted: 05/27/2024] [Indexed: 06/21/2024] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent type of liver disease worldwide. The exact pathophysiology behind MASLD remains unclear; however, it is thought that a combination of factors or "hits" act as precipitants for disease onset and progression. Abundant evidence supports the roles of diet, genes, metabolic dysregulation, and the intestinal microbiome in influencing the accumulation of lipids in hepatocytes and subsequent progression to inflammation and fibrosis. Currently, there is no cure for MASLD, but lifestyle changes have been the prevailing cornerstones of management. Research is now focusing on the intestinal microbiome as a potential therapeutic target for MASLD, with the spotlight shifting to probiotics, antibiotics, and fecal microbiota transplantation. In this review, we provide an overview of how intestinal microbiota interact with the immune system to contribute to the pathogenesis of MASLD and metabolic dysfunction-associated steatohepatitis (MASH). We also summarize key microbial taxa implicated in the disease and discuss evidence supporting microbial-targeted therapies in its management.
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Affiliation(s)
- Jelena Popov
- Boston Combined Residency Program, Boston Children’s Hospital & Boston Medical Center, Boston, MA 02115, USA;
| | - Tijana Despot
- College of Medicine and Health, University College Cork, T12 YN60 Cork, Ireland; (T.D.); (I.K.)
| | - David Avelar Rodriguez
- Department of Pediatric Gastroenterology, Hepatology & Nutrition, The Hospital for Sick Children, University of Toronto, Toronto, ON M5G 1E8, Canada;
| | - Irfan Khan
- College of Medicine and Health, University College Cork, T12 YN60 Cork, Ireland; (T.D.); (I.K.)
| | - Eugene Mech
- School of Medicine, University College Dublin, D04 C1P1 Dublin, Ireland;
| | - Mahrukh Khan
- Department of Pediatrics, Faculty of Health Sciences, McMaster University, Hamilton, ON L8S 4L8, Canada;
- Department of Medical Sciences, Faculty of Health Sciences, McMaster University, Hamilton, ON L8S 4L8, Canada
| | - Milan Bojadzija
- Department of Internal Medicine, Subotica General Hospital, 24000 Subotica, Serbia;
| | - Nikhil Pai
- Department of Pediatrics, Faculty of Health Sciences, McMaster University, Hamilton, ON L8S 4L8, Canada;
- Division of Gastroenterology, Hepatology and Nutrition, McMaster Children’s Hospital, Hamilton, ON L8S 4L8, Canada
- Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Division of Gastroenterology, Hepatology, and Nutrition, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
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Zhang S, Chau HT, Tun HM, Huang FY, Wong DKH, Mak LY, Yuen MF, Seto WK. Virological response to nucleos(t)ide analogues treatment in chronic hepatitis B patients is associated with Bacteroides-dominant gut microbiome. EBioMedicine 2024; 103:105101. [PMID: 38583259 PMCID: PMC11002572 DOI: 10.1016/j.ebiom.2024.105101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2023] [Revised: 03/13/2024] [Accepted: 03/20/2024] [Indexed: 04/09/2024] Open
Abstract
BACKGROUND Gut dysbiosis is present in chronic hepatitis B virus (HBV) infection. In this study, we integrated microbiome and metabolome analysis to investigate the role of gut microbiome in virological response to nucleos(t)ide analogues (NAs) treatment. METHODS Chronic HBV patients were prospectively recruited for steatosis and fibrosis assessments via liver elastography, with full-length 16S sequencing performed to identify the compositional gut microbiota differences. Fasting plasma bile acids were quantified by liquid chromatography-tandem mass spectrometry. FINDINGS All patients (n = 110) were characterized into three distinct microbial clusters by their dominant genus: c-Bacteroides, c-Blautia, and c-Prevotella. Patients with c-Bacteroides had a higher plasma ursodeoxycholic acids (UDCA) level and an increase in 7-alpha-hydroxysteroid dehydrogenase (secondary bile acid biotransformation) than other clusters. In NAs-treated patients (n = 84), c-Bacteroides was associated with higher odds of plasma HBV-DNA undetectability when compared with non-c-Bacteroides clusters (OR 3.49, 95% CI 1.43-8.96, p = 0.01). c-Blautia was positively associated with advanced fibrosis (OR 2.74, 95% CI 1.09-7.31, p = 0.04). No such associations were found in treatment-naïve patients. Increased Escherichia coli relative abundance (0.21% vs. 0.03%, p = 0.035) was found in on-treatment patients (median treatment duration 98.1 months) with advanced fibrosis despite HBV DNA undetectability. An enrichment in l-tryptophan biosynthesis was observed in patients with advanced fibrosis, which exhibited a positive correlation with Escherichia coli. INTERPRETATION Collectively, unique bacterial signatures, including c-Bacteroides and c-Blautia, were associated with virological undetectability and fibrosis evolution during NAs therapy in chronic HBV, setting up intriguing possibilities in optimizing HBV treatment. FUNDING This study was supported by the Guangdong Natural Science Fund (2019A1515012003).
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Affiliation(s)
- Saisai Zhang
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, China
| | - Hau-Tak Chau
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, China
| | - Hein Min Tun
- The Jockey Club School of Public Health and Primary Care, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China; System Microbiology and Antimicrobial Resistance (SMART) Lab, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Fung-Yu Huang
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, China
| | - Danny Ka-Ho Wong
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, China; State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China
| | - Lung-Yi Mak
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, China; State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China
| | - Man-Fung Yuen
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, China; State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China.
| | - Wai-Kay Seto
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, China; State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China; Department of Medicine, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China.
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10
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Huang L, Li Y, Tang R, Yang P, Zhuo Y, Jiang X, Che L, Lin Y, Xu S, Li J, Fang Z, Zhao X, Li H, Yang M, Feng B, Wu D, Hua L. Bile acids metabolism in the gut-liver axis mediates liver injury during lactation. Life Sci 2024; 338:122380. [PMID: 38142738 DOI: 10.1016/j.lfs.2023.122380] [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: 08/14/2023] [Revised: 12/12/2023] [Accepted: 12/19/2023] [Indexed: 12/26/2023]
Abstract
AIMS The obesity epidemic, especially in pregnant women, linked to a higher risk of liver diseases. Bile acids (BAs) are known to participate in liver metabolism, but this function during obesogenic reproductive process remains largely uncertain. The study aims to identify whether a high-fat diet (HFD) during pregnancy negatively disturbs liver metabolism and the potential role of BAs and gut microbiota (GM)in a sow model. MAIN METHODS Reproductive (RP) or non-reproductive (NRP) sows were fed a 15 % HFD containing compound oil. Body condition, blood parameters, and BAs levels/profile during gestation and lactation were monitored. The tissues and colonic GM were collected after euthanasia at the end of lactation. HepG2 hepatocytes were used to test the effects of BAs on liver damage and the mechanism. KEY FINDINGS Reproductive sows fed an HFD (HF-RP) experienced increased weight loss, and elevated plasma non-esterified fatty acid (NEFA) during lactation, consistent with exacerbated lipolysis, aggravating the risk of liver damage. HF-RP sows exhibited an enlarged BAs pool size and alterations in composition (higher levels of CDCA and LCA species) along with a drastic change in the GM (increased Firmicutes/Bacteroidetes ratio and declined Lactobacillus abundance). Furthermore, the liver FXR-SHP pathway, BAs synthesis and transport underwent adaptive regulation to sustain the BAs homeostasis and hepatic lipid metabolism. CDCA alleviated endoplasmic reticulum (ER) stress induced by palmitic acid via FXR pathway, in HepG2 cells. SIGNIFICANCE Lactation BAs metabolism signal in gut-liver axis coordinated the risk of liver damage induced by exacerbated lipolysis in obesogenic pregnancy.
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Affiliation(s)
- Long Huang
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, PR China; Key Laboratory of Animal Disease-Resistant Nutrition of the Ministry of Education of China, Sichuan Agricultural University, Chengdu 611130, PR China; Key Laboratory of Animal Disease-Resistant Nutrition of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, PR China
| | - Yingjie Li
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, PR China; Key Laboratory of Animal Disease-Resistant Nutrition of the Ministry of Education of China, Sichuan Agricultural University, Chengdu 611130, PR China; Key Laboratory of Animal Disease-Resistant Nutrition of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, PR China
| | - Rui Tang
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, PR China; Key Laboratory of Animal Disease-Resistant Nutrition of the Ministry of Education of China, Sichuan Agricultural University, Chengdu 611130, PR China; Key Laboratory of Animal Disease-Resistant Nutrition of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, PR China
| | - Pu Yang
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, PR China; Key Laboratory of Animal Disease-Resistant Nutrition of the Ministry of Education of China, Sichuan Agricultural University, Chengdu 611130, PR China; Key Laboratory of Animal Disease-Resistant Nutrition of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, PR China
| | - Yong Zhuo
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, PR China; Key Laboratory of Animal Disease-Resistant Nutrition of the Ministry of Education of China, Sichuan Agricultural University, Chengdu 611130, PR China; Key Laboratory of Animal Disease-Resistant Nutrition of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, PR China
| | - Xuemei Jiang
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, PR China; Key Laboratory of Animal Disease-Resistant Nutrition of the Ministry of Education of China, Sichuan Agricultural University, Chengdu 611130, PR China; Key Laboratory of Animal Disease-Resistant Nutrition of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, PR China
| | - Lianqiang Che
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, PR China; Key Laboratory of Animal Disease-Resistant Nutrition of the Ministry of Education of China, Sichuan Agricultural University, Chengdu 611130, PR China; Key Laboratory of Animal Disease-Resistant Nutrition of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, PR China
| | - Yan Lin
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, PR China; Key Laboratory of Animal Disease-Resistant Nutrition of the Ministry of Education of China, Sichuan Agricultural University, Chengdu 611130, PR China; Key Laboratory of Animal Disease-Resistant Nutrition of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, PR China
| | - Shengyu Xu
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, PR China; Key Laboratory of Animal Disease-Resistant Nutrition of the Ministry of Education of China, Sichuan Agricultural University, Chengdu 611130, PR China; Key Laboratory of Animal Disease-Resistant Nutrition of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, PR China
| | - Jian Li
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, PR China; Key Laboratory of Animal Disease-Resistant Nutrition of the Ministry of Education of China, Sichuan Agricultural University, Chengdu 611130, PR China; Key Laboratory of Animal Disease-Resistant Nutrition of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, PR China
| | - Zhengfeng Fang
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, PR China; Key Laboratory of Animal Disease-Resistant Nutrition of the Ministry of Education of China, Sichuan Agricultural University, Chengdu 611130, PR China; Key Laboratory of Animal Disease-Resistant Nutrition of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, PR China
| | - Xilun Zhao
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, PR China; Key Laboratory of Animal Disease-Resistant Nutrition of the Ministry of Education of China, Sichuan Agricultural University, Chengdu 611130, PR China; Key Laboratory of Animal Disease-Resistant Nutrition of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, PR China
| | - Hua Li
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, PR China; Key Laboratory of Animal Disease-Resistant Nutrition of the Ministry of Education of China, Sichuan Agricultural University, Chengdu 611130, PR China; Key Laboratory of Animal Disease-Resistant Nutrition of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, PR China
| | - Min Yang
- Pet Nutrition and Health Research Center, Chengdu Agricultural College, Chengdu 611130, PR China
| | - Bin Feng
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, PR China; Key Laboratory of Animal Disease-Resistant Nutrition of the Ministry of Education of China, Sichuan Agricultural University, Chengdu 611130, PR China; Key Laboratory of Animal Disease-Resistant Nutrition of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, PR China
| | - De Wu
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, PR China; Key Laboratory of Animal Disease-Resistant Nutrition of the Ministry of Education of China, Sichuan Agricultural University, Chengdu 611130, PR China; Key Laboratory of Animal Disease-Resistant Nutrition of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, PR China.
| | - Lun Hua
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, PR China; Key Laboratory of Animal Disease-Resistant Nutrition of the Ministry of Education of China, Sichuan Agricultural University, Chengdu 611130, PR China; Key Laboratory of Animal Disease-Resistant Nutrition of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, PR China.
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Ma L, Lv J, Zhang A. Depletion of S-adenosylmethionine induced by arsenic exposure is involved in liver injury of rat through perturbing histone H3K36 trimethylation dependent bile acid metabolism. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2023; 334:122228. [PMID: 37481032 DOI: 10.1016/j.envpol.2023.122228] [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: 03/17/2023] [Revised: 06/22/2023] [Accepted: 07/18/2023] [Indexed: 07/24/2023]
Abstract
Long-term exposure to arsenic, a common environmental pollutant, can induce various types of liver injury, but the mechanism and treatment measures remain unclear. This study constructed a rat model of arsenic-induced liver injury, with methyl group donor S-adenosylmethionine (SAM) supplementation and Rosa roxburghii Tratt juice intervention, to explore the epigenetic mechanism and intervention method of arsenic-induced liver injury from the perspective of hepatic bile acid metabolism. The results showed that arsenic exposure induced the accumulation of total bile acids (TBA) in the liver and serum of rats, and the abnormalities in liver function and liver histopathology. Arsenic reduced histone H3K36 trimethylation (H3K36me3) in the liver via consuming methyl group donor SAM. The reduction of H3K36me3 was involved in arsenic-induced bile acid accumulation by inhibiting the transcription of negative feedback regulators Fxr and Fgfr4 for hepatic bile acid synthesis. SAM supplementation reversed arsenic-induced bile acid accumulation and liver injury by reactivating H3k36me3-dependent transcription of Fxr and Fgfr4. Moreover, this study found that Rosa roxburghii Tratt juice could rescue arsenic-induced SAM consumption, recover H3K36me3-dependent negative feedback regulation of hepatic bile acid synthesis, and alleviate arsenic-induced bile acid accumulation and liver injury. In conclusion, arsenic exposure perturbed H3K36me3-dependent hepatic bile acid metabolism via depleting SAM, thereby inducing hepatic bile acid accumulation and liver injury, which was ameliorated by the supporting effect of Rosa roxburghii Tratt juice on SAM. This study contributes to understanding the mechanism of arsenic-induced liver injury from the perspective of SAM-dependent epigenetics, providing new insight into its prevention and treatment.
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Affiliation(s)
- Lu Ma
- The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Department of Toxicology, School of Public Health, Guizhou Medical University, Guiyang, 550025, Guizhou, PR China.
| | - Jiaxin Lv
- The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Department of Toxicology, School of Public Health, Guizhou Medical University, Guiyang, 550025, Guizhou, PR China.
| | - Aihua Zhang
- The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Department of Toxicology, School of Public Health, Guizhou Medical University, Guiyang, 550025, Guizhou, PR China.
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12
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Zhou T, Li L, Zhu Z, Chen X, Wang Q, Zhu WH. Serum-Based Detection of Liver Pathology Using a Fluorogenic Alkaline Phosphatase Probe. Chembiochem 2023; 24:e202300321. [PMID: 37218114 DOI: 10.1002/cbic.202300321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 05/19/2023] [Accepted: 05/22/2023] [Indexed: 05/24/2023]
Abstract
Development of "ultrahigh contrast" fluorogenic probes for trapping alkaline phosphatase (ALP) activities in human serum is highly desirable for clinical auxiliary diagnosis for hepatobiliary diseases. However, the intrinsic dilemma of incomplete ionization of intramolecular charge transfer (ICT)-based ALP fluorophores and autofluorescence interference of serum result in low sensitivity and accuracy. Given that unique halogen effects could lead to a drastic decrease in the pKa value and a significant enhancement in the fluorescence quantum yield, herein we report an enzyme-activatable near-infrared probe based on a difluoro-substituted dicyanomethylene-4H-chromenep for achieving fluorescent quantification of human serum ALP. Rational design strategy is demonstrated by altering the substituted halogen groups to well regulate the pKa for meeting the physiological precondition. Owing to the complete ionization at pH 7.4 with tremendous fluorescence enhancement, the difluoro-substituted DCM-2F-HP manifests a linear relationship between the emission intensity and ALP concentration in both solution and serum samples. Along with measuring 77 human serum samples, the DCM-2F-HP based fluorescence method not only exhibits significant correlations with clinical colorimetry, but also distinguishes ALP patients from healthy volunteers, as well as assessing the progress of liver disease, thus providing a potential toolbox for quantitatively detecting ALP and warning the stage of hepatopathy.
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Affiliation(s)
- Tijian Zhou
- Shanghai Key Laboratory of Functional Materials Chemistry, Key Laboratory for Advanced Materials and Institute of Fine Chemicals, Joint International Research Laboratory of Precision Chemistry and Molecular Engineering, Feringa Nobel Prize Scientist Joint Research Center, Frontiers Science Center for Materiobiology and Dynamic Chemistry, School of Chemistry and Molecular Engineering, East China University of Science and Technology, 200237, Shanghai, China
| | - Li Li
- Department of Pathology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Zhirong Zhu
- Shanghai Key Laboratory of Functional Materials Chemistry, Key Laboratory for Advanced Materials and Institute of Fine Chemicals, Joint International Research Laboratory of Precision Chemistry and Molecular Engineering, Feringa Nobel Prize Scientist Joint Research Center, Frontiers Science Center for Materiobiology and Dynamic Chemistry, School of Chemistry and Molecular Engineering, East China University of Science and Technology, 200237, Shanghai, China
| | - Xiaoyan Chen
- Department of Pathology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Qi Wang
- Shanghai Key Laboratory of Functional Materials Chemistry, Key Laboratory for Advanced Materials and Institute of Fine Chemicals, Joint International Research Laboratory of Precision Chemistry and Molecular Engineering, Feringa Nobel Prize Scientist Joint Research Center, Frontiers Science Center for Materiobiology and Dynamic Chemistry, School of Chemistry and Molecular Engineering, East China University of Science and Technology, 200237, Shanghai, China
| | - Wei-Hong Zhu
- Shanghai Key Laboratory of Functional Materials Chemistry, Key Laboratory for Advanced Materials and Institute of Fine Chemicals, Joint International Research Laboratory of Precision Chemistry and Molecular Engineering, Feringa Nobel Prize Scientist Joint Research Center, Frontiers Science Center for Materiobiology and Dynamic Chemistry, School of Chemistry and Molecular Engineering, East China University of Science and Technology, 200237, Shanghai, China
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13
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Jiang T, Yang Z, Zhang Y, Zhang W, Doherty M, Li H, Yang T, Yang Y, Li J, Wang Y, Zeng C, Lei G, Wei J. Dysbiosis of gut microbiota, a potential mediator of bile acid compositions, and prevalence of hand synovitis: a community-based study. Rheumatology (Oxford) 2023; 62:3179-3187. [PMID: 36692134 DOI: 10.1093/rheumatology/kead042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 01/11/2023] [Accepted: 01/14/2023] [Indexed: 01/25/2023] Open
Abstract
OBJECTIVES Hand synovitis, a potentially modifiable pathological lesion, is common and associated with pain and hand OA; nevertheless, its pathogenesis remains uncertain. This study investigated the relationship between gut microbiota dysbiosis and hand synovitis prevalence and evaluated whether bile acids mediate the association. METHODS Participants were derived from a community-based observational study. Synovitis in each hand joint was assessed using US. Gut microbiota was evaluated using 16S ribosomal RNA amplicon sequencing on faeces, and plasma bile acids were measured by HPLC mass spectrometry. We examined the relationship between gut microbiota dysbiosis and hand synovitis prevalence, as well as the extent to which bile acids were involved in the association. RESULTS Among 1336 participants (mean age: 63.2 years; women: 58.8%), 18.3% had prevalent hand synovitis (unilateral in 13.6% and bilateral in 4.7%). β-diversity, but not α-diversity, of gut microbiota was significantly associated with prevalent hand synovitis. Higher relative abundance of the genus Prevotella and lower relative abundance of the genus Blautia were significantly associated with the prevalence of hand synovitis. Similar associations were also observed for laterality and the number of joints affected by hand synovitis. The association between Prevotella and hand synovitis was partially mediated through its effect on tauroursodeoxycholic acid and glycoursodeoxycholic acid, the mediation proportions being 25.7% and 21.6%, respectively. CONCLUSION Our findings suggest that gut microbiota dysbiosis is associated with the prevalence of hand synovitis. Such an association appears to be partially mediated by plasma bile acids.
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Affiliation(s)
- Ting Jiang
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, China
- Department of Ultrasonography, Xiangya Hospital, Central South University, Changsha, China
- Academic Rheumatology, School of Medicine, University of Nottingham, Nottingham, UK
- Pain Centre Versus Arthritis UK, Nottingham, UK
| | - Zidan Yang
- Hunan Key Laboratory of Joint Degeneration and Injury, Xiangya Hospital, Central South University, Changsha, China
| | - Yuqing Zhang
- Division of Rheumatology, Allergy, and Immunology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, USA
- The Mongan Institute, Massachusetts General Hospital, Harvard Medical School, Boston, USA
| | - Weiya Zhang
- Academic Rheumatology, School of Medicine, University of Nottingham, Nottingham, UK
- Pain Centre Versus Arthritis UK, Nottingham, UK
| | - Michael Doherty
- Academic Rheumatology, School of Medicine, University of Nottingham, Nottingham, UK
- Pain Centre Versus Arthritis UK, Nottingham, UK
| | - Hui Li
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Joint Degeneration and Injury, Xiangya Hospital, Central South University, Changsha, China
| | - Tuo Yang
- Academic Rheumatology, School of Medicine, University of Nottingham, Nottingham, UK
- Pain Centre Versus Arthritis UK, Nottingham, UK
- Health Management Center, Xiangya Hospital, Central South University, Changsha, China
| | - Yuanheng Yang
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, China
- Department of Plastic and Cosmetic Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Jiatian Li
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, China
| | - Yuqing Wang
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, China
| | - Chao Zeng
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Joint Degeneration and Injury, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Guanghua Lei
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Joint Degeneration and Injury, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Jie Wei
- Hunan Key Laboratory of Joint Degeneration and Injury, Xiangya Hospital, Central South University, Changsha, China
- Health Management Center, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
- Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, Changsha, China
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Chen X, Li H, Liu Y, Qi J, Dong B, Huang S, Zhao S, Zhu Y. Dimethyl Sulfoxide Inhibits Bile Acid Synthesis in Healthy Mice but Does Not Protect Mice from Bile-Acid-Induced Liver Damage. BIOLOGY 2023; 12:1105. [PMID: 37626991 PMCID: PMC10452260 DOI: 10.3390/biology12081105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 07/23/2023] [Accepted: 08/07/2023] [Indexed: 08/27/2023]
Abstract
Bile acids serve a vital function in lipid digestion and absorption; however, their accumulation can precipitate liver damage. In our study, we probed the effects of dimethyl sulfoxide (DMSO) on bile acid synthesis and the ensuing liver damage in mice induced by bile acids. Our findings indicate that DMSO efficaciously curbs bile acid synthesis by inhibiting key enzymes involved in the biosynthetic pathway, both in cultured primary hepatocytes and in vivo. Contrarily, we observed that DMSO treatment did not confer protection against bile-acid-induced liver damage in two distinct mouse models: one induced by a 0.1% DDC diet, leading to bile duct obstruction, and another induced by a CDA-HFD, resulting in non-alcoholic steatohepatitis (NASH). Histopathological and biochemical analyses unveiled a comparable extent of liver injury and fibrosis levels in DMSO-treated mice, characterized by similar levels of increase in Col1a1 and Acta2 expression and equivalent total liver collagen levels. These results suggest that, while DMSO can promptly inhibit bile acid synthesis in healthy mice, compensatory mechanisms might rapidly override this effect, negating any protective impact against bile-acid-induced liver damage in mice. Through these findings, our study underscores the need to reconsider treating DMSO as a mere inert solvent and prompts further exploration to identify more effective therapeutic strategies for the prevention and treatment of bile-acid-associated liver diseases.
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Affiliation(s)
- Xi Chen
- USDA/ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Huiqiao Li
- USDA/ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Yu’e Liu
- Tongji University Cancer Center, Shanghai Tenth People’s Hospital of Tongji University, School of Medicine, Tongji University, Shanghai 200092, China
| | - Jing Qi
- Department of Emergency, The Third Xiangya Hospital of Central South University, Changsha 410013, China;
| | - Bingning Dong
- Gastroenterology, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
| | - Shixia Huang
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Shangang Zhao
- Barshop Institute for Longevity and Aging Studies, Division of Endocrinology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
| | - Yi Zhu
- USDA/ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
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Duan G, Huang P, Zheng C, Zheng J, Yu J, Zhang P, Wan M, Li F, Guo Q, Yin Y, Duan Y. Development and Recovery of Liver Injury in Piglets by Incremental Injection of LPS. Antioxidants (Basel) 2023; 12:1143. [PMID: 37371873 DOI: 10.3390/antiox12061143] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 05/21/2023] [Accepted: 05/22/2023] [Indexed: 06/29/2023] Open
Abstract
This study aimed to explore the effects of the incremental injection of lipopolysaccharide (LPS) on liver histopathology, inflammation, oxidative status, and mitochondrial function in piglets. Forty healthy Duroc × Landrace × Yorkshire castrated boars (21 ± 2 days old, weight 6.84 ± 0.11 kg) were randomly assigned to five groups (n = 8) and then slaughtered on days 0 (group 0, without LPS injection), 1 (group 1), 5 (group 5), 9 (group 9), and 15 (group 15) of LPS injection, respectively. The results showed that, compared to the piglets without LPS injection, LPS injection caused liver injury in the early phase, as manifested by the increased activities of serum liver injury-related parameters (aspartate amino transferase, alanine aminotransferase, alkaline phosphatase, cholinesterase, and total bile acid) on day 1, and impaired liver morphology (disordered hepatic cell cord arrangement, dissolved and vacuolized hepatocytes, karyopycnosis, and inflammatory cell infiltration and congestion) on days 1 and 5. Meanwhile, LPS injection caused liver inflammation, oxidative stress, and mitochondrial dysfunction on days 1 and 5, as reflected by the upregulated mRNA expression of TNF-α, IL-6, IL-1β, TLR4, MyD88, and NF-κB; increased MPO and MDA content; and impaired mitochondrial morphology. However, these parameters were ameliorated in the later phase (days 9~15). Taken together, our data indicate that the incremental injection of the LPS-induced liver injury of piglets could be self-repaired.
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Affiliation(s)
- Geyan Duan
- CAS Key Laboratory of Agro-Ecological Processes in Subtropical Region, Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Scientific Observing and Experimental Station of Animal Nutrition and Feed Science in South-Central, Ministry of Agriculture, Changsha 410125, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Pan Huang
- CAS Key Laboratory of Agro-Ecological Processes in Subtropical Region, Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Scientific Observing and Experimental Station of Animal Nutrition and Feed Science in South-Central, Ministry of Agriculture, Changsha 410125, China
| | - Changbing Zheng
- College of Animal Science and Technology, Hunan Agricultural University, Changsha 410128, China
| | - Jie Zheng
- CAS Key Laboratory of Agro-Ecological Processes in Subtropical Region, Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Scientific Observing and Experimental Station of Animal Nutrition and Feed Science in South-Central, Ministry of Agriculture, Changsha 410125, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Jiayi Yu
- CAS Key Laboratory of Agro-Ecological Processes in Subtropical Region, Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Scientific Observing and Experimental Station of Animal Nutrition and Feed Science in South-Central, Ministry of Agriculture, Changsha 410125, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Peiwen Zhang
- College of Animal Science and Technology, Hunan Agricultural University, Changsha 410128, China
| | - Mengliao Wan
- College of Animal Science and Technology, Hunan Agricultural University, Changsha 410128, China
| | - Fengna Li
- CAS Key Laboratory of Agro-Ecological Processes in Subtropical Region, Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Scientific Observing and Experimental Station of Animal Nutrition and Feed Science in South-Central, Ministry of Agriculture, Changsha 410125, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Qiuping Guo
- CAS Key Laboratory of Agro-Ecological Processes in Subtropical Region, Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Scientific Observing and Experimental Station of Animal Nutrition and Feed Science in South-Central, Ministry of Agriculture, Changsha 410125, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yulong Yin
- CAS Key Laboratory of Agro-Ecological Processes in Subtropical Region, Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Scientific Observing and Experimental Station of Animal Nutrition and Feed Science in South-Central, Ministry of Agriculture, Changsha 410125, China
- University of Chinese Academy of Sciences, Beijing 100049, China
- College of Animal Science and Technology, Hunan Agricultural University, Changsha 410128, China
| | - Yehui Duan
- CAS Key Laboratory of Agro-Ecological Processes in Subtropical Region, Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Scientific Observing and Experimental Station of Animal Nutrition and Feed Science in South-Central, Ministry of Agriculture, Changsha 410125, China
- University of Chinese Academy of Sciences, Beijing 100049, China
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16
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Qu P, Rom O, Li K, Jia L, Gao X, Liu Z, Ding S, Zhao M, Wang H, Chen S, Xiong X, Zhao Y, Xue C, Zhao Y, Chu C, Wen B, Finney AC, Zheng Z, Cao W, Zhao J, Bai L, Zhao S, Sun D, Zeng R, Lin J, Liu W, Zheng L, Zhang J, Liu E, Chen YE. DT-109 ameliorates nonalcoholic steatohepatitis in nonhuman primates. Cell Metab 2023; 35:742-757.e10. [PMID: 37040763 DOI: 10.1016/j.cmet.2023.03.013] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 01/03/2023] [Accepted: 03/17/2023] [Indexed: 04/13/2023]
Abstract
Nonalcoholic steatohepatitis (NASH) prevalence is rising with no pharmacotherapy approved. A major hurdle in NASH drug development is the poor translatability of preclinical studies to safe/effective clinical outcomes, and recent failures highlight a need to identify new targetable pathways. Dysregulated glycine metabolism has emerged as a causative factor and therapeutic target in NASH. Here, we report that the tripeptide DT-109 (Gly-Gly-Leu) dose-dependently attenuates steatohepatitis and fibrosis in mice. To enhance the probability of successful translation, we developed a nonhuman primate model that histologically and transcriptionally mimics human NASH. Applying a multiomics approach combining transcriptomics, proteomics, metabolomics, and metagenomics, we found that DT-109 reverses hepatic steatosis and prevents fibrosis progression in nonhuman primates, not only by stimulating fatty acid degradation and glutathione formation, as found in mice, but also by modulating microbial bile acid metabolism. Our studies describe a highly translatable NASH model and highlight the need for clinical evaluation of DT-109.
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Affiliation(s)
- Pengxiang Qu
- Laboratory Animal Center, Xi'an Jiaotong University Health Science Center, 76 Yanta West Road, Xi'an, Shaanxi 710061, China
| | - Oren Rom
- Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, 2800 Plymouth Road, Ann Arbor, MI 48109, USA; Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA 71103, USA; Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA 71103, USA; Center for Cardiovascular Diseases and Sciences, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA 71103, USA
| | - Ke Li
- Beijing Tiantan Hospital, China National Clinical Research Center for Neurological Diseases, Advanced Innovation Center for Human Brain Protection, Capital Medical University, 6 Tiantan Xili, Chongwen District, Beijing 100050, China
| | - Linying Jia
- Laboratory Animal Center, Xi'an Jiaotong University Health Science Center, 76 Yanta West Road, Xi'an, Shaanxi 710061, China
| | - Xiaojing Gao
- Key Laboratory of Systems Health Science of Zhejiang Province, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China; CAS Key Laboratory of Systems Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
| | - Zhipeng Liu
- Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA
| | - Shusi Ding
- Beijing Tiantan Hospital, China National Clinical Research Center for Neurological Diseases, Advanced Innovation Center for Human Brain Protection, Capital Medical University, 6 Tiantan Xili, Chongwen District, Beijing 100050, China
| | - Mingming Zhao
- The Institute of Cardiovascular Sciences, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science of Ministry of Education, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing Key Laboratory of Cardiovascular Receptors Research, Health Science Center, Peking University, 38 Xue Yuan Road, Beijing 100191, China
| | - Huiqing Wang
- The Institute of Cardiovascular Sciences, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science of Ministry of Education, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing Key Laboratory of Cardiovascular Receptors Research, Health Science Center, Peking University, 38 Xue Yuan Road, Beijing 100191, China
| | - Shuangshuang Chen
- Department of Endocrinology and Metabolism, Fudan Institute of Metabolic Diseases, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Xuhui District, Shanghai 200031, China
| | - Xuelian Xiong
- Department of Endocrinology and Metabolism, Fudan Institute of Metabolic Diseases, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Xuhui District, Shanghai 200031, China
| | - Ying Zhao
- Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, 2800 Plymouth Road, Ann Arbor, MI 48109, USA
| | - Chao Xue
- Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, 2800 Plymouth Road, Ann Arbor, MI 48109, USA
| | - Yang Zhao
- Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, 2800 Plymouth Road, Ann Arbor, MI 48109, USA
| | - Chengshuang Chu
- CAS Key Laboratory of Systems Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
| | - Bo Wen
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA
| | - Alexandra C Finney
- Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA 71103, USA
| | - Zuowen Zheng
- Spring Biological Technology Development Co., Ltd, Fangchenggang, Guangxi 538000, China
| | - Wenbin Cao
- Laboratory Animal Center, Xi'an Jiaotong University Health Science Center, 76 Yanta West Road, Xi'an, Shaanxi 710061, China
| | - Jinpeng Zhao
- Laboratory Animal Center, Xi'an Jiaotong University Health Science Center, 76 Yanta West Road, Xi'an, Shaanxi 710061, China
| | - Liang Bai
- Laboratory Animal Center, Xi'an Jiaotong University Health Science Center, 76 Yanta West Road, Xi'an, Shaanxi 710061, China
| | - Sihai Zhao
- Laboratory Animal Center, Xi'an Jiaotong University Health Science Center, 76 Yanta West Road, Xi'an, Shaanxi 710061, China
| | - Duxin Sun
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA
| | - Rong Zeng
- Key Laboratory of Systems Health Science of Zhejiang Province, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China; CAS Key Laboratory of Systems Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
| | - Jiandie Lin
- Life Sciences Institute and Department of Cell & Developmental Biology, University of Michigan Medical Center, Ann Arbor, MI 48109, USA
| | - Wanqing Liu
- Department of Pharmaceutical Sciences and Department of Pharmacology, Wayne State University, Detroit, MI 48201, USA
| | - Lemin Zheng
- Beijing Tiantan Hospital, China National Clinical Research Center for Neurological Diseases, Advanced Innovation Center for Human Brain Protection, Capital Medical University, 6 Tiantan Xili, Chongwen District, Beijing 100050, China; The Institute of Cardiovascular Sciences, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science of Ministry of Education, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing Key Laboratory of Cardiovascular Receptors Research, Health Science Center, Peking University, 38 Xue Yuan Road, Beijing 100191, China.
| | - Jifeng Zhang
- Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, 2800 Plymouth Road, Ann Arbor, MI 48109, USA.
| | - Enqi Liu
- Laboratory Animal Center, Xi'an Jiaotong University Health Science Center, 76 Yanta West Road, Xi'an, Shaanxi 710061, China.
| | - Y Eugene Chen
- Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, 2800 Plymouth Road, Ann Arbor, MI 48109, USA.
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17
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Liu AN, Xu CF, Liu YR, Sun DQ, Jiang L, Tang LJ, Zhu PW, Chen SD, Liu WY, Wang XD, Targher G, Byrne CD, Wong VWS, Fu J, Su MM, Loomba R, Zheng MH, Ni Y. Secondary bile acids improve risk prediction for non-invasive identification of mild liver fibrosis in nonalcoholic fatty liver disease. Aliment Pharmacol Ther 2023; 57:872-885. [PMID: 36670060 PMCID: PMC10792530 DOI: 10.1111/apt.17362] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 10/03/2022] [Accepted: 12/07/2022] [Indexed: 01/22/2023]
Abstract
BACKGROUND Dysregulated bile acid (BA) metabolism has been linked to steatosis, inflammation, and fibrosis in nonalcoholic fatty liver disease (NAFLD). AIM To determine whether circulating BA levels accurately stage liver fibrosis in NAFLD. METHODS We recruited 550 Chinese adults with biopsy-proven NAFLD and varying levels of fibrosis. Ultra-performance liquid chromatography coupled with tandem mass spectrometry was performed to quantify 38 serum BAs. RESULTS Compared to those without fibrosis, patients with mild fibrosis (stage F1) had significantly higher levels of secondary BAs, and increased diastolic blood pressure (DBP), alanine aminotransferase (ALT), body mass index, and waist circumstance (WC). The combination of serum BAs with WC, DBP, ALT, or Homeostatic Model Assessment for Insulin Resistance performed well in identifying mild fibrosis, in men and women, and in those with/without obesity, with AUROCs 0.80, 0.88, 0.75 and 0.78 in the training set (n = 385), and 0.69, 0.80, 0.61 and 0.69 in the testing set (n = 165), respectively. In comparison, the combination of BAs and clinical/biochemical biomarkers performed less well in identifying significant fibrosis (F2-4). In women and in non-obese subjects, AUROCs were 0.75 and 0.71 in the training set, 0.65 and 0.66 in the validation set, respectively. However, these AUROCs were higher than those observed for the fibrosis-4 index, NAFLD fibrosis score, and Hepamet fibrosis score. CONCLUSIONS Secondary BA levels were significantly increased in NAFLD, especially in those with mild fibrosis. The combination of serum BAs and clinical/biochemical biomarkers for identifying mild fibrosis merits further assessment.
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Affiliation(s)
- A-Na Liu
- National Clinical Research Center for Child Health, The Children’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Cui-Fang Xu
- National Clinical Research Center for Child Health, The Children’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Ya-Ru Liu
- National Clinical Research Center for Child Health, The Children’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Dan-Qin Sun
- Department of Nephrology, The Affiliated Wuxi No. 2 People’s Hospital of Nanjing Medical University, Wuxi, China
- Affiliated Wuxi Clinical College of Nantong University, Wuxi, China
| | - Ling Jiang
- National Clinical Research Center for Child Health, The Children’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Liang-Jie Tang
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Pei-Wu Zhu
- Department of Laboratory Medicine, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Sui-Dan Chen
- Department of Pathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Wen-Yue Liu
- Department of Endocrinology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xiao-Dong Wang
- Key Laboratory of Diagnosis and Treatment for the Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, China
| | - Giovanni Targher
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Verona, Verona, Italy
| | - Christopher D. Byrne
- Southampton National Institute for Health and Care Research Biomedical Research Centre, University Hospital Southampton & University of Southampton, Southampton General Hospital, Southampton, UK
| | - Vincent Wai-Sun Wong
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
- State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China
| | - Junfen Fu
- National Clinical Research Center for Child Health, The Children’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Ming-Ming Su
- Clinical Mass Spectrometry Innovation Center, Shanghai Keyi Biotechnology Co., Ltd., Shanghai, China
| | - Rohit Loomba
- NAFLD Research Center, Division of Gastroenterology, University of California, San Diego, La Jolla, California, USA
| | - Ming-Hua Zheng
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Key Laboratory of Diagnosis and Treatment for the Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, China
- Institute of Hepatology, Wenzhou Medical University, Wenzhou, China
| | - Yan Ni
- National Clinical Research Center for Child Health, The Children’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
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18
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Qi L, Chen Y. Circulating Bile Acids as Biomarkers for Disease Diagnosis and Prevention. J Clin Endocrinol Metab 2023; 108:251-270. [PMID: 36374935 DOI: 10.1210/clinem/dgac659] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 10/11/2022] [Accepted: 11/11/2022] [Indexed: 11/15/2022]
Abstract
CONTEXT Bile acids (BAs) are pivotal signaling molecules that regulate energy metabolism and inflammation. Recent epidemiological studies have reported specific alterations in circulating BA profiles in certain disease states, including obesity, type 2 diabetes mellitus (T2DM), nonalcoholic fatty liver disease (NAFLD), and Alzheimer disease (AD). In the past decade, breakthroughs have been made regarding the translation of BA profiling into clinical use for disease prediction. In this review, we summarize and synthesize recent data on variation in circulating BA profiles in patients with various diseases to evaluate the value of these biomarkers in human plasma for early diagnosis. EVIDENCE ACQUISITION This review is based on a collection of primary and review literature gathered from a PubMed search for BAs, obesity, T2DM, insulin resistance (IR), NAFLD, hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), colon cancer, and AD, among other keywords. EVIDENCE SYNTHESIS Individuals with obesity, T2DM, HCC, CCA, or AD showed specific alterations in circulating BA profiles. These alterations may have existed long before the initial diagnosis of these diseases. The intricate relationship between obesity, IR, and NAFLD complicates the establishment of clear and independent associations between BA profiles and nonalcoholic steatohepatitis. Alterations in the levels of total BAs and several BA species were seen across the entire spectrum of NAFLD, demonstrating significant increases with the worsening of histological features. CONCLUSIONS Aberrant circulating BA profiles are an early event in the onset and progression of obesity, T2DM, HCC, and AD. The pleiotropic effects of BAs explain these broad connections. Circulating BA profiles could provide a basis for the development of biomarkers for the diagnosis and prevention of a wide range of diseases.
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Affiliation(s)
- Li Qi
- Department of Rheumatology and Immunology, Shengjing Hospital of China Medical University, Shenyang 110022, Liaoning Province, China
| | - Yongsheng Chen
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
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Investigation of the Therapeutic Effect of Total Alkaloids of Corydalis saxicola Bunting on CCl 4-Induced Liver Fibrosis in Rats by LC/MS-Based Metabolomics Analysis and Network Pharmacology. Metabolites 2022; 13:metabo13010009. [PMID: 36676934 PMCID: PMC9866371 DOI: 10.3390/metabo13010009] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Revised: 12/07/2022] [Accepted: 12/16/2022] [Indexed: 12/24/2022] Open
Abstract
Liver fibrosis is a pathological result of liver injury that usually leads to a pathophysiological wound healing response. The total alkaloids of Corydalis saxicola Bunting (TACS) have been used for hepatoprotective effects on the liver. However, its exact therapeutic mechanisms of liver fibrosis are not yet well understood. To explore the potential anti-fibrosis mechanism of TACS, metabolomics coupled with network pharmacology were applied to reveal the underlying mechanisms. Ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) combined with multivariate statistical analyses were performed to estimate changes in metabolic profiles. As a result, a total of 23 metabolites in rats with liver fibrosis were altered; of these, 11 had been downregulated and 12 had been upregulated compared with the control group. After TACS treatment, the levels of 13 metabolites were significantly restored compared with the CCl4-treated group, of which 4 metabolites were up-regulated and 9 metabolites were down-regulated. Many of these metabolites are involved in the bile acid metabolism, glutathione metabolism, tryptophan metabolism and purine metabolism. Then, three key targets, including cytochrome P450 family1 subfamily A member 1 (CYP1A1), ornithine decarboxylase 1 (OCD1) and monoamine oxidase Type B (MAOB) were predicted as potential therapeutic targets of TACS against liver fibrosis through network pharmacology analysis. Finally, palmatine, tetrahydropalmatine and dehydrocavidine were screened as potential active compounds responsible for the anti-fibrosis effect of TACS by molecular docking analysis. This study reveals that TACS exerted anti-fibrosis effects by regulating the liver metabolic pathway with multiple components and multiple targets, which is helpful to further clarify the hepatoprotective mechanisms of natural plant extracts.
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20
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Pan H, Zhou M, Ju Z, Luo J, Jin J, Shen L, Zhou P, Huang R. Potential role of gut microbiota-LCA-INSR axis in high fat-diet-induced non-alcoholic fatty liver dysfunction: From perspective of radiation variation. Curr Res Food Sci 2022; 5:1685-1700. [PMID: 36204709 PMCID: PMC9530674 DOI: 10.1016/j.crfs.2022.09.022] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2022] [Revised: 09/09/2022] [Accepted: 09/17/2022] [Indexed: 11/28/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a progressive disease of the liver covering a range of conditions from hepatic steatosis to liver fibrosis. NAFLD could be induced by High-fat-diet(HFD). Ionizing radiation is widely used in medical diagnosis and therapy as well as is a common risk factor in occupational environment. Whether the exposure of various dose of radiation has effects on HFD-induced NAFLD remains unclear. Here, we reported that radiation exposure promoted HFD-induced NAFLD in a dose-response manner. Furthermore, the gut microbiota composition had significant difference among mice with or without radiation treatment. Specifically, the Bacteroidetes/Firmicutes ratio, the abundance of A. muciniphila, Butyricococcus, and Clostridiaceae decreased significantly in the mice with co-exposure of high dose of radiation and HFD treatment. A fecal transplantation trial (FMT) further verified the role of gut microbiota in the regulation of the liver response to co-exposure of high dose of radiation and HFD treatment. Notably, the gut microbiome analysis showed plasma lithocholic acid (LCA) level increased in the mice with co-exposure of high dose of radiation and HFD treatment. Following antibiotic and probiotic treatments there was a significantly decreased LCA bile acid concentration and subsequent promotion of INSR/PI3K/Akt insulin signaling in the liver tissues. Our results demonstrate that the co-exposure of radiation and HFD aggravates the HFD-induced NAFLD through gut microbiota-LCA-INSR axis. Probiotics supplementation is a potential way to protect against co-exposure of radiation and HFD-induced liver damage. Meanwhile, our study provide a new insight that population with potential HFD-induced damage should pay more attention on preventing from liver damage while exposing radiation.
Gut microbiota-lithocholic acid-insulin receptor (LCA-INSR) axis involves the promotion effects of radiation on HFD-induced NAFLD. Probiotics improve the liver damage induced by co-exposure of radiation and HFD.
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Affiliation(s)
- Huiji Pan
- Department of Occupational and Environmental Health, Xiangya School of Public Health, Central South University, Changsha, Hunan Province, 410078, China
| | - Meiling Zhou
- Department of Occupational and Environmental Health, Xiangya School of Public Health, Central South University, Changsha, Hunan Province, 410078, China
- Department of Radiation Biology, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, AMMS, Beijing, China
| | - Zhao Ju
- Department of Occupational and Environmental Health, Xiangya School of Public Health, Central South University, Changsha, Hunan Province, 410078, China
- Department of Radiation Biology, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, AMMS, Beijing, China
| | - Jinhua Luo
- Department of Occupational and Environmental Health, Xiangya School of Public Health, Central South University, Changsha, Hunan Province, 410078, China
| | - Jing Jin
- Department of Occupational and Environmental Health, Xiangya School of Public Health, Central South University, Changsha, Hunan Province, 410078, China
| | - Liangfang Shen
- Department of Oncology, Xiangya Hospital, Central South University, China
| | - Pingkun Zhou
- Department of Radiation Biology, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, AMMS, Beijing, China
| | - Ruixue Huang
- Department of Occupational and Environmental Health, Xiangya School of Public Health, Central South University, Changsha, Hunan Province, 410078, China
- Corresponding author.
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21
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Dietary Cholic Acid Exacerbates Liver Fibrosis in NASH Model of Sprague–Dawley Rats Fed a High-Fat and High-Cholesterol Diet. Int J Mol Sci 2022; 23:ijms23169268. [PMID: 36012527 PMCID: PMC9409005 DOI: 10.3390/ijms23169268] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 08/10/2022] [Accepted: 08/15/2022] [Indexed: 12/02/2022] Open
Abstract
Background: Recently, we established a novel rodent model of nonalcoholic steatohepatitis (NASH) with advanced fibrosis induced by a high-fat and high-cholesterol (HFC) diet containing cholic acid (CA), which is known to cause hepatotoxicity. The present study aimed to elucidate the direct impact of dietary CA on the progression of NASH induced by feeding the HFC diet. Methods: Nine-week-old male Sprague–Dawley rats were randomly assigned to receive a normal, HFC, or CA-supplemented (0.1%, 0.5% or 2.0%, w/w) HFC diet for 9 weeks. Results: Histopathological assessment revealed that the supplementation of CA dose-dependently aggravated hepatic steatosis, inflammation, and fibrosis, reaching stage 4 cirrhosis in the 2.0% CA diet group. In contrast, the rats that were fed the HFC diet without any added CA developed mild steatosis and inflammation without fibrosis. The hepatic cholesterol content and mRNA expression involved in inflammatory response and fibrogenesis was higher in a CA dose-dependent manner. The hepatic chenodeoxycholic acid levels were higher in 2.0% CA diet group than in the control, although hepatic levels of total bile acid and CA did not increase dose-dependently with CA intake. Conclusion: Adding CA to the HFC diet altered bile acid metabolism and inflammatory response and triggered the development of fibrosis in the rat liver.
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22
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Rivera-Andrade A, Petrick JL, Alvarez CS, Graubard BI, Florio AA, Kroker-Lobos MF, Parisi D, Freedman ND, Lazo M, Guallar E, Groopman JD, Ramirez-Zea M, McGlynn KA. Circulating bile acid concentrations and non-alcoholic fatty liver disease in Guatemala. Aliment Pharmacol Ther 2022; 56:321-329. [PMID: 35484638 PMCID: PMC9233027 DOI: 10.1111/apt.16948] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Revised: 03/21/2022] [Accepted: 04/12/2022] [Indexed: 02/06/2023]
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is a major liver disease worldwide. Bile acid dysregulation may be a key feature in its pathogenesis and progression. AIMS To characterise the relationship between bile acid levels and NAFLD at the population level METHODS: We conducted a cross-sectional study in Guatemala in 2016 to examine the prevalence of NAFLD. Participants (n = 415) completed questionnaires, donated blood samples and had a brief medical exam. NAFLD was determined by calculation of the fatty liver index. The levels of 15 circulating bile acids were determined by LC-MS/MS. Adjusted prevalence odds ratios (PORadj ) and 95% CI were calculated to examine the relationships between bile acid levels (in tertiles) and NAFLD. RESULTS Persons with NAFLD had significantly higher levels of the conjugated primary bile acids glycocholic acid (GCA) (PORadj T3 vs T1 = 1.85), taurocholic acid (TCA) (PORadj T3 vs T1 = 2.45) and taurochenodeoxycholic acid (TCDCA) (PORadj T3 vs T1 = 2.10), as well as significantly higher levels the unconjugated secondary bile acid, deoxycholic acid (DCA) (PORadj T3 vs T1 = 1.78) and its conjugated form, taurodeoxycholic acid (TDCA) (PORadj T3 vs T1 = 1.81). CONCLUSIONS The bile acid levels of persons with and without NAFLD differed significantly. Among persons with NAFLD, higher levels of the conjugated forms of CA (i.e. GCA, TCA) and the secondary bile acids that derive from CA (i.e. DCA, TDCA) may indicate there is hepatic overproduction of CA, which may affect the liver via aberrant signalling mediated by the bile acids.
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Affiliation(s)
- Alvaro Rivera-Andrade
- Institute of Nutrition of Central America and Panama (INCAP) Research Center for the Prevention of Chronic Diseases, Institute of Nutrition of Central America and Panama, Guatemala City, Guatemala
| | | | - Christian S. Alvarez
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
| | - Barry I. Graubard
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
| | - Andrea A. Florio
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA,Department of Nutrition, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA
| | - Maria F. Kroker-Lobos
- Institute of Nutrition of Central America and Panama (INCAP) Research Center for the Prevention of Chronic Diseases, Institute of Nutrition of Central America and Panama, Guatemala City, Guatemala
| | | | - Neal D. Freedman
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
| | - Mariana Lazo
- Department of General Internal Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, USA,Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA
| | - Eliseo Guallar
- Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA
| | - John D. Groopman
- Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA,Department of Environmental Health and Engineering, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA
| | - Manuel Ramirez-Zea
- Institute of Nutrition of Central America and Panama (INCAP) Research Center for the Prevention of Chronic Diseases, Institute of Nutrition of Central America and Panama, Guatemala City, Guatemala
| | - Katherine A. McGlynn
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
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Callender C, Attaye I, Nieuwdorp M. The Interaction between the Gut Microbiome and Bile Acids in Cardiometabolic Diseases. Metabolites 2022; 12:65. [PMID: 35050187 PMCID: PMC8778259 DOI: 10.3390/metabo12010065] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 12/20/2021] [Accepted: 01/06/2022] [Indexed: 12/24/2022] Open
Abstract
Cardio-metabolic diseases (CMD) are a spectrum of diseases (e.g., type 2 diabetes, atherosclerosis, non-alcohol fatty liver disease (NAFLD), and metabolic syndrome) that are among the leading causes of morbidity and mortality worldwide. It has long been known that bile acids (BA), which are endogenously produced signalling molecules from cholesterol, can affect CMD risk and progression and directly affect the gut microbiome (GM). Moreover, studies focusing on the GM and CMD risk have dramatically increased in the past decade. It has also become clear that the GM can function as a "new" endocrine organ. BA and GM have a complex and interdependent relationship with several CMD pathways. This review aims to provide a comprehensive overview of the interplay between BA metabolism, the GM, and CMD risk and progression.
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Affiliation(s)
- Cengiz Callender
- Department of Internal and Vascular Medicine, Amsterdam University Medical Center, 1105 AZ Amsterdam, The Netherlands; (I.A.); (M.N.)
| | - Ilias Attaye
- Department of Internal and Vascular Medicine, Amsterdam University Medical Center, 1105 AZ Amsterdam, The Netherlands; (I.A.); (M.N.)
| | - Max Nieuwdorp
- Department of Internal and Vascular Medicine, Amsterdam University Medical Center, 1105 AZ Amsterdam, The Netherlands; (I.A.); (M.N.)
- Department of Experimental Vascular Medicine, Amsterdam University Medical Center, 1105 AZ Amsterdam, The Netherlands
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24
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Yang R, Qian L. Research on Gut Microbiota-Derived Secondary Bile Acids in Cancer Progression. Integr Cancer Ther 2022; 21:15347354221114100. [PMID: 35880833 PMCID: PMC9421216 DOI: 10.1177/15347354221114100] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022] Open
Abstract
The interaction between gut microbiota-derived metabolites and the body plays a
significant role in the occurrence and development of cancer. Secondary bile
acids (BAs) are the important products produced from gut microbial fermentation
of primary BAs, mainly deoxycholic acid (DCA) and lithocholic acid (LCA). In the
gut, they can influence the structure of the microbial communities. Several
studies have demonstrated that secondary BAs, as signaling molecules, can
activate a variety of signaling pathways. They can inhibit the apoptosis of
cancer cells, induce the progression of cancer cell cycles, enhance the ability
of metastasis and invasion of cancer cells, and promote the transformation of
cells into cancer stem cells (CSCs). Moreover, secondary BAs promote cancer by
regulating the function of immune cells. Therefore, targeted manipulation of gut
microbial and secondary BAs has the potential to be developed as for treatment
and prevention of various cancers.
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Affiliation(s)
- Rong Yang
- Medical College, Yangzhou University, Yangzhou, China
| | - Li Qian
- Medical College, Yangzhou University, Yangzhou, China
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25
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Schyman P, Printz RL, Pannala VR, AbdulHameed MDM, Estes SK, Shiota C, Boyd KL, Shiota M, Wallqvist A. Genomics and metabolomics of early-stage thioacetamide-induced liver injury: An interspecies study between guinea pig and rat. Toxicol Appl Pharmacol 2021; 430:115713. [PMID: 34492290 PMCID: PMC8511347 DOI: 10.1016/j.taap.2021.115713] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Revised: 08/10/2021] [Accepted: 09/02/2021] [Indexed: 12/27/2022]
Abstract
To study the complex processes involved in liver injuries, researchers rely on animal investigations, using chemically or surgically induced liver injuries, to extrapolate findings and infer human health risks. However, this presents obvious challenges in performing a detailed comparison and validation between the highly controlled animal models and development of liver injuries in humans. Furthermore, it is not clear whether there are species-dependent and -independent molecular initiating events or processes that cause liver injury before they eventually lead to end-stage liver disease. Here, we present a side-by-side study of rats and guinea pigs using thioacetamide to examine the similarities between early molecular initiating events during an acute-phase liver injury. We exposed Sprague Dawley rats and Hartley guinea pigs to a single dose of 25 or 100 mg/kg thioacetamide and collected blood plasma for metabolomic analysis and liver tissue for RNA-sequencing. The subsequent toxicogenomic analysis identified consistent liver injury trends in both genomic and metabolomic data within 24 and 33 h after thioacetamide exposure in rats and guinea pigs, respectively. In particular, we found species similarities in the key injury phenotypes of inflammation and fibrogenesis in our gene module analysis for liver injury phenotypes. We identified expression of several common genes (e.g., SPP1, TNSF18, SERPINE1, CLDN4, TIMP1, CD44, and LGALS3), activation of injury-specific KEGG pathways, and alteration of plasma metabolites involved in amino acid and bile acid metabolism as some of the key molecular processes that changed early upon thioacetamide exposure and could play a major role in the initiation of acute liver injury.
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Affiliation(s)
- Patric Schyman
- Department of Defense Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Development Command, Fort Detrick, MD, USA; The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, USA
| | - Richard L Printz
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Venkat R Pannala
- Department of Defense Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Development Command, Fort Detrick, MD, USA; The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, USA.
| | - Mohamed Diwan M AbdulHameed
- Department of Defense Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Development Command, Fort Detrick, MD, USA; The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, USA
| | - Shanea K Estes
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Chiyo Shiota
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Kelli Lynn Boyd
- Department of Pathology, Microbiology and Immunology, Division of Comparative Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Masakazu Shiota
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN, USA.
| | - Anders Wallqvist
- Department of Defense Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Development Command, Fort Detrick, MD, USA.
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26
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Gao X, Ruan Y, Zhu X, Lin X, Xin Y, Li X, Mai M, Guo H. Deoxycholic Acid Promotes Pyroptosis in Free Fatty Acid-Induced Steatotic Hepatocytes by Inhibiting PINK1-Mediated Mitophagy. Inflammation 2021; 45:639-650. [PMID: 34674097 DOI: 10.1007/s10753-021-01573-1] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Revised: 09/28/2021] [Accepted: 09/29/2021] [Indexed: 02/06/2023]
Abstract
Nonalcoholic steatohepatitis (NASH) is the inflammatory subtype of nonalcoholic fatty liver disease (NAFLD), which can lead to liver fibrosis and cirrhosis. Bile acid levels are correlated with markers of hepatic injury in NASH, suggesting a possible role for bile acids in the progression of NAFLD. Here, we examined the role of deoxycholic acid (DCA) in driving steatotic hepatocytes to pyroptosis, a pro-inflammatory form of programmed cell death. HepG2 cells were stimulated with odium oleate and sodium palmitate for modeling steatotic hepatocytes and then treated with DCA alone or in combination with a specific mitophagy agonist, carbonyl cyanide 3-chlorophenylhydrazone (CCCP). Our results showed that DCA dose-dependently induced a pro-inflammatory response in steatotic hepatocytes but had no significant effect on lipid accumulation. Moreover, activation of the NLRP3 inflammasome and pyroptosis were triggered by DCA. Expression levels of the mitophagy markers PTEN-induced kinase 1 (PINK1) and E3 ubiquitin ligase Parkin were significantly diminished by DCA, whereas induction of mitophagy by CCCP prevented DCA-induced inflammatory response and restored the pyroptosis. Collectively, our data showed that DCA-induced pyroptosis involves the inhibition of PINK1-mediated mitophagy and the activation of the NLRP3 inflammasome. These findings provide insight into the association of DCA with mitophagy, pyroptosis, and inflammation in NASH.
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Affiliation(s)
- Xuebin Gao
- Department of Nutrition, School of Public Health, Guangdong Medical University, Dongguan, 523808, China
| | - Yongdui Ruan
- Department of Traditional Chinese Medicine, the First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, 523710, China
| | - Xuan Zhu
- Department of Nutrition, School of Public Health, Guangdong Medical University, Dongguan, 523808, China
| | - Xiaozhuan Lin
- Department of Nutrition, School of Public Health, Guangdong Medical University, Dongguan, 523808, China
| | - Yan Xin
- Department of Nutrition, School of Public Health, Guangdong Medical University, Dongguan, 523808, China
| | - Xiang Li
- Department of Nutrition, School of Public Health, Guangdong Medical University, Dongguan, 523808, China
| | - Meiqing Mai
- Department of Nutrition, School of Public Health, Guangdong Medical University, Dongguan, 523808, China
| | - Honghui Guo
- Department of Nutrition, School of Public Health, Guangdong Medical University, Dongguan, 523808, China. .,Dongguan Key Laboratory of Environmental Medicine, Guangdong Medical University, Dongguan, 523808, China.
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27
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Lv S, Yu H, Liu X, Gao X. The Study on the Mechanism of Hugan Tablets in Treating Drug-Induced Liver Injury Induced by Atorvastatin. Front Pharmacol 2021; 12:683707. [PMID: 34262454 PMCID: PMC8275032 DOI: 10.3389/fphar.2021.683707] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 05/12/2021] [Indexed: 01/12/2023] Open
Abstract
Atorvastatin is a widely used lipid-lowering drug in the clinic. Research shows that taking long-term atorvastatin has the risk of drug-induced liver injury (DILI) in most patients. Hugan tablets, a commonly used drug for liver disease, can effectively lower transaminase and protect the liver. However, the underlying mechanism of Hugan tablets alleviating atorvastatin-induced DILI remains unclear. To address this problem, comprehensive chemical profiling and network pharmacology methods were used in the study. First, the strategy of "compound-single herb-TCM prescription" was applied to characterize the ingredients of Hugan tablets. Then, active ingredients and potential targets of Hugan tablets in DILI treatment were screened using network pharmacology, molecular docking, and literature research. In the end, the mechanism of Hugan tablets in treating atorvastatin-induced DILI was elucidated. The results showed that Hugan tablets can effectively alleviate DILI induced by atorvastatin in model rats, and 71 compounds were characterized from Hugan tablets. Based on these compounds, 271 potential targets for the treatment of DILI were predicted, and 10 key targets were chosen by characterizing protein-protein interactions. Then, 30 potential active ingredients were screened through the molecular docking with these 10 key targets, and their biological activity was explained based on literature research. Finally, the major 19 active ingredients of Hugan tablets were discovered. In addition, further enrichment analysis of 271 targets indicated that the PI3K-Akt, TNF, HIF-1, Rap1, and FoxO signaling pathways may be the primary pathways regulated by Hugan tablets in treating DILI. This study proved that Hugan tablets could alleviate atorvastatin-induced DILI through multiple components, targets, and pathways.
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Affiliation(s)
| | | | | | - Xiaoyan Gao
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
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28
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Marques V, Afonso MB, Bierig N, Duarte-Ramos F, Santos-Laso Á, Jimenez-Agüero R, Eizaguirre E, Bujanda L, Pareja MJ, Luís R, Costa A, Machado MV, Alonso C, Arretxe E, Alustiza JM, Krawczyk M, Lammert F, Tiniakos DG, Flehmig B, Cortez-Pinto H, Banales JM, Castro RE, Normann A, Rodrigues CMP. Adiponectin, Leptin, and IGF-1 Are Useful Diagnostic and Stratification Biomarkers of NAFLD. Front Med (Lausanne) 2021; 8:683250. [PMID: 34249975 PMCID: PMC8260936 DOI: 10.3389/fmed.2021.683250] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2021] [Accepted: 05/10/2021] [Indexed: 12/15/2022] Open
Abstract
Background: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease where liver biopsy remains the gold standard for diagnosis. Here we aimed to evaluate the role of circulating adiponectin, leptin, and insulin-like growth factor 1 (IGF-1) levels as non-invasive NAFLD biomarkers and assess their correlation with the metabolome. Materials and Methods: Leptin, adiponectin, and IGF-1 serum levels were measured by ELISA in two independent cohorts of biopsy-proven obese NAFLD patients and healthy-liver controls (discovery: 38 NAFLD, 13 controls; validation: 194 NAFLD, 31 controls) and correlated with clinical data, histology, genetic parameters, and serum metabolomics. Results: In both cohorts, leptin increased in NAFLD vs. controls (discovery: AUROC 0.88; validation: AUROC 0.83; p < 0.0001). The leptin levels were similar between obese and non-obese healthy controls, suggesting that obesity is not a confounding factor. In the discovery cohort, adiponectin was lower in non-alcoholic steatohepatitis (NASH) vs. non-alcoholic fatty liver (AUROC 0.87; p < 0.0001). For the validation cohort, significance was attained for homozygous for PNPLA3 allele c.444C (AUROC 0.63; p < 0.05). Combining adiponectin with specific serum lipids improved the assay performance (AUROC 0.80; p < 0.0001). For the validation cohort, IGF-1 was lower with advanced fibrosis (AUROC 0.67, p < 0.05), but combination with international normalized ratio (INR) and ferritin increased the assay performance (AUROC 0.81; p < 0.01). Conclusion: Serum leptin discriminates NAFLD, and adiponectin combined with specific lipids stratifies NASH. IGF-1, INR, and ferritin distinguish advanced fibrosis.
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Affiliation(s)
- Vanda Marques
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Marta B. Afonso
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | | | - Filipa Duarte-Ramos
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
- EPIUnit–Instituto de Saúde Pública, Universidade do Porto, Oporto, Portugal
| | - Álvaro Santos-Laso
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
| | - Raul Jimenez-Agüero
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
| | - Emma Eizaguirre
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
| | - Luis Bujanda
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Instituto de Salud Carlos III), Madrid, Spain
| | | | - Rita Luís
- Department of Pathological Anatomy, Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte, Lisbon, Portugal
| | - Adília Costa
- Department of Pathological Anatomy, Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte, Lisbon, Portugal
| | - Mariana V. Machado
- Faculdade de Medicina, Clinica Universitária de Gastrenterologia, Universidade de Lisboa, Lisbon, Portugal
- Department of Gastroenterology, Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte, Lisbon, Portugal
| | | | - Enara Arretxe
- OWL Metabolomics, Bizkaia Technology Park, Derio, Spain
| | - José M. Alustiza
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
- Radiology Service, Osatek, Donostia, Spain
| | - Marcin Krawczyk
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany
- Laboratory of Metabolic Liver Diseases, Department of General, Transplant and Liver Surgery, Centre for Preclinical Research, Medical University of Warsaw, Warsaw, Poland
| | - Frank Lammert
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany
| | - Dina G. Tiniakos
- Faculty of Medical Sciences, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
- Department of Pathology, Aretaieio Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | | | - Helena Cortez-Pinto
- Faculdade de Medicina, Clinica Universitária de Gastrenterologia, Universidade de Lisboa, Lisbon, Portugal
- Department of Gastroenterology, Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte, Lisbon, Portugal
| | - Jesus M. Banales
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Instituto de Salud Carlos III), Madrid, Spain
- IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
| | - Rui E. Castro
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | | | - Cecília M. P. Rodrigues
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
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Thomas CE, Luu HN, Wang R, Xie G, Adams-Haduch J, Jin A, Koh WP, Jia W, Behari J, Yuan JM. Association between Pre-Diagnostic Serum Bile Acids and Hepatocellular Carcinoma: The Singapore Chinese Health Study. Cancers (Basel) 2021; 13:2648. [PMID: 34071196 PMCID: PMC8198655 DOI: 10.3390/cancers13112648] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 05/20/2021] [Accepted: 05/22/2021] [Indexed: 12/25/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a commonly diagnosed malignancy with poor prognosis. Rising incidence of HCC may be due to rising prevalence of metabolic dysfunction-associated fatty liver disease, where altered bile acid metabolism may be implicated in HCC development. Thirty-five bile acids were quantified using ultra-performance liquid chromatography triple-quadrupole mass spectrometry assays in pre-diagnostic serum of 100 HCC cases and 100 matched controls from the Singapore Chinese Health Study. Conditional logistic regression was used to assess associations for bile acid levels with risk of HCC. Conjugated primary bile acids were significantly elevated whereas the ratios of secondary bile acids over primary bile acids were significantly lower in HCC cases than controls. The respective odds ratios and 95% confidence intervals of HCC were 6.09 (1.75-21.21) for highest vs. lowest tertile of cholic acid species and 30.11 (5.88-154.31) for chenodeoxycholic acid species. Doubling ratio of taurine-over glycine-conjugated chenodeoxycholic acid was associated significantly with 40% increased risk of HCC whereas doubling ratio of secondary over primary bile acid species was associated with 30-40% reduced risk of HCC. In conclusion, elevated primary bile acids and taurine over glycine-conjugated ratios were strongly associated with HCC risk whereas the ratios of secondary bile acids over primary bile acids were inversely associated with HCC risk.
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Affiliation(s)
- Claire E. Thomas
- Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA; (C.E.T.); (H.N.L.)
- UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA 15232, USA; (R.W.); (J.A.-H.); (J.B.)
| | - Hung N. Luu
- Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA; (C.E.T.); (H.N.L.)
- UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA 15232, USA; (R.W.); (J.A.-H.); (J.B.)
| | - Renwei Wang
- UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA 15232, USA; (R.W.); (J.A.-H.); (J.B.)
| | - Guoxiang Xie
- University of Hawaii Cancer Center, Honolulu, HI 96813, USA; (G.X.); (W.J.)
| | - Jennifer Adams-Haduch
- UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA 15232, USA; (R.W.); (J.A.-H.); (J.B.)
| | - Aizhen Jin
- Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117545, Singapore; (A.J.); (W.-P.K.)
| | - Woon-Puay Koh
- Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117545, Singapore; (A.J.); (W.-P.K.)
| | - Wei Jia
- University of Hawaii Cancer Center, Honolulu, HI 96813, USA; (G.X.); (W.J.)
| | - Jaideep Behari
- UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA 15232, USA; (R.W.); (J.A.-H.); (J.B.)
- Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Jian-Min Yuan
- Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA; (C.E.T.); (H.N.L.)
- UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA 15232, USA; (R.W.); (J.A.-H.); (J.B.)
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30
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Wei W, Wang HF, Zhang Y, Zhang YL, Niu BY, Yao SK. Altered metabolism of bile acids correlates with clinical parameters and the gut microbiota in patients with diarrhea-predominant irritable bowel syndrome. World J Gastroenterol 2020; 26:7153-7172. [PMID: 33362374 PMCID: PMC7723672 DOI: 10.3748/wjg.v26.i45.7153] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Revised: 09/21/2020] [Accepted: 10/13/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Bile acids (BAs) have attracted attention in the research of irritable bowel syndrome with predominant diarrhea (IBS-D) due to their ability to modulate bowel function and their tight connection with the gut microbiota. The composition of the fecal BA pool in IBS-D patients is reportedly different from that in healthy populations. We hypothesized that BAs may participate in the pathogenesis of IBS-D and the altered BA profile may be correlated with the gut microbiome. AIM To investigate the role of BAs in the pathogenesis of IBS-D and the correlation between fecal BAs and gut microbiota. METHODS Fifty-five IBS-D patients diagnosed according to the Rome IV criteria and twenty-eight age-, sex-, and body mass index-matched healthy controls (HCs) were enrolled in this study at the gastroenterology department of China-Japan Friendship Hospital. First, clinical manifestations were assessed with standardized questionnaires, and visceral sensitivity was evaluated via the rectal distension test using a high-resolution manometry system. Fecal primary BAs including cholic acid (CA) and chenodeoxycholic acid (CDCA), secondary BAs including deoxycholic acid (DCA), lithocholic acid (LCA), and ursodeoxycholic acid (UDCA) as well as the corresponding tauro- and glyco-BAs were examined by ultraperformance liquid chromatography coupled to tandem mass spectrometry. The gut microbiota was analyzed using 16S rRNA gene sequencing. Correlations between fecal BAs with clinical features and gut microbiota were explored. RESULTS Fecal CA (IBS-D: 3037.66 [282.82, 6917.47] nmol/g, HC: 20.19 [5.03, 1304.28] nmol/g; P < 0.001) and CDCA (IBS-D: 1721.86 [352.80, 2613.83] nmol/g, HC: 57.16 [13.76, 1639.92] nmol/g; P < 0.001) were significantly increased, while LCA (IBS-D: 1621.65 [58.99, 2396.49] nmol/g, HC: 2339.24 [1737.09, 2782.40]; P = 0.002] and UDCA (IBS-D: 8.92 [2.33, 23.93] nmol/g, HC: 17.21 [8.76, 33.48] nmol/g; P = 0.025) were significantly decreased in IBS-D patients compared to HCs. Defecation frequency was positively associated with CA (r = 0.294, P = 0.030) and CDCA (r = 0.290, P = 0.032) and negatively associated with DCA (r = -0.332, P = 0.013) and LCA (r = -0.326, P = 0.015) in IBS-D patients. In total, 23 of 55 IBS-D patients and 15 of 28 HCs participated in the visceral sensitivity test. The first sensation threshold was negatively correlated with CDCA (r = -0.459, P = 0.028) in IBS-D patients. Furthermore, the relative abundance of the family Ruminococcaceae was significantly decreased in IBS-D patients (P < 0.001), and 12 genera were significantly lower in IBS-D patients than in HCs (P < 0.05), with 6 belonging to Ruminococcaceae. Eleven of these genera were negatively correlated with primary BAs and positively correlated with secondary BAs in all subjects. CONCLUSION The altered metabolism of BAs in the gut of IBS-D patients was associated with diarrhea and visceral hypersensitivity and might be ascribed to dysbiosis, especially the reduction of genera in Ruminococcaceae.
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Affiliation(s)
- Wei Wei
- Graduate School, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Hui-Fen Wang
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Yu Zhang
- Graduate School, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Yan-Li Zhang
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Bing-Yu Niu
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, China
- Graduate School, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Shu-Kun Yao
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, China
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