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Hupa-Breier KL, Schenk H, Campos-Murguia A, Wellhöner F, Heidrich B, Dywicki J, Hartleben B, Böker C, Mall J, Terkamp C, Wilkens L, Becker F, Rudolph KL, Manns MP, Mederacke YS, Marhenke S, Redeker H, Lieber M, Iordanidis K, Taubert R, Wedemeyer H, Noyan F, Hardtke-Wolenski M, Jaeckel E. Novel translational mouse models of metabolic dysfunction-associated steatotic liver disease comparable to human MASLD with severe obesity. Mol Metab 2025; 93:102104. [PMID: 39855563 PMCID: PMC11815970 DOI: 10.1016/j.molmet.2025.102104] [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: 11/27/2024] [Revised: 01/21/2025] [Accepted: 01/21/2025] [Indexed: 01/27/2025] Open
Abstract
OBJECTIVE Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common cause of chronic liver disease, especially in patients with severe obesity. However, current mouse models for MASLD do not reflect the polygenetic background nor the metabolic changes in this population. Therefore, we investigated two novel mouse models of MASLD with a polygenetic background for the metabolic syndrome. METHODS TALLYHO/JngJ mice and NONcNZO10/LtJ mice were fed a high-fat- high-carbohydrate (HF-HC) diet with a surplus of cholesterol diet. A second group of TH mice was additional treated with empagliflozin. RESULTS After sixteen weeks of feeding, both strains developed metabolic syndrome with severe obesity and histological manifestation of steatohepatitis, which was associated with significantly increased intrahepatic CD8+cells, CD4+cells and Tregs, contributing to a significant increase in pro-inflammatory and pro-fibrotic gene activation as well as ER stress and oxidative stress. In comparison with the human transcriptomic signature, we could demonstrate a good metabolic similarity, especially for the TH mouse model. Furthermore, TH mice also developed signs of kidney injury as an extrahepatic comorbidity of MASLD. Additional treatment with empagliflozin in TH mice attenuates hepatic steatosis and improves histological manifestation of MASH. CONCLUSIONS Overall, we have developed two promising new mouse models that are suitable for preclinical studies of MASLD as they recapitulate most of the key features of MASLD.
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Affiliation(s)
- Katharina L Hupa-Breier
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany.
| | - Heiko Schenk
- Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany
| | - Alejandro Campos-Murguia
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Freya Wellhöner
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Benjamin Heidrich
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Janine Dywicki
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Björn Hartleben
- Institute of Pathology, Hannover Medical School, Hannover, Germany
| | - Clara Böker
- Department of General, Visceral, Vascular and Bariatric Surgery, Klinikum Nordstadt, 30167, Hannover, Germany
| | - Julian Mall
- Department of General, Visceral, Vascular and Bariatric Surgery, Klinikum Nordstadt, 30167, Hannover, Germany
| | - Christoph Terkamp
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Ludwig Wilkens
- Department of Pathology, Nordstadt Hospital Hannover, 30167, Hannover, Germany
| | - Friedrich Becker
- Research Group on Stem Cell and Metabolism Aging, Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), 07745, Jena, Germany
| | - Karl Lenhard Rudolph
- Research Group on Stem Cell and Metabolism Aging, Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), 07745, Jena, Germany
| | - Michael Peter Manns
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Young-Seon Mederacke
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Silke Marhenke
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Hanna Redeker
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Maren Lieber
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Konstantinos Iordanidis
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Richard Taubert
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Fatih Noyan
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Matthias Hardtke-Wolenski
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany; Institute of Medical Microbiology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Elmar Jaeckel
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany; Ajmera Transplant Centre, Toronto General Hospital, United Health Network, University of Toronto, Toronto, Canada
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Liu Y, Chen Z, Li C, Sun T, Luo X, Jiang B, Liu M, Wang Q, Li T, Cao J, Li Y, Chen Y, Kuai L, Xiao F, Xu H, Cui H. Associations between changes in the gut microbiota and liver cirrhosis: a systematic review and meta-analysis. BMC Gastroenterol 2025; 25:16. [PMID: 39806278 PMCID: PMC11727502 DOI: 10.1186/s12876-025-03589-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2024] [Accepted: 01/02/2025] [Indexed: 01/16/2025] Open
Abstract
OBJECTIVE Summaries of the relationships between the microbiota and liver cirrhosis and their conclusions are not consistent. This study describes microbial differences in patients with liver cirrhosis by performing a meta-analysis. METHODS We searched PubMed, Embase, Web of Science, and the Cochrane Library and collected related articles published before March 10, 2024. Ratio of autochthonous to non-autochthonous taxa was calculated as the cirrhosis dysbiosis ratio (CDR). Using a random-effects model, the standard mean deviation (SMD) and 95% confidence interval (CI) were calculated. We subsequently performed subgroup, sensitivity, and publication bias analyses. cirrhosis dysbiosis ratio. RESULTS A total of 53 eligible papers including 5076 participants were included. The pooled estimates revealed a moderately significant reduction in gut microbiome richness in patients with liver cirrhosis compared with controls, including the Shannon, Chao1, observed species, ACE, and PD indices, but no significant difference was observed for the Simpson index. Over 80% of the studies reported significant differences in β diversity. Families Enterobacteriaceae and Pasteurellaceae, belonging to the phylum Proteobacteria, along with the family Streptococcaceae and the genera Haemophilus, Streptococcus, and Veillonella, were significantly associated with liver cirrhosis compared to the control group. In contrast, the healthy group exhibited a higher abundance of the class Clostridia, particularly the families Lachnospiraceae and Ruminococcaceae, which are known for their diversity and role as common gut commensals. Furthermore, the class Bacilli, predominantly represented by the genus Streptococcus, was markedly enriched in the cirrhosis group. CONCLUSIONS The microbiota richness of liver cirrhosis patients was lower than that of healthy controls. Alterations in gut microbiota linked to liver cirrhosis were characterized by a decrease in Lachnospiraceae, Ruminococcaceae, and Clostridia and an enrichment of Enterobacteriaceae, Pasteurellaceae, Streptococcaceae, Bacilli, and Streptococcus.
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Affiliation(s)
- Ye Liu
- Beijing Hospital, Peking University Fifth School of Clinical Medicine, National Center of Gerontology, Beijing, China
- Clinical Biobank, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital, National Center of Gerontology of National Health Commission, Beijing, China
| | - Ziwei Chen
- Clinical Biobank, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Chang Li
- Beijing Hospital, Peking University Fifth School of Clinical Medicine, National Center of Gerontology, Beijing, China
- Clinical Biobank, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Tianhan Sun
- Department of General Surgery, Department of Hepato-Bilio-Pancreatic Surgery, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine , Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Xuanmei Luo
- Clinical Biobank, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Boyue Jiang
- Department of General Surgery, Department of Hepato-Bilio-Pancreatic Surgery, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine , Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Meilan Liu
- Department of General Surgery, Department of Hepato-Bilio-Pancreatic Surgery, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine , Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Qing Wang
- Department of General Surgery, Department of Hepato-Bilio-Pancreatic Surgery, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine , Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Tong Li
- Department of General Surgery, Department of Hepato-Bilio-Pancreatic Surgery, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine , Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Jianfu Cao
- Department of General Surgery, Department of Hepato-Bilio-Pancreatic Surgery, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine , Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Yayu Li
- Clinical Biobank, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Yuan Chen
- Clinical Biobank, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Lu Kuai
- Clinical Biobank, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Fei Xiao
- Beijing Hospital, Peking University Fifth School of Clinical Medicine, National Center of Gerontology, Beijing, China.
- Clinical Biobank, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China.
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital, National Center of Gerontology of National Health Commission, Beijing, China.
- Clinical Biobank, Beijing Hospital, No. 1 Dahua Road, Dong Dan, Beijing, 100730, China.
| | - Hongtao Xu
- Department of Laboratory Medicine, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China.
- Department of Laboratory Medicine, Beijing Hospital, No. 1 Dahua Road, Dong Dan, Beijing, 100730, China.
| | - Hongyuan Cui
- Department of General Surgery, Department of Hepato-Bilio-Pancreatic Surgery, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine , Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
- Department of General Surgery, Beijing Hospital, No. 1 Dahua Road, Dong Dan, Beijing, 100730, China.
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Ghozzi M, Mankai A, Mechi F, Ben Chedly Z, Kallala O, Melayah S, Trabelsi A, Ghedira I. High frequency of anti-Saccharomyces cerevisiae antibodies in chronic hepatitis C. Arab J Gastroenterol 2024; 25:378-382. [PMID: 39289081 DOI: 10.1016/j.ajg.2024.07.013] [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: 11/24/2023] [Revised: 07/16/2024] [Accepted: 07/26/2024] [Indexed: 09/19/2024]
Abstract
BACKGROUND AND STUDY AIM Chronic hepatitis C (CHC) is a liver disease caused by the hepatitis C virus. Anti-Saccharomyces cerevisiae (S. cerevisiae) antibodies (ASCA) are frequently reported in autoimmune diseases but rarely in viral infections. We aimed to determine the frequency of ASCA in adult patients with CHC. PATIENTS AND METHODS Eighty-eight patients with CHC and 160 healthy blood donors were included in this study. ASCA-IgG and IgA levels were determined using enzyme linked immunosorbent assay. For statistical analysis, we used open EPI version 3 as software. Correlations were determined by Spearman's test using IBM® SPSS® Statistics. RESULTS ASCA (IgG or IgA) were present in 31.8 % of patients and in 3.7 % of controls (p < 10-6). ASCA-IgG and ASCA-IgA were more frequent in patients with CHC than in healthy subjects (23.9 % vs. 3.1 %; p < 10-5 and 9.1 % vs. 0.6 %; p = 0.002, respectively). In patients, mean levels of ASCA-IgG and IgA were significantly higher than in controls (9.95 ± 11.78 U/mL vs. 2.28 ± 2.86 U/mL, p < 10-6 and 5.96 ± 7.69 U/mL vs. 0.56 ± 0.12 U/mL, p < 10-6; respectively). In patients with CHC, the mean level of ASCA-IgG was significantly higher than that of ASCA-IgA (9.95 ± 11.78 U/mL vs. 5.96 ± 7.69 U/mL, p = 0.008). CONCLUSION The frequency of ASCA was significantly higher in patients with CHC than in healthy controls.
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Affiliation(s)
- Mariam Ghozzi
- Department of Immunology, Faculty of Pharmacy, Monastir University, Monastir, Tunisia; Laboratory of Immunology, Farhat Hached Hospital, Sousse, Tunisia; Research Unit "Epidemiology and Immunogenetics of Viral Infections, LR14SP02", Sahloul University Hospital, Sousse, Tunisia.
| | - Amani Mankai
- High School of Sciences and Techniques of Health, Tunis El Manar University, Tunis, Tunisia; Research Unit "Obesity: Etiopathology and Treatment, UR18ES01", National Institute of Nutrition and Food Technology, Tunis, Tunisia
| | - Fatma Mechi
- Department of Immunology, Faculty of Pharmacy, Monastir University, Monastir, Tunisia
| | - Zeineb Ben Chedly
- Department of Immunology, Faculty of Pharmacy, Monastir University, Monastir, Tunisia
| | - Ouafa Kallala
- Research Unit "Epidemiology and Immunogenetics of Viral Infections, LR14SP02", Sahloul University Hospital, Sousse, Tunisia; Laboratory of Microbiology, Sahloul University Hospital, Sousse, Tunisia; Department of Microbiology, Faculty of Pharmacy, Monastir University, Monastir, Tunisia
| | - Sarra Melayah
- Department of Immunology, Faculty of Pharmacy, Monastir University, Monastir, Tunisia; Laboratory of Immunology, Farhat Hached Hospital, Sousse, Tunisia; LR12SP11, Biochemistry Department, Sahloul University Hospital, Sousse, Tunisia
| | - Abdelhalim Trabelsi
- Research Unit "Epidemiology and Immunogenetics of Viral Infections, LR14SP02", Sahloul University Hospital, Sousse, Tunisia; Laboratory of Microbiology, Sahloul University Hospital, Sousse, Tunisia; Department of Microbiology, Faculty of Pharmacy, Monastir University, Monastir, Tunisia
| | - Ibtissem Ghedira
- Department of Immunology, Faculty of Pharmacy, Monastir University, Monastir, Tunisia; Laboratory of Immunology, Farhat Hached Hospital, Sousse, Tunisia
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Midori Y, Nosaka T, Hiramatsu K, Akazawa Y, Tanaka T, Takahashi K, Naito T, Matsuda H, Ohtani M, Nakamoto Y. Isolation of mucosa-associated microbiota dysbiosis in the ascending colon in hepatitis C virus post-sustained virologic response cirrhotic patients. Front Cell Infect Microbiol 2024; 14:1371429. [PMID: 38650735 PMCID: PMC11033736 DOI: 10.3389/fcimb.2024.1371429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Accepted: 03/25/2024] [Indexed: 04/25/2024] Open
Abstract
Background Achieving sustained virologic response (SVR) in patients infected with hepatitis C virus (HCV) reduces all-cause mortality. However, the mechanisms and risk factors for liver fibrosis and portal hypertension post-SVR remain incompletely understood. In the gut-liver axis, mucosa-associated microbiota (MAM) substantially influence immune and metabolic functions, displaying spatial heterogeneity at the anatomical intestinal site. We analyzed MAM composition and function to isolate the locoregional MAM involved in chronic liver disease progression in HCV post-SVR patients. Methods We collected MAM samples from three intestinal sites (terminal ileum, ascending colon, and sigmoid colon) via brushing during colonoscopy in 23 HCV post-SVR patients and 25 individuals without liver disease (controls). The 16S rRNA of bacterial DNA in specimens collected with a brush and in feces was sequenced. The molecular expression of intestinal tissues and hepatic tissues were evaluated by quantitative real-time PCR. Results In the post-SVR group, the microbial β-diversity of MAM, especially in the ascending colon, differed from the control group and was associated with liver fibrosis progression. In PICRUSt analysis, MAM in the ascending colon in the liver cirrhosis (LC) group showed compromised functions associated with the intestinal barrier and bile acid production, and FGF19 expression was markedly decreased in the terminal ileum biopsy tissue in the LC group. At the genus level, six short-chain fatty acid (SCFA)-producing bacterial genera, Blautia, Alistipes, Roseburia, Agathobaculum, Dorea, and Pseudoflavonifractor were reduced in the ascending colon of post-SVR LC patients. Conclusion In patients of HCV post-SVR, we identified the association between the degree of liver fibrosis and dysbiosis of mucosa-associated SCFA-producing bacterial genera that may be related to intestinal barrier and bile acid production in the ascending colon.
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Affiliation(s)
- Yohei Midori
- Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | - Takuto Nosaka
- Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | - Katsushi Hiramatsu
- Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
- Department of General Internal Medicine, Fukui-ken Saiseikai Hospital, Fukui, Japan
| | - Yu Akazawa
- Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | - Tomoko Tanaka
- Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | - Kazuto Takahashi
- Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | - Tatsushi Naito
- Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | - Hidetaka Matsuda
- Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | - Masahiro Ohtani
- Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | - Yasunari Nakamoto
- Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
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Rodrigues SG, van der Merwe S, Krag A, Wiest R. Gut-liver axis: Pathophysiological concepts and medical perspective in chronic liver diseases. Semin Immunol 2024; 71:101859. [PMID: 38219459 DOI: 10.1016/j.smim.2023.101859] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 10/11/2023] [Accepted: 12/04/2023] [Indexed: 01/16/2024]
Affiliation(s)
- Susana G Rodrigues
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland
| | - Schalk van der Merwe
- Department of Gastroenterology and Hepatology, University hospital Gasthuisberg, University of Leuven, Belgium
| | - Aleksander Krag
- Institute of Clinical Research, University of Southern Denmark, Odense, Denmark; Centre for Liver Research, Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark, University of Southern Denmark, Odense, Denmark
| | - Reiner Wiest
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland.
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Shah YR, Ali H, Tiwari A, Guevara-Lazo D, Nombera-Aznaran N, Pinnam BSM, Gangwani MK, Gopakumar H, Sohail AH, Kanumilli S, Calderon-Martinez E, Krishnamoorthy G, Thakral N, Dahiya DS. Role of fecal microbiota transplant in management of hepatic encephalopathy: Current trends and future directions. World J Hepatol 2024; 16:17-32. [PMID: 38313244 PMCID: PMC10835490 DOI: 10.4254/wjh.v16.i1.17] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Revised: 12/02/2023] [Accepted: 01/03/2024] [Indexed: 01/23/2024] Open
Abstract
Fecal microbiota transplantation (FMT) offers a potential treatment avenue for hepatic encephalopathy (HE) by leveraging beneficial bacterial displacement to restore a balanced gut microbiome. The prevalence of HE varies with liver disease severity and comorbidities. HE pathogenesis involves ammonia toxicity, gut-brain communication disruption, and inflammation. FMT aims to restore gut microbiota balance, addressing these factors. FMT's efficacy has been explored in various conditions, including HE. Studies suggest that FMT can modulate gut microbiota, reduce ammonia levels, and alleviate inflammation. FMT has shown promise in alcohol-associated, hepatitis B and C-associated, and non-alcoholic fatty liver disease. Benefits include improved liver function, cognitive function, and the slowing of disease progression. However, larger, controlled studies are needed to validate its effectiveness in these contexts. Studies have shown cognitive improvements through FMT, with potential benefits in cirrhotic patients. Notably, trials have demonstrated reduced serious adverse events and cognitive enhancements in FMT arms compared to the standard of care. Although evidence is promising, challenges remain: Limited patient numbers, varied dosages, administration routes, and donor profiles. Further large-scale, controlled trials are essential to establish standardized guidelines and ensure FMT's clinical applications and efficacy. While FMT holds potential for HE management, ongoing research is needed to address these challenges, optimize protocols, and expand its availability as a therapeutic option for diverse hepatic conditions.
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Affiliation(s)
- Yash R Shah
- Department of Internal Medicine, Trinity Health Oakland/Wayne State University, Pontiac, MI 48341, United States
| | - Hassam Ali
- Division of Gastroenterology and Hepatology, East Carolina University/Brody School of Medicine, Greenville, NC 27858, United States
| | - Angad Tiwari
- Department of Internal Medicine, Maharani Laxmi Bai Medical College, Jhansi 284001, India
| | - David Guevara-Lazo
- Faculty of Medicine, Universidad Peruana Cayetano Heredia, Lima 15102, Peru
| | | | - Bhanu Siva Mohan Pinnam
- Department of Internal Medicine, John H. Stroger Hospital of Cook County, Chicago, IL 60612, United States
| | - Manesh Kumar Gangwani
- Department of Internal Medicine, The University of Toledo, Toledo, OH 43606, United States
| | - Harishankar Gopakumar
- Department of Gastroenterology and Hepatology, University of Illinois College of Medicine at Peoria, Peoria, IL 61605, United States
| | - Amir H Sohail
- Department of Surgery, University of New Mexico, Albuquerque, NM 87106, United States
| | | | - Ernesto Calderon-Martinez
- Department of Internal Medicine, Universidad Nacional Autonoma de Mexico, Ciudad De Mexico 04510, Mexico
| | - Geetha Krishnamoorthy
- Department of Internal Medicine, Trinity Health Oakland/Wayne State University, Pontiac, MI 48341, United States
| | - Nimish Thakral
- Department of Digestive Diseases and Nutrition, University of Kentucky, Lexington, KY 40536, United States
| | - Dushyant Singh Dahiya
- Division of Gastroenterology, Hepatology & Motility, The University of Kansas School of Medicine, Kansas City, KS 66160, United States.
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Nie G, Zhang H, Xie D, Yan J, Li X. Liver cirrhosis and complications from the perspective of dysbiosis. Front Med (Lausanne) 2024; 10:1320015. [PMID: 38293307 PMCID: PMC10824916 DOI: 10.3389/fmed.2023.1320015] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Accepted: 12/26/2023] [Indexed: 02/01/2024] Open
Abstract
The gut-liver axis refers to the intimate relationship and rigorous interaction between the gut and the liver. The intestinal barrier's integrity is critical for maintaining liver homeostasis. The liver operates as a second firewall in this interaction, limiting the movement of potentially dangerous compounds from the gut and, as a result, contributing in barrier management. An increasing amount of evidence shows that increased intestinal permeability and subsequent bacterial translocation play a role in liver damage development. The major pathogenic causes in cirrhotic individuals include poor intestinal permeability, nutrition, and intestinal flora dysbiosis. Portal hypertension promotes intestinal permeability and bacterial translocation in advanced liver disease, increasing liver damage. Bacterial dysbiosis is closely related to the development of cirrhosis and its related complications. This article describes the potential mechanisms of dysbiosis in liver cirrhosis and related complications, such as spontaneous bacterial peritonitis, hepatorenal syndrome, portal vein thrombosis, hepatic encephalopathy, and hepatocellular carcinoma, using dysbiosis of the intestinal flora as an entry point.
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Affiliation(s)
- Guole Nie
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
| | - Honglong Zhang
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
| | - Danna Xie
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
| | - Jun Yan
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, China
- Key Laboratory of Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou, China
- Cancer Prevention and Control Center of Lanzhou University Medical School, Lanzhou, China
- Gansu Institute of Hepatobiliary and Pancreatic Surgery, Lanzhou, China
- Gansu Clinical Medical Research Center of General Surgery, Lanzhou, China
| | - Xun Li
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, China
- Key Laboratory of Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou, China
- Cancer Prevention and Control Center of Lanzhou University Medical School, Lanzhou, China
- Gansu Institute of Hepatobiliary and Pancreatic Surgery, Lanzhou, China
- Gansu Clinical Medical Research Center of General Surgery, Lanzhou, China
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LeFort KR, Rungratanawanich W, Song BJ. Contributing roles of mitochondrial dysfunction and hepatocyte apoptosis in liver diseases through oxidative stress, post-translational modifications, inflammation, and intestinal barrier dysfunction. Cell Mol Life Sci 2024; 81:34. [PMID: 38214802 PMCID: PMC10786752 DOI: 10.1007/s00018-023-05061-7] [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: 09/08/2023] [Revised: 11/16/2023] [Accepted: 11/22/2023] [Indexed: 01/13/2024]
Abstract
This review provides an update on recent findings from basic, translational, and clinical studies on the molecular mechanisms of mitochondrial dysfunction and apoptosis of hepatocytes in multiple liver diseases, including but not limited to alcohol-associated liver disease (ALD), metabolic dysfunction-associated steatotic liver disease (MASLD), and drug-induced liver injury (DILI). While the ethanol-inducible cytochrome P450-2E1 (CYP2E1) is mainly responsible for oxidizing binge alcohol via the microsomal ethanol oxidizing system, it is also responsible for metabolizing many xenobiotics, including pollutants, chemicals, drugs, and specific diets abundant in n-6 fatty acids, into toxic metabolites in many organs, including the liver, causing pathological insults through organelles such as mitochondria and endoplasmic reticula. Oxidative imbalances (oxidative stress) in mitochondria promote the covalent modifications of lipids, proteins, and nucleic acids through enzymatic and non-enzymatic mechanisms. Excessive changes stimulate various post-translational modifications (PTMs) of mitochondrial proteins, transcription factors, and histones. Increased PTMs of mitochondrial proteins inactivate many enzymes involved in the reduction of oxidative species, fatty acid metabolism, and mitophagy pathways, leading to mitochondrial dysfunction, energy depletion, and apoptosis. Unique from other organelles, mitochondria control many signaling cascades involved in bioenergetics (fat metabolism), inflammation, and apoptosis/necrosis of hepatocytes. When mitochondrial homeostasis is shifted, these pathways become altered or shut down, likely contributing to the death of hepatocytes with activation of inflammation and hepatic stellate cells, causing liver fibrosis and cirrhosis. This review will encapsulate how mitochondrial dysfunction contributes to hepatocyte apoptosis in several types of liver diseases in order to provide recommendations for targeted therapeutics.
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Affiliation(s)
- Karli R LeFort
- Section of Molecular Pharmacology and Toxicology, National Institute on Alcohol Abuse and Alcoholism, 9000 Rockville Pike, Bethesda, MD, 20892, USA.
| | - Wiramon Rungratanawanich
- Section of Molecular Pharmacology and Toxicology, National Institute on Alcohol Abuse and Alcoholism, 9000 Rockville Pike, Bethesda, MD, 20892, USA
| | - Byoung-Joon Song
- Section of Molecular Pharmacology and Toxicology, National Institute on Alcohol Abuse and Alcoholism, 9000 Rockville Pike, Bethesda, MD, 20892, USA.
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9
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Kouroumalis E, Tsomidis I, Voumvouraki A. Viral Liver Disease and Intestinal Gut–Liver Axis. GASTROINTESTINAL DISORDERS 2024; 6:64-93. [DOI: 10.3390/gidisord6010005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2025] Open
Abstract
The intestinal microbiota is closely related to liver diseases via the intestinal barrier and bile secretion to the gut. Impairment of the barrier can translocate microbes or their components to the liver where they can contribute to liver damage and fibrosis. The components of the barrier are discussed in this review along with the other elements of the so-called gut–liver axis. This bidirectional relation has been widely studied in alcoholic and non-alcoholic liver disease. However, the involvement of microbiota in the pathogenesis and treatment of viral liver diseases have not been extensively studied, and controversial data have been published. Therefore, we reviewed data regarding the integrity and function of the intestinal barrier and the changes of the intestinal microbioma that contribute to progression of Hepatitis B (HBV) and Hepatitis C (HCV) infection. Their consequences, such as cirrhosis and hepatic encephalopathy, were also discussed in connection with therapeutic interventions such as the effects of antiviral eradication and the use of probiotics that may influence the outcome of liver disease. Profound alterations of the microbioma with significant reduction in microbial diversity and changes in the abundance of both beneficial and pathogenic bacteria were found.
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Affiliation(s)
- Elias Kouroumalis
- Department of Gastroenterology, Medical School, University of Crete, 71500 Heraklion, Greece
| | - Ioannis Tsomidis
- Department of Gastroenterology, Medical School, University of Crete, 71500 Heraklion, Greece
| | - Argyro Voumvouraki
- 1st Department of Internal Medicine, AHEPA University Hospital, 54621 Thessaloniki, Greece
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10
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Grobe B, Wellhöner F, Klein F, Chhatwal P, Vital M, Pieper DH, Voigtländer T, Lenzen H, Wedemeyer H, Solbach P, Heidrich B. Next Generation Sequencing Outperforms Cultivation-Based Methods for Detection of Bacterial Genera in Bile After Liver Transplantation. J Clin Exp Hepatol 2024; 14:101265. [PMID: 38076367 PMCID: PMC10709207 DOI: 10.1016/j.jceh.2023.08.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Accepted: 08/02/2023] [Indexed: 02/19/2024] Open
Abstract
Background and aims Bacterial cholangitis is a common complication in patients with ischemic type biliary lesions and/or anastomotic strictures after liver transplantation (LTX). Patients frequently need antibiotics and endoscopic retrograde cholangiography (ERC) to improve the bile flow. Antibiotic treatment is based on findings in standard microbiological cultivation (SMC) of bile. However, the cultivation techniques are limited to a subset of bacteria easy-to-cultivate. Therefore, the aim of our study was to evaluate the value of next generation sequencing as an additional diagnostic tool to SMC in ischemic type biliary lesions and/or anastomotic strictures. Methods We sequenced the V1-V2 region of the 16S rRNA gene in 242 stored bile samples in patients after LTX and compared the results with findings of SMC. SMC was performed in n = 135 (56%) fresh bile samples in addition to NGS. SMC was part of the clinical routine in these patients. Results NGS detected bacterial genera in bile samples more often than SMC (P = 5.42 × 10-74). SMC showed insufficient discovery of bacterial genera compared to NGS with better performance in patients receiving antibiotics prior to ERC. SMC missed many bacterial genera detected by NGS. Conclusions NGS was more sensitive in detecting bacteria in bile than SMC, no clinical parameters could be used to improve discovery rates in SMC and many genera were missed by SMC. Therefore, NGS should be used in a combined approach with SMC for improved diagnostics to achieve more specific and targeted antibiotic treatments.
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Affiliation(s)
- Björn Grobe
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
- Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Carl-Neuberg-Straße 1, Hannover 30625, Germany
| | - Freya Wellhöner
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Friederike Klein
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
- Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Carl-Neuberg-Straße 1, Hannover 30625, Germany
- Microbial Interactions and Processes Research Group, Helmholtz Center for Infection Research, Braunschweig, Germany
| | - Patrick Chhatwal
- Institute for Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany
| | - Marius Vital
- Microbial Interactions and Processes Research Group, Helmholtz Center for Infection Research, Braunschweig, Germany
| | - Dietmar H. Pieper
- Microbial Interactions and Processes Research Group, Helmholtz Center for Infection Research, Braunschweig, Germany
| | - Torsten Voigtländer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Henrike Lenzen
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
- Integrated Research and Treatment Center Transplantation (IFB-Tx), Hannover Medical School, Hannover, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Philipp Solbach
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
- Integrated Research and Treatment Center Transplantation (IFB-Tx), Hannover Medical School, Hannover, Germany
- Medical Department I, University Hospital Schleswig-Holstein, Lübeck, Germany
| | - Benjamin Heidrich
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
- Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Carl-Neuberg-Straße 1, Hannover 30625, Germany
- Microbial Interactions and Processes Research Group, Helmholtz Center for Infection Research, Braunschweig, Germany
- Institute for Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany
- Integrated Research and Treatment Center Transplantation (IFB-Tx), Hannover Medical School, Hannover, Germany
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11
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Xiang Z, Wu J, Li J, Zheng S, Wei X, Xu X. Gut Microbiota Modulation: A Viable Strategy to Address Medical Needs in Hepatocellular Carcinoma and Liver Transplantation. ENGINEERING 2023; 29:59-72. [DOI: 10.1016/j.eng.2022.12.012] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/05/2024]
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12
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Chuaypen N, Jinato T, Avihingsanon A, Nookaew I, Tanaka Y, Tangkijvanich P. Long-term benefit of DAAs on gut dysbiosis and microbial translocation in HCV-infected patients with and without HIV coinfection. Sci Rep 2023; 13:14413. [PMID: 37660163 PMCID: PMC10475021 DOI: 10.1038/s41598-023-41664-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Accepted: 08/29/2023] [Indexed: 09/04/2023] Open
Abstract
Long-term effect of Direct-acting antivirals (DAAs) on gut microbiota, short-chain fatty acids (SCFAs) and microbial translocation in patients with hepatitis C virus (HCV) infection who achieve sustained virological response (SVR) were limited. A longitudinal study of 50 patients with HCV monoinfection and 19 patients with HCV/HIV coinfection received DAAs were conducted. Fecal specimens collected at baseline and at week 72 after treatment completion (FUw72) were analyzed for 16S rRNA sequencing and the butyryl-CoA:acetateCoA transferase (BCoAT) gene expression using real-time PCR. Plasma lipopolysaccharide binding protein (LBP) and intestinal fatty acid binding protein (I-FABP) were quantified by ELISA assays. SVR rates in mono- and coinfected patients were comparable (94% vs. 100%). The improvement of gut dysbiosis and microbial translocation was found in responders but was not in non-responders. Among responders, significant restoration of alpha-diversity, BCoAT and LBP were observed in HCV patients with low-grade fibrosis (F0-F1), while HCV/HIV patients exhibited partial improvement at FUw72. I-FABP did not decline significantly in responders. Treatment induced microbiota changes with increasing abundance of SCFAs-producing bacteria, including Blautia, Fusicatenibacter, Subdoligranulum and Bifidobacterium. In conclusion, long-term effect of DAAs impacted the restoration of gut dysbiosis and microbial translocation. However, early initiation of DAAs required for an alteration of gut microbiota, enhanced SCFAs-producing bacteria, and could reduce HCV-related complications.
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Affiliation(s)
- Natthaya Chuaypen
- Department of Biochemistry, Center of Excellence in Hepatitis and Liver Cancer, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Thananya Jinato
- Department of Biochemistry, Center of Excellence in Hepatitis and Liver Cancer, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
- Doctor of Philosophy Program in Medical Sciences, Graduate Affairs, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Anchalee Avihingsanon
- The HIV Netherlands Australia Thailand Research Collaboration (HIV-NAT), Bangkok, Thailand
| | - Intawat Nookaew
- Department of Biomedical Informatics, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Yasuhito Tanaka
- Division of Integrated Medical and Pharmaceutical Sciences, Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Pisit Tangkijvanich
- Department of Biochemistry, Center of Excellence in Hepatitis and Liver Cancer, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
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Gamal-AbdelNaser A, Mohammed WS, ElHefnawi M, AbdAllah M, Elsharkawy A, Zahran FM. The oral microbiome of treated and untreated chronic HCV infection: A preliminary study. Oral Dis 2023; 29:843-852. [PMID: 34396636 DOI: 10.1111/odi.14007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 07/16/2021] [Accepted: 08/12/2021] [Indexed: 02/07/2023]
Abstract
OBJECTIVES Chronic hepatitis C virus (HCV) infection is a debilitating disease that is lately treated using direct-acting antivirals (DAAs). Changes in the oral microbiome were detected in other liver diseases; however, oral microbiome was never investigated in patients having chronic HCV infection, whether pre- or post-treatment. MATERIALS AND METHODS This case-control preliminary study enrolled three equal groups: Group (I): untreated HCV patients; group (II): HCV patients who achieved viral clearance after DAA administration; and group (III): healthy controls. For each participant, a buccal swab was harvested and its 16S rRNA was sequenced. RESULTS The oral microbiome of chronic HCV patients had a significantly distinct bacterial community compared to healthy controls, characterized by high diversity and abundance of certain pathogenic species. These changes resemble that of oral lichen planus patients. After treatment by DAAs, the oral microbiome shifted to a community with partial similarity to both the diseased and the healthy ones. CONCLUSIONS Chronic HCV is associated with dysbiotic oral microbiome having abundant pathogenic bacteria. With HCV clearance by DAAs, the oral microbiome shifts to approach the healthy composition.
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Affiliation(s)
- Ayat Gamal-AbdelNaser
- Department of Oral Medicine and Periodontology, Faculty of Dentistry, Cairo University, Cairo, Egypt
| | - Waleed S Mohammed
- Department of Biotechnology, Faculty of Agriculture, Al-Azhar University, Cairo, Egypt
| | - Mahmoud ElHefnawi
- Biomedical Informatics and Chemoinformatics Group, Informatics & Systems Department, National Research Centre, Giza, Egypt
| | - Mohamed AbdAllah
- Medical Research Division, National Research Centre, Giza, Egypt
| | - Aisha Elsharkawy
- Endemic Medicine and Hepatogastroentrology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Fat'heya M Zahran
- Department of Oral Medicine and Periodontology, Faculty of Dentistry, Cairo University, Cairo, Egypt
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14
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Huang X, Yang Y, Li X, Zhu X, Lin D, Ma Y, Zhou M, Cui X, Zhang B, Dang D, Lü Y, Yue C. The gut microbiota: A new perspective for tertiary prevention of hepatobiliary and gallbladder diseases. Front Nutr 2023; 10:1089909. [PMID: 36814514 PMCID: PMC9940272 DOI: 10.3389/fnut.2023.1089909] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Accepted: 01/11/2023] [Indexed: 02/10/2023] Open
Abstract
The gut microbiota is a complex ecosystem that has coevolved with the human body for hundreds of millions of years. In the past 30 years, with the progress of gene sequencing and omics technology, the research related to gut microbiota has developed rapidly especially in the field of digestive system diseases and systemic metabolic diseases. Mechanical, biological, immune, and other factors make the intestinal flora form a close bidirectional connection with the liver and gallbladder, which can be called the "gut-liver-biliary axis." Liver and gallbladder, as internal organs of the peritoneum, suffer from insidious onset, which are not easy to detect. The diagnosis is often made through laboratory chemical tests and imaging methods, and intervention measures are usually taken only when organic lesions have occurred. At this time, some people may have entered the irreversible stage of disease development. We reviewed the literature describing the role of intestinal flora in the pathogenesis and biotherapy of hepatobiliary diseases in the past 3-5 years, including the dynamic changes of intestinal flora at different stages of the disease, as well as the signaling pathways involved in intestinal flora and its metabolites, etc. After summarizing the above contents, we hope to highlight the potential of intestinal flora as a new clinical target for early prevention, early diagnosis, timely treatment and prognosis of hepatobiliary diseases. GRAPHICAL ABSTRACT.
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Affiliation(s)
- Xiaoyu Huang
- Yan’an Key Laboratory of Microbial Drug Innovation and Transformation, School of Basic Medicine, Yan’an University, Yan’an, Shaanxi, China
| | - Yi Yang
- Yan’an Key Laboratory of Microbial Drug Innovation and Transformation, School of Basic Medicine, Yan’an University, Yan’an, Shaanxi, China
| | - Xueli Li
- Yan’an Key Laboratory of Microbial Drug Innovation and Transformation, School of Basic Medicine, Yan’an University, Yan’an, Shaanxi, China
- Shaanxi Key Laboratory of Chemical Reaction Engineering, College of Chemistry and Chemical Engineering, Yan’an University, Yan’an, Shaanxi, China
| | - Xiaoya Zhu
- Yan’an Key Laboratory of Microbial Drug Innovation and Transformation, School of Basic Medicine, Yan’an University, Yan’an, Shaanxi, China
| | - Dan Lin
- Yan’an Key Laboratory of Microbial Drug Innovation and Transformation, School of Basic Medicine, Yan’an University, Yan’an, Shaanxi, China
| | - Yueran Ma
- Yan’an Key Laboratory of Microbial Drug Innovation and Transformation, School of Basic Medicine, Yan’an University, Yan’an, Shaanxi, China
| | - Min Zhou
- Yan’an Key Laboratory of Microbial Drug Innovation and Transformation, School of Basic Medicine, Yan’an University, Yan’an, Shaanxi, China
| | - Xiangyi Cui
- Yan’an Key Laboratory of Microbial Drug Innovation and Transformation, School of Basic Medicine, Yan’an University, Yan’an, Shaanxi, China
| | - Bingyu Zhang
- Yan’an Key Laboratory of Microbial Drug Innovation and Transformation, School of Basic Medicine, Yan’an University, Yan’an, Shaanxi, China
| | - Dongmei Dang
- Yan’an Key Laboratory of Microbial Drug Innovation and Transformation, School of Basic Medicine, Yan’an University, Yan’an, Shaanxi, China
| | - Yuhong Lü
- Yan’an Key Laboratory of Microbial Drug Innovation and Transformation, School of Basic Medicine, Yan’an University, Yan’an, Shaanxi, China
| | - Changwu Yue
- Yan’an Key Laboratory of Microbial Drug Innovation and Transformation, School of Basic Medicine, Yan’an University, Yan’an, Shaanxi, China
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15
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Huang PY, Chen CH, Tsai MJ, Yao CC, Wang HM, Kuo YH, Chang KC, Hung CH, Chuah SK, Tsai MC. Effects of direct anti-viral agents on the gut microbiota in patients with chronic hepatitis C. J Formos Med Assoc 2023; 122:157-163. [PMID: 36155707 DOI: 10.1016/j.jfma.2022.08.022] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 08/21/2022] [Accepted: 08/30/2022] [Indexed: 02/01/2023]
Abstract
BACKGROUND/PURPOSE Gut microbiology is associated with liver disease due to gut-liver circulation via the gut microbial-liver axis. There is a paucity of data regarding the effects of treatment to cure hepatitis C virus (HCV) infection on the gut microbiota. The aim of this study was to evaluate the fecal microbiota before and after treatment with direct antiviral agents (DAA) in patients with HCV infection. METHODS This prospective study was conducted at Kaohsiung Chung-Gung Memorial Hospital, Taiwan, between December 2019 and November 2020. We recruited patients with chronic hepatitis C (CHC) receiving DAA treatment. Fecal samples were collected twice: at baseline (before DAA treatment; CHC group) and 24 weeks after the end of treatment (EOT; SVR24 group), and once from healthy controls at baseline (control group). The taxonomic composition of the gut microbiota was determined using 16 S ribosomal RNA gene sequencing of stool samples. RESULTS A total of 60 patients with CHC and 60 healthy controls matched by age and gender were enrolled. All patients achieved a sustained virologic response (SVR). Alpha diversity was not significantly difference between any groups. Analysis of similarities (ANOSIM) revealed minor differences in the microbial community structure between the control group and CHC group (R = 0.0146, P = 0.098) and less significant differences between the CHC group and SVR24 group (R = -0.0139; P = 0.94). Three phyla and eight genera were differentially abundant between the control group and CHC group. CONCLUSION Individuals with CHC do not exhibit significant gut microbiota alterations and eradication of HCV by DAA is not associated with significant modification of the gut microbiota.
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Affiliation(s)
- Pao-Yuan Huang
- Division of Hepato-gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan
| | - Chien-Hung Chen
- Division of Hepato-gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan; Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
| | - Mu-Jung Tsai
- Kaohsiung Municipal Kaohsiung Senior High School, Kaohsiung 807, Taiwan
| | - Chih-Chien Yao
- Division of Hepato-gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan
| | - Hsin-Ming Wang
- Division of Hepato-gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan
| | - Yuan-Hung Kuo
- Division of Hepato-gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan; Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
| | - Kuo-Chin Chang
- Division of Hepato-gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan; Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
| | - Chao-Hung Hung
- Division of Hepato-gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan
| | - Seng-Kee Chuah
- Division of Hepato-gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan
| | - Ming-Chao Tsai
- Division of Hepato-gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan; Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan; School of Medicine, College of Medicine, National Sun Yat-sen University, Kaohsiung 804, Taiwan.
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16
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Liu S, Yang X. Intestinal flora plays a role in the progression of hepatitis-cirrhosis-liver cancer. Front Cell Infect Microbiol 2023; 13:1140126. [PMID: 36968098 PMCID: PMC10034054 DOI: 10.3389/fcimb.2023.1140126] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2023] [Accepted: 02/23/2023] [Indexed: 03/29/2023] Open
Abstract
The liver is a vital metabolism and detoxification organ of human body, which is involved in the biotransformation and metabolism of the organism. Hepatitis - cirrhosis - liver cancer are significant and common part of liver diseases. The pathogenesis of liver diseases is generally as followed: inflammation and other pathogenic factors cause persistent damage to the liver, leading to the activation of hepatic stellate cells (HSCs) and excessive deposition of extracellular matrix. Patients with chronic hepatitis have a high risk of developing into liver fibrosis, cirrhosis, and even life-threatening liver cancer, which poses a great threat to public health.As the first organ to come into contact with blood from the gut, the liver is profoundly affected by the intestinal flora and its metabolites, with leaky gut and flora imbalance being the triggers of the liver's pathological response. So far, no one has reviewed the role of intestinal flora in this process from the perspective of the progression of hepatitis-cirrhosis-liver cancer and this article reviews the evidence supporting the effect of intestinal flora in the progression of liver disease.
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17
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Huang L, Yu Q, Peng H, Zhen Z. Alterations of gut microbiome and effects of probiotic therapy in patients with liver cirrhosis: A systematic review and meta-analysis. Medicine (Baltimore) 2022; 101:e32335. [PMID: 36595801 PMCID: PMC9794299 DOI: 10.1097/md.0000000000032335] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Alterations in the gut microbiome usually occur in liver cirrhosis. Gut microbiome dysregulation damages the liver and accelerates the development of liver fibrosis. Probiotic treatment has gradually become a major method for improving the prognosis of liver cirrhosis and reducing its complications. However, alterations in the gut microbiome have revealed different results, and the therapeutic effects of various probiotics are inconsistent. METHODS We searched the PubMed, Medline, EMBASE, ScienceDirect, and Cochrane databases up to August 2022 and conducted a systematic review and meta-analysis of 17 relevant studies. RESULTS The counts of Enterobacter (standardized mean difference [SMD] -1.79, 95% confidence interval [CI]: -3.08 to -0.49) and Enterococcus (SMD -1.41, 95% CI: -2.26 to -0.55) increased significantly in patients with cirrhosis, while the counts of Lactobacillus (SMD 0.63, 95% CI: 0.12-1.15) and Bifidobacterium (SMD 0.44, 95% CI: 0.12-0.77) decreased significantly. Blood ammonia (weighted mean difference [WMD] 14.61, 95% CI: 7.84-21.37) and the incidence of hepatic encephalopathy (WMD 0.40, 95% CI: 0.27-0.61) were significantly decreased in the probiotic group. As for mortality (MD 0.75, 95% CI: 0.48-1.16) and the incidence of spontaneous bacterial peritonitis (WMD -0.02, 95% CI: -0.07 to 0.03), no significant differences were found between the probiotic and placebo groups. CONCLUSION In summary, the gut microbiome in cirrhosis manifests as decreased counts of Lactobacillus and Bifidobacterium and increased counts of Enterobacter and Enterococcus. Targeted supplementation of probiotics in cirrhosis, including Lactobacillus combined with Bifidobacterium or Bifidobacterium alone, can reduce blood ammonia and the incidence of hepatic encephalopathy. The effect is similar to that of lactulose, but it has no obvious effect on mortality and spontaneous bacterial peritonitis.
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Affiliation(s)
- Long Huang
- Department of No. 1 Surgery, The First Hospital Affiliated to Anhui University of Traditional Chinese Medicine, Hefei, Anhui Province, China
- * Correspondence: Long Huang, The First Hospital Affiliated to Anhui University of Traditional Chinese Medicine, No. 117 Meishan Road, Hefei, Anhui Province 230031, China (e-mail: )
| | - Qingsheng Yu
- Department of No. 1 Surgery, The First Hospital Affiliated to Anhui University of Traditional Chinese Medicine, Hefei, Anhui Province, China
| | - Hui Peng
- Department of No. 1 Surgery, The First Hospital Affiliated to Anhui University of Traditional Chinese Medicine, Hefei, Anhui Province, China
| | - Zhou Zhen
- Department of Surgery, The Second Hospital Affiliated to Anhui University of Traditional Chinese Medicine, Hefei, Anhui Province, China
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18
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Role of Intestinal Microbes in Chronic Liver Diseases. Int J Mol Sci 2022; 23:ijms232012661. [PMID: 36293518 PMCID: PMC9603943 DOI: 10.3390/ijms232012661] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 10/15/2022] [Accepted: 10/19/2022] [Indexed: 11/07/2022] Open
Abstract
With the recent availability and upgrading of many emerging intestinal microbes sequencing technologies, our research on intestinal microbes is changing rapidly. A variety of investigations have found that intestinal microbes are essential for immune system regulation and energy metabolism homeostasis, which impacts many critical organs. The liver is the first organ to be traversed by the intestinal portal vein, and there is a strong bidirectional link between the liver and intestine. Many intestinal factors, such as intestinal microbes, bacterial composition, and intestinal bacterial metabolites, are deeply involved in liver homeostasis. Intestinal microbial dysbiosis and increased intestinal permeability are associated with the pathogenesis of many chronic liver diseases, such as alcoholic fatty liver disease (AFLD), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), chronic hepatitis B (CHB), chronic hepatitis C (CHC), autoimmune liver disease (AIH) and the development of hepatocellular carcinoma (HCC). Intestinal permeability and dysbacteriosis often lead to Lipopolysaccharide (LPS) and metabolites entering in serum. Then, Toll-like receptors activation in the liver induces the exposure of the intestine and liver to many small molecules with pro-inflammatory properties. And all of these eventually result in various liver diseases. In this paper, we have discussed the current evidence on the role of various intestinal microbes in different chronic liver diseases. As well as potential new therapeutic approaches are proposed in this review, such as antibiotics, probiotics, and prebiotics, which may have an improvement in liver diseases.
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Marascio N, De Caro C, Quirino A, Mazzitelli M, Russo E, Torti C, Matera G. The Role of the Microbiota Gut-Liver Axis during HCV Chronic Infection: A Schematic Overview. J Clin Med 2022; 11:5936. [PMID: 36233804 PMCID: PMC9572099 DOI: 10.3390/jcm11195936] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2022] [Revised: 10/03/2022] [Accepted: 10/04/2022] [Indexed: 11/30/2022] Open
Abstract
Hepatitis C virus (HCV) still represents one of the most important worldwide health care problems. Since 2011, direct-acting antiviral (DAA) drugs have increased the number of people who have achieved a sustained virological response (SVR). Even if the program to eradicate HCV by 2030 is still ongoing, the SARS-CoV-2 pandemic has created a delay due to the reallocation of public health resources. HCV is characterized by high genetic variability and is responsible for hepatic and extra-hepatic diseases. Depending on the HCV genotype/subtype and comorbidities of patients, tailored treatment is necessary. Recently, it has been shown that liver damage impacts gut microbiota, altering the microbial community (dysbiosis) during persistent viral replication. An increasing number of studies are trying to clarify the role of the gut-liver axis during HCV chronic infection. DAA therapy, by restoring the gut microbiota equilibrium, seems to improve liver disease progression in both naïve and treated HCV-positive patients. In this review, we aim to discuss a snapshot of selected peer-reviewed papers concerning the interplay between HCV and the gut-liver axis.
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Affiliation(s)
- Nadia Marascio
- Clinical Microbiology Unit, Department of Health Science, “Magna Graecia” University, 88100 Catanzaro, Italy
| | - Carmen De Caro
- System and Applied Pharmacology, Department of Health Science, “Magna Graecia” University, 88100 Catanzaro, Italy
| | - Angela Quirino
- Clinical Microbiology Unit, Department of Health Science, “Magna Graecia” University, 88100 Catanzaro, Italy
| | - Maria Mazzitelli
- Infectious and Tropical Diseases Unit, University Hospital of Padua, 35128 Padua, Italy
| | - Emilio Russo
- System and Applied Pharmacology, Department of Health Science, “Magna Graecia” University, 88100 Catanzaro, Italy
| | - Carlo Torti
- Infectious and Tropical Diseases Unit, Department of Medical and Surgical Sciences, “Magna Graecia” University, 88100 Catanzaro, Italy
| | - Giovanni Matera
- Clinical Microbiology Unit, Department of Health Science, “Magna Graecia” University, 88100 Catanzaro, Italy
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20
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Cox IJ, Peña Rodríguez M, Fagan A, Rojas-Lara MV, Le Guennec A, Rodriguez-Alvarez F, McGeorge S, Escalona-Nandez I, Torre A, Bajaj JS. Stool microbiota show greater linkages with plasma metabolites compared to salivary microbiota in a multinational cirrhosis cohort. Liver Int 2022; 42:2274-2282. [PMID: 35635305 DOI: 10.1111/liv.15329] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 05/03/2022] [Accepted: 05/27/2022] [Indexed: 02/13/2023]
Abstract
BACKGROUND AND AIMS Cirrhosis is associated with changes in gut microbiota in both saliva and stool. The relative linkage patterns of stool versus saliva microbiota with systemic metabolomics are unclear and may differ across countries. We hypothesized that stool microbiota have greater linkages with plasma metabolites than saliva microbiota, which may depend on country of origin. METHODS Age-balanced controls and outpatient patients with cirrhosis, compensated and decompensated, from the USA and Mexico (MX) underwent plasma collection and dietary recall. Plasma metabolomics were analysed using nuclear magnetic resonance spectroscopy. Microbiota in stool and saliva samples were analysed using 16S rRNA analyses. Correlation network differences between both saliva and stool gut microbiota and plasma metabolites were compared between subject groupings and within/between countries. RESULTS A total of 313 age-balanced subjects-135 USA (47 control, 48 compensated and 40 decompensated) and 178 MX (71 control, 56 compensated and 51 decompensated)-were enrolled. Cirrhosis severity, including lactulose and rifaximin use, were comparable. Plasma metabolites differed with advancing cirrhosis, between countries and according to 90-day hospitalizations. Correlation networks demonstrated more microbiome-metabolite linkages in stool compared to saliva in both populations, although there were no salivary correlation metrics across decompensated subjects in either country. Stool Lactobacillus showed a positive correlation to plasma lactate in decompensated cirrhosis from MX but not USA. CONCLUSIONS Stool microbiota were more extensively linked with systemic metabolites than were saliva microbiota, irrespective of cirrhosis severity and country. These changes were more prominent in decompensated cirrhosis and were centred around plasma lactate, which might reflect the interaction of diet and lactulose therapy.
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Affiliation(s)
- Isobel Jane Cox
- The Roger Williams Institute of Hepatology London, Foundation for Liver Research, London, UK.,Faculty of Life Sciences & Medicine, King's College London, London, UK
| | - Marcela Peña Rodríguez
- Laboratory for the Diagnosis of Emerging and Reemerging Diseases (LaDEER), University Center for Health Sciences, University of Guadalajara, Guadalajara, Mexico
| | - Andrew Fagan
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Internal Medicine, Virginia Commonwealth University and Central Virginia Veterans Healthcare System, Richmond, Virginia, USA
| | - Mayra V Rojas-Lara
- Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Adrien Le Guennec
- Randall Centre for Cell & Molecular Biophysics and Centre for Biomolecular Spectroscopy, King's College London, London, UK
| | | | - Sara McGeorge
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Internal Medicine, Virginia Commonwealth University and Central Virginia Veterans Healthcare System, Richmond, Virginia, USA
| | - Ivonne Escalona-Nandez
- Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Aldo Torre
- Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Jasmohan S Bajaj
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Internal Medicine, Virginia Commonwealth University and Central Virginia Veterans Healthcare System, Richmond, Virginia, USA
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21
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Ullah N, Kakakhel MA, Khan I, Gul Hilal M, Lajia Z, Bai Y, Sajjad W, Yuxi L, Ullah H, M Almohaimeed H, Alshanwani AR, Assiri R, Aggad WS, Alharbi NA, Alshehri AM, Liu G, Sun H, Zhang C. Structural and compositional segregation of the gut microbiota in HCV and liver cirrhotic patients: A clinical pilot study. Microb Pathog 2022; 171:105739. [PMID: 36055570 DOI: 10.1016/j.micpath.2022.105739] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2022] [Revised: 08/17/2022] [Accepted: 08/22/2022] [Indexed: 12/09/2022]
Abstract
Gut microbial dysbiosis during the development of Hepatitis C virus and liver-related diseases is not well studied. Nowadays, HCV and liver cirrhosis are the major concerns that cause gut bacterial alteration, which leads to dysbiosis. For this purpose, the present study was aimed at correlating the gut bacterial community of the control group in comparison to HCV and liver cirrhotic patients. A total of 23 stool samples were collected, including control (9), liver cirrhotic (8), and HCV (6). The collected samples were subjected to 16S rRNA Illumina gene sequencing. In comparison with control, a significant gut bacterial alteration was observed in the progression of HCV and liver cirrhosis. Overall, Firmicutes were significantly abundant in the whole study. No significant difference was observed in the alpha diversity of the control and patient studies. Additionally, the beta diversity based on non-metric multidimensional scaling (NMDS) has a significant difference (p = 0.005) (ANOSIM R2 = 0.14) in all groups. The discriminative results based on the LEfSe tool revealed that the HCV-infected patients had higher Enterobacteriaceae and Enterobacterial, as well as Lactobacillus and Bacilli in comparison than the liver-cirrhotic patients. These taxa were significantly different from the control group (p < 0.05). Regarding prospects, a detailed analysis of the function through metagenomics and transcriptomics is needed.
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Affiliation(s)
- Naeem Ullah
- School of Life Sciences, Lanzhou University, 730000, PR China; MOE Key Laboratory of Cell Activities and Stress Adaptations, School of Life Sciences, Lanzhou University, Lanzhou, 730000, PR China; Gansu Key Laboratory of Biomonitoring and Bioremediation for Environmental Pollution, Lanzhou University, Lanzhou, 73000, PR China
| | - Mian Adnan Kakakhel
- School of Life Sciences, Lanzhou University, 730000, PR China; MOE Key Laboratory of Cell Activities and Stress Adaptations, School of Life Sciences, Lanzhou University, Lanzhou, 730000, PR China
| | - Israr Khan
- School of Life Sciences, Lanzhou University, 730000, PR China; MOE Key Laboratory of Cell Activities and Stress Adaptations, School of Life Sciences, Lanzhou University, Lanzhou, 730000, PR China; Gansu Key Laboratory of Biomonitoring and Bioremediation for Environmental Pollution, Lanzhou University, Lanzhou, 73000, PR China
| | - Mian Gul Hilal
- School of Life Sciences, Lanzhou University, 730000, PR China
| | - Zha Lajia
- School of Life Sciences, Lanzhou University, 730000, PR China
| | - Yanrui Bai
- School of Life Sciences, Lanzhou University, 730000, PR China
| | - Wasim Sajjad
- State Key Laboratory of Cryospheric Science, Northwest Institute of Eco-Environment and Resources, Chinese Academy of Sciences, Lanzhou, 730000, China
| | - Li Yuxi
- School of Life Sciences, Lanzhou University, 730000, PR China
| | - Habib Ullah
- School of Life Sciences, Lanzhou University, 730000, PR China
| | - Hailah M Almohaimeed
- Department of Basic Science, College of Medicine, Princess Nourah Bint Abdulrahman University, P.O.Box 84428, Riyadh, 11671, Saudi Arabia
| | - Aliah R Alshanwani
- Physiology Department, College of Medicine, King Saud University, Saudi Arabia
| | - Rasha Assiri
- Department of Basic Medical Sciences, College of Medicine, Princess Nourah Bint Abdulrahman University, Riyadh, 11671, Saudi Arabia
| | - Waheeb S Aggad
- Department of Anatomy, College of Medicine, University of Jeddah, P.O.Box 8304, Jeddah, 23234, Saudi Arabia
| | - Nada Abdullah Alharbi
- Department of Basic Medical Sciences, College of Medicine, Princess Nourah Bint Abdulrahman University, Riyadh, 11671, Saudi Arabia; Department of Basic Medical Sciences, Unaizah College of Medicine and Medical Sciences, Qassim University, Qassim, Saudi Arabia
| | | | - Guanlan Liu
- School of Life Sciences, Lanzhou University, 730000, PR China
| | - Hui Sun
- School of Life Sciences, Lanzhou University, 730000, PR China
| | - Chunjiang Zhang
- School of Life Sciences, Lanzhou University, 730000, PR China.
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22
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Ashour Z, Shahin R, Ali-Eldin Z, El-Shayeb M, El-Tayeb T, Bakr S. Potential impact of gut Lactobacillus acidophilus and Bifidobacterium bifidum on hepatic histopathological changes in non-cirrhotic hepatitis C virus patients with different viral load. Gut Pathog 2022; 14:25. [PMID: 35706051 PMCID: PMC9199141 DOI: 10.1186/s13099-022-00501-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Accepted: 05/16/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Composition of gut microbiota has recently been suggested as a key factor persuading the pathogenesis of numerous human diseases including hepatic cirrhosis. OBJECTIVE To evaluate the potential impact of Lactobacillus acidophilus and Bifidobacterium bifidum microbiota on the progression of hepatic histopathological changes among patients with non-cirrhotic chronic hepatitis C (HCV) infection with different viral load. Additionally, to assess fecal composition of Lactobacillus acidophilus ATCC-4356 and Bifidobacterium bifidum ATCC-11863 microbiota genotypes MATERIAL AND METHODS: This study was carried out on 40 non-cirrhotic chronically infected HCV patients, and 10 healthy-controls. Liver biopsy and HCV genomic viral load were assessed for all patients after full clinical examination. Lactobacillus acidophilus ATCC-4356 and Bifidobacterium bifidum ATCC-11863 microbiota were assessed in all fecal samples using PCR assay, after counting total lactic acid bacteria. RESULTS There was a significantly higher difference between the count of both total lactic acid and Lactobacillus acidophilus of healthy controls compared to patients (P-value < 0.001). Though the count of total lactic acid bacteria, and Lactobacillus acidophilus were higher in the cases with early stage of fibrosis (score ≤ 1) compared to those with score > 1, there were no statistically significant differences with both the serum level of hepatitis C viremia (P = 0.850 and 0.977 respectively) and the score of fibrosis (P = 0.246 and 0.260 respectively). Genotypic analysis for the composition of the studied microbiota revealed that diversity was higher in healthy controls compared to patients. CONCLUSIONS The progression of hepatic fibrosis in HCV chronically infected patients seems to be plausible based on finding the altered Lactobacillus acidophilus and Bifidobacterium bifidum gut microbiota composition. Thus, modulation of these microbiota seems to be a promising target for prevention and control of HCV infection.
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Affiliation(s)
- Zeinab Ashour
- Department of Internal Medicine, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Rasha Shahin
- Department of Internal Medicine, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Zeinab Ali-Eldin
- Department of Internal Medicine, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Mohamed El-Shayeb
- Department of Internal Medicine, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Tarek El-Tayeb
- Department of Agricultural Microbiology, Faculty of Agriculture, Ain Shams University, Cairo, Egypt
| | - Salwa Bakr
- Department of Clinical Pathology/Hematology & Transfusion Medicine, Faculty of Medicine, Fayoum University, Fayoum, 63514, Egypt.
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Manzoor R, Ahmed W, Afify N, Memon M, Yasin M, Memon H, Rustom M, Al Akeel M, Alhajri N. Trust Your Gut: The Association of Gut Microbiota and Liver Disease. Microorganisms 2022; 10:1045. [PMID: 35630487 PMCID: PMC9146349 DOI: 10.3390/microorganisms10051045] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 05/08/2022] [Accepted: 05/16/2022] [Indexed: 02/07/2023] Open
Abstract
The gut microbiota composition is important for nutrient metabolism, mucosal barrier function, immunomodulation, and defense against pathogens. Alterations in the gut microbiome can disturb the gut ecosystem. These changes may lead to the loss of beneficial bacteria or an increase in potentially pathogenic bacteria. Furthermore, these have been shown to contribute to the pathophysiology of gastrointestinal and extra-intestinal diseases. Pathologies of the liver, such as non-alcoholic liver disease, alcoholic liver disease, cirrhosis, hepatocellular carcinoma, autoimmune hepatitis, viral hepatitis, and primary sclerosing cholangitis have all been linked to changes in the gut microbiome composition. There is substantial evidence that links gut dysbiosis to the progression and complications of these pathologies. This review article aimed to describe the changes seen in the gut microbiome in liver diseases and the association between gut dysbiosis and liver disease, and finally, explore treatment options that may improve gut dysbiosis in patients with liver disease.
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Affiliation(s)
- Ridda Manzoor
- College of Medicine and Health Sciences, Khalifa University, Abu Dhabi P.O. Box 127788, United Arab Emirates; (R.M.); (W.A.); (N.A.); (M.M.); (M.Y.); (H.M.); (M.R.)
| | - Weshah Ahmed
- College of Medicine and Health Sciences, Khalifa University, Abu Dhabi P.O. Box 127788, United Arab Emirates; (R.M.); (W.A.); (N.A.); (M.M.); (M.Y.); (H.M.); (M.R.)
| | - Nariman Afify
- College of Medicine and Health Sciences, Khalifa University, Abu Dhabi P.O. Box 127788, United Arab Emirates; (R.M.); (W.A.); (N.A.); (M.M.); (M.Y.); (H.M.); (M.R.)
| | - Mashal Memon
- College of Medicine and Health Sciences, Khalifa University, Abu Dhabi P.O. Box 127788, United Arab Emirates; (R.M.); (W.A.); (N.A.); (M.M.); (M.Y.); (H.M.); (M.R.)
| | - Maryam Yasin
- College of Medicine and Health Sciences, Khalifa University, Abu Dhabi P.O. Box 127788, United Arab Emirates; (R.M.); (W.A.); (N.A.); (M.M.); (M.Y.); (H.M.); (M.R.)
| | - Hamda Memon
- College of Medicine and Health Sciences, Khalifa University, Abu Dhabi P.O. Box 127788, United Arab Emirates; (R.M.); (W.A.); (N.A.); (M.M.); (M.Y.); (H.M.); (M.R.)
| | - Mohammad Rustom
- College of Medicine and Health Sciences, Khalifa University, Abu Dhabi P.O. Box 127788, United Arab Emirates; (R.M.); (W.A.); (N.A.); (M.M.); (M.Y.); (H.M.); (M.R.)
| | - Mohannad Al Akeel
- Division of Family Medicine, Department of Health, Abu Dhabi P.O. Box 5674, United Arab Emirates;
| | - Noora Alhajri
- Department of Medicine, Sheikh Shakhbout Medical City (SSMC), Abu Dhabi P.O. Box 11001, United Arab Emirates
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24
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Mizutani T, Ishizaka A, Koga M, Tsutsumi T, Yotsuyanagi H. Role of Microbiota in Viral Infections and Pathological Progression. Viruses 2022; 14:950. [PMID: 35632692 PMCID: PMC9144409 DOI: 10.3390/v14050950] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 04/29/2022] [Accepted: 04/29/2022] [Indexed: 02/04/2023] Open
Abstract
Viral infections are influenced by various microorganisms in the environment surrounding the target tissue, and the correlation between the type and balance of commensal microbiota is the key to establishment of the infection and pathogenicity. Some commensal microorganisms are known to resist or promote viral infection, while others are involved in pathogenicity. It is also becoming evident that the profile of the commensal microbiota under normal conditions influences the progression of viral diseases. Thus, to understand the pathogenesis underlying viral infections, it is important to elucidate the interactions among viruses, target tissues, and the surrounding environment, including the commensal microbiota, which should have different relationships with each virus. In this review, we outline the role of microorganisms in viral infections. Particularly, we focus on gaining an in-depth understanding of the correlations among viral infections, target tissues, and the surrounding environment, including the commensal microbiota and the gut virome, and discussing the impact of changes in the microbiota (dysbiosis) on the pathological progression of viral infections.
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Affiliation(s)
- Taketoshi Mizutani
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba 277-8562, Japan
- Division of Infectious Diseases, Advanced Clinical Research Center, the Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan; (A.I.); (M.K.); (T.T.); (H.Y.)
| | - Aya Ishizaka
- Division of Infectious Diseases, Advanced Clinical Research Center, the Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan; (A.I.); (M.K.); (T.T.); (H.Y.)
| | - Michiko Koga
- Division of Infectious Diseases, Advanced Clinical Research Center, the Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan; (A.I.); (M.K.); (T.T.); (H.Y.)
| | - Takeya Tsutsumi
- Division of Infectious Diseases, Advanced Clinical Research Center, the Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan; (A.I.); (M.K.); (T.T.); (H.Y.)
| | - Hiroshi Yotsuyanagi
- Division of Infectious Diseases, Advanced Clinical Research Center, the Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan; (A.I.); (M.K.); (T.T.); (H.Y.)
- Department of Infectious Diseases and Applied Immunology, IMSUT Hospital of Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
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25
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Klein F, Wellhöner F, Plumeier I, Kahl S, Chhatwal P, Vital M, Voigtländer T, Pieper DH, Manns MP, Lenzen H, Solbach P, Heidrich B. The biliary microbiome in ischaemic-type biliary lesions can be shaped by stenting but is resilient to antibiotic treatment. Liver Int 2022; 42:1070-1083. [PMID: 35152539 DOI: 10.1111/liv.15194] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Revised: 02/02/2022] [Accepted: 02/07/2022] [Indexed: 02/13/2023]
Abstract
This study aims to characterize the biliary microbiome as neglected factor in patients with ischaemic-type biliary lesions (ITBL) after liver transplantation. Therefore, the V1-V2 region of the 16S rRNA gene was sequenced in 175 bile samples. Samples from patients with anastomotic strictures (AS) served as controls. Multivariate analysis and in silico metagenomics were applied cross-sectionally and longitudinally. The microbial community differed significantly between ITBL and AS in terms of alpha and beta diversity. Both, antibiotic treatment and stenting were associated independently with differences in the microbial community structure. In contrast to AS, in ITBL stenting was associated with pronounced differences in the biliary microbiome, whereas no differences associated with antibiotic treatment could be observed in ITBL contrasting the pronounced differences found in AS. Bacterial pathways involved in the production of antibacterial metabolites were increased in ITBL with antibiotic treatment. After liver transplantation, the biliary tract harbours a complex microbial community with significant differences between ITBL and AS. Fundamental changes in the microbial community in ITBL can be achieved with biliary stenting. However, the effect of antibiotic treatment in ITBL was minimal. Therefore, antibiotics should be administered wisely in order to reduce emerging resistance of the biliary microbiome towards external antibiotics.
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Affiliation(s)
- Friederike Klein
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,German Center for Infection Research (DZIF), Hannover/Braunschweig, Germany.,Microbial Interactions and Processes Research Group, Helmholtz Center for Infection Research, Braunschweig, Germany
| | - Freya Wellhöner
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Iris Plumeier
- Microbial Interactions and Processes Research Group, Helmholtz Center for Infection Research, Braunschweig, Germany
| | - Silke Kahl
- Microbial Interactions and Processes Research Group, Helmholtz Center for Infection Research, Braunschweig, Germany
| | - Patrick Chhatwal
- Institute for Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany
| | - Marius Vital
- Microbial Interactions and Processes Research Group, Helmholtz Center for Infection Research, Braunschweig, Germany
| | - Torsten Voigtländer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Dietmar H Pieper
- Microbial Interactions and Processes Research Group, Helmholtz Center for Infection Research, Braunschweig, Germany
| | - Michael P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Henrike Lenzen
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,Integrated Research and Treatment Center Transplantation (IFB-Tx), Hannover Medical School, Hanover, Germany
| | - Philipp Solbach
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,German Center for Infection Research (DZIF), Hannover/Braunschweig, Germany.,Integrated Research and Treatment Center Transplantation (IFB-Tx), Hannover Medical School, Hanover, Germany
| | - Benjamin Heidrich
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,German Center for Infection Research (DZIF), Hannover/Braunschweig, Germany.,Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany
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26
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Hartmann P. Editorial: The Microbiome in Hepatobiliary and Intestinal Disease. Front Physiol 2022; 13:893074. [PMID: 35492588 PMCID: PMC9044070 DOI: 10.3389/fphys.2022.893074] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Accepted: 03/11/2022] [Indexed: 12/12/2022] Open
Affiliation(s)
- Phillipp Hartmann
- Department of Pediatrics, University of California, San Diego, San Diego, CA, United States
- Division of Gastroenterology, Hepatology and Nutrition, Rady Children’s Hospital San Diego, San Diego, CA, United States
- *Correspondence: Phillipp Hartmann,
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27
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Compositions of gut microbiota before and shortly after hepatitis C viral eradication by direct antiviral agents. Sci Rep 2022; 12:5481. [PMID: 35361930 PMCID: PMC8971444 DOI: 10.1038/s41598-022-09534-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Accepted: 03/08/2022] [Indexed: 12/24/2022] Open
Abstract
It is unclear whether dysbiosis in hepatitis C virus (HCV) infected patients results from the viral infection per se or develops as a result of hepatic dysfunction. We aimed to characterize compositions in gut microbiome before and shortly after HCV clearance. In this prospective cohort study, adult patients with confirmed HCV viremia were screened before receiving direct antiviral agents. Those with recent exposure to antibiotics or probiotics (within one month), prior abdominal surgery, or any malignancy were ineligible. Stool was collected before antiviral therapy started and at 12 weeks after the treatment completed. From the extracted bacterial DNA, 16 s rRNA gene was amplified and sequenced. Each patient was matched 1:2 in age and sex with uninfected controls. A total of 126 individuals were enrolled into analysis. The gut microbiome was significantly different between HCV-infected patients (n = 42), with or without cirrhosis, and their age-and sex-matched controls (n = 84) from the levels of phylum to amplicon sequence variant (all p values < 0.01 by principal coordinates analysis). All patients achieved viral eradication and exhibited no significant changes in the overall composition of gut microbiome following viral eradication (all p values > 0.5), also without significant difference in alpha diversity (all p values > 0.5). For the purpose of exploration, we also reported bacteria found differently abundant before and after HCV eradication, including Coriobacteriaceae, Peptostreptococcaceae, Staphylococcaceae, Morganellaceae, Pasteurellaceae, Succinivibrionaceae, and Moraxellaceae. Gut microbiota is altered in HCV-infected patients as compared with uninfected controls, but the overall microbial compositions do not significantly change shortly after HCV eradication.
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28
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Philips CA, Augustine P. Gut Barrier and Microbiota in Cirrhosis. J Clin Exp Hepatol 2022; 12:625-638. [PMID: 35535069 PMCID: PMC9077238 DOI: 10.1016/j.jceh.2021.08.027] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Accepted: 08/31/2021] [Indexed: 12/12/2022] Open
Abstract
Gut microbiota and their homeostatic functions are central to the maintenance of the intestinal mucosal barrier. The gut barrier functions as a structural, biological, and immunological barrier, preventing local and systemic invasion and inflammation of pathogenic taxa, resulting in the propagation or causation of organ-specific (liver disease) or systemic diseases (sepsis) in the host. In health, commensal bacteria are involved in regulating pathogenic bacteria, sinister bacterial products, and antigens; and help control and kill pathogenic organisms by secreting antimicrobial metabolites. Gut microbiota also participates in the extraction, synthesis, and absorption of nutrient metabolites, maintains intestinal epithelial integrity and regulates the development, homeostasis, and function of innate and adaptive immune cells. Cirrhosis is associated with local and systemic immune, vascular, and inflammatory changes directly or indirectly linked to perturbations in quality and quantity of intestinal microbiota and intestinal mucosal integrity. Dysbiosis and gut barrier dysfunction are directly involved in the pathogenesis of compensated cirrhosis and the type and severity of complications in decompensated cirrhosis, such as bacterial infections, encephalopathy, extrahepatic organ failure, and progression to acute on chronic liver failure. This paper reviews the normal gut barrier, gut barrier dysfunction, and dysbiosis-associated clinical events in patients with cirrhosis. The role of dietary interventions, antibiotics, prebiotics, probiotics, synbiotics, and healthy donor fecal microbiota transplantation (FMT) to modulate the gut microbiota for improving patient outcomes is further discussed.
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Affiliation(s)
- Cyriac A. Philips
- Department of Translational Hepatology, Monarch Liver Laboratory, The Liver Institute, Center of Excellence in GI Sciences, Rajagiri Hospital, Chunangamvely, Aluva, Ernakulam, Kerala, India
| | - Philip Augustine
- Department of Gastroenterology and Advanced GI Endoscopy, Center of Excellence in GI Sciences, Rajagiri Hospital, Chunangamvely, Aluva, Ernakulam, Kerala, India
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IgA anti-beta-2 glycoprotein I antibodies in chronic hepatitis C. Arab J Gastroenterol 2022; 23:26-31. [DOI: 10.1016/j.ajg.2021.12.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 11/13/2021] [Accepted: 12/09/2021] [Indexed: 11/20/2022]
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Abstract
PURPOSE OF REVIEW Although gut dysbiosis can hasten disease progression in end-stage liver disease and contribute to disease severity, morbidity and mortality, its impact during and after transplant needs further study. RECENT FINDINGS Changes in the microbiome are associated with hepatic decompensation. Immune homeostasis is further disrupted during transplant and with immunosuppressants required after transplant. There is increasing evidence of the role of microbiota in peri and posttransplant complications. SUMMARY Although transplant is highly successful with acceptable survival rates, infections, rejection, disease recurrence and death remain important complications. Prognostication and interventions involving the gut microbiome could be beneficial.
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Affiliation(s)
- Nikki Duong
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and Richmond VA Medical Center, Richmond, Virginia, USA
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Neag MA, Mitre AO, Catinean A, Buzoianu AD. Overview of the microbiota in the gut-liver axis in viral B and C hepatitis. World J Gastroenterol 2021; 27:7446-7461. [PMID: 34887642 PMCID: PMC8613744 DOI: 10.3748/wjg.v27.i43.7446] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 08/13/2021] [Accepted: 11/03/2021] [Indexed: 02/06/2023] Open
Abstract
Viral B and C hepatitis are a major current health issue, both diseases having a chronic damaging effect on the liver and its functions. Chronic liver disease can lead to even more severe and life-threatening conditions, such as liver cirrhosis and hepatocellular carcinoma. Recent years have uncovered an important interplay between the liver and the gut microbiome: the gut-liver axis. Hepatitis B and C infections often cause alterations in the gut microbiota by lowering the levels of ‘protective’ gut microorganisms and, by doing so, hinder the microbiota ability to boost the immune response. Treatments aimed at restoring the gut microbiota balance may provide a valuable addition to current practice therapies and may help limit the chronic changes observed in the liver of hepatitis B and C patients. This review aims to summarize the current knowledge on the anato-functional axis between the gut and liver and to highlight the influence that hepatitis B and C viruses have on the microbiota balance, as well as the influence of treatments aimed at restoring the gut microbiota on infected livers and disease progression.
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Affiliation(s)
- Maria Adriana Neag
- Department of Pharmacology, Toxicology and Clinical Pharmacology, Iuliu Hatieganu University of Medicine and Pharmacy of Cluj-Napoca, Cluj-Napoca 400337, Romania
| | - Andrei Otto Mitre
- Faculty of Medicine, Iuliu Hatieganu University of Medicine and Pharmacy of Cluj-Napoca, Cluj-Napoca 400012, Romania
| | - Adrian Catinean
- Department of Internal Medicine, Iuliu Hatieganu University of Medicine and Pharmacy of Cluj-Napoca, Cluj-Napoca 400006, Romania
| | - Anca Dana Buzoianu
- Department of Pharmacology, Toxicology and Clinical Pharmacology, Iuliu Hatieganu University of Medicine and Pharmacy of Cluj-Napoca, Cluj-Napoca 400337, Romania
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Chuaypen N, Jinato T, Avihingsanon A, Chirapongsathorn S, Cheevadhanarak S, Nookaew I, Tanaka Y, Tangkijvanich P. Improvement of Gut Diversity and Composition After Direct-Acting Antivirals in Hepatitis C Virus-Infected Patients With or Without Human Immunodeficiency Virus Coinfection. J Infect Dis 2021; 224:1410-1421. [PMID: 33598686 PMCID: PMC8557699 DOI: 10.1093/infdis/jiab094] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Accepted: 02/12/2021] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND The influence of direct-acting antivirals (DAAs) on the composition of gut microbiota in hepatitis C virus (HCV)-infected patients with or without human immunodeficiency virus (HIV) is unclear. METHODS We enrolled 62 patients with HCV monoinfection and 24 patients with HCV/HIV coinfection receiving elbasvir-grazoprevir from a clinical trial. Fecal specimens collected before treatment and 12 weeks after treatment were analyzed using amplicon-based 16S ribosomal RNA sequencing. RESULTS Sustained virological response rates in the monoinfection and coinfection groups were similar (98.4% vs 95.8%). Pretreatment bacterial communities in the patient groups were less diverse and distinct from those of healthy controls. Compared with HCV-monoinfected patients, HCV/HIV-coinfected individuals showed comparable microbial alpha diversity but decreased Firmicutes-Bacteroidetes ratios. The improvement of microbial dysbiosis was observed in responders achieving sustained virological response across fibrosis stages but was not found in nonresponders. Responders with a low degree of fibrosis exhibited a recovery in alpha diversity to levels comparable to those in healthy controls. Reciprocal alterations of increased beneficial bacteria and reduced pathogenic bacteria were also observed in responders. CONCLUSIONS This study indicates a short-term effect of direct-acting antivirals in restoration of microbial dysbiosis. The favorable changes in gut microbiota profiles after viral eradication might contribute toward the reduction of HCV-related complications among infected individuals.
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Affiliation(s)
- Natthaya Chuaypen
- Center of Excellence in Hepatitis and Liver Cancer, Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Thananya Jinato
- Center of Excellence in Hepatitis and Liver Cancer, Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Anchalee Avihingsanon
- The HIV Netherlands Australia Thailand Research Collaboration (HIV-NAT), Bangkok, Thailand
| | - Sakkarin Chirapongsathorn
- Division of Gastroenterology and Hepatology, Department of Medicine, Phramongkutklao Hospital, College of Medicine, Royal Thai Army, Bangkok, Thailand
| | - Supapon Cheevadhanarak
- Systems Biology and Bioinformatics Research Group, Pilot Plant Development and Training Institute, King Mongkut’s University of Technology Thonburi, Bangkok, Thailand
- School of Bioresources and Technology, King Mongkut’s University of Technology Thonburi, Bangkok, Thailand
| | - Intawat Nookaew
- Department of Biomedical Informatics, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
| | - Yasuhito Tanaka
- Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Pisit Tangkijvanich
- Center of Excellence in Hepatitis and Liver Cancer, Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
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Ding X, Zhou J, Chai Y, Yan Z, Liu X, Dong Y, Mei X, Jiang Y, Lei H. A metagenomic study of the gut microbiome in PTB'S disease. Microbes Infect 2021; 24:104893. [PMID: 34710620 DOI: 10.1016/j.micinf.2021.104893] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 09/29/2021] [Accepted: 10/10/2021] [Indexed: 11/18/2022]
Abstract
BACKGROUND There is an abundant link between the gut microbiota and human health and it plays a critical role in the clinic. It is recognized that microbial dysregulation contributes to the pathogenesis of tuberculosis (TB), but the underlying mechanisms remain unclear. In this study, we investigated the association of gut microbiome composition with TB as well as its possible roles in the development of this disease. METHODS Fecal samples were collected from 10 TB patients and 20 healthy control samples. DNA extracted from fecal samples was subjected to 16S rDNA gene sequencing analysis on the Illumina MiSeq platform. RESULTS Compared with healthy control samples, the gut microbiome of patients with TB was characterized by the decreased Alpha diversity. Perhaps, the decrease of microbial diversity which results in microbial dysregulation is the reason for clinical patients with more symptoms. The PTB group showed the most unique microbiota by higher abundance of Bifidobacteriaceae, Bifidobacteriales, Coriobacteriaceae, Coriobacteriales, Actinobacteria, Caulobacteraceae, Phyllobacteriaceae, Rhizobiales, Burkholderiaceae, Burkholderiaceae. Inflammatory status in PTB patients may be associated with the increased abundance of Clostridia and decreased abundance of Prevotella. We found that the abundance of Solobacterium and Actinobacteria was higher in the patients. There were 4 significant differences (p<0.05) in the two groups which belonged to four metabolic categories, including endocytosis, phosphotransferase system (PTS), toluene degradation, and amoebiasis. CONCLUSION We applied the approach of metagenomic sequencing to characterize the features of gut microbiota in PTB patients. The present study provided a detailed analysis of the characterization of the gut microbiota in patients based on the clinic. According to the metagenome analysis, our results indicated that the gut microbiota in PTB patients was significantly different from healthy control samples as characterized by the bacteria and metabolic pathway. The richness of the gut microbiota in patients was revealed. It was hypothesized that the above-mentioned changes of the gut microbiota could exert an impact on the development of PTB through the downstream regulation of the immune status of the host by way of the gut-lung axis.
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Affiliation(s)
- Xiudong Ding
- 8th Medical Center of PLA General Hospital, China
| | | | - Yinghui Chai
- 8th Medical Center of PLA General Hospital, China
| | - Zengkui Yan
- 8th Medical Center of PLA General Hospital, China
| | - Xin Liu
- 8th Medical Center of PLA General Hospital, China
| | - Yueming Dong
- 8th Medical Center of PLA General Hospital, China
| | - Xue Mei
- 8th Medical Center of PLA General Hospital, China
| | - Ying Jiang
- 8th Medical Center of PLA General Hospital, China.
| | - Hong Lei
- 8th Medical Center of PLA General Hospital, China.
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Guo X, Lan Z, Wen Y, Zheng C, Rong Z, Liu T, Chen S, Yang X, Zheng H, Wu W. Synbiotics Supplements Lower the Risk of Hand, Foot, and Mouth Disease in Children, Potentially by Providing Resistance to Gut Microbiota Dysbiosis. Front Cell Infect Microbiol 2021; 11:729756. [PMID: 34660342 PMCID: PMC8515124 DOI: 10.3389/fcimb.2021.729756] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Accepted: 08/27/2021] [Indexed: 11/17/2022] Open
Abstract
Background Hand, foot and mouth disease (HFMD) is an acute enterovirus-induced disease. Gut microbiota dysbiosis has been identified as a factor that plays an important role in enteral virus infection, but the gut microbiota profile in hand, foot and mouth disease has rarely been studied in a large population. Methods A total of 749 children (HFMD: n = 262, healthy control: n = 487) aged 2 to 7 years were recruited from hospitals and communities in the period from May to July, 2017. Clinical and demographical information was collected by trained personnel, and fecal samples were collected and processed for 16S ribosomal RNA(rRNA) gene sequencing. Results We observed a significant alteration in the microbiota profile of children with HFMD compared with that of control children. Patients with enteroviruses A71(EV71) positive had more dysbiotic gut microbiota than those with coxsackievirus A16 (CAV16) positive. We found that Prevotella and Streptococcus were enriched in children with HFMD, whereas beneficial bacteria, including Bifidobacterium and Faecalibacterium, were depleted. Children with synbiotics supplements had lower risk of HFMD and we observed that the gut microbiota of HFMD patients who were administered synbiotics exhibited potential resistance to the dysbiosis detected in HFMD. Conclusions This study suggested that the gut microbiota of patients with hand, foot and mouth disease exhibits dysbiosis and that synbiotics supplements potentially helps maintain the homeostasis of the gut flora.
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Affiliation(s)
- Xiaoying Guo
- Guangdong Provincial Institute of Public Health, Guangdong Provincial Center for Disease Control and Prevention, Guangzhou, China
- School of Public Health, Southern Medical University, Guangzhou, China
| | - Zixin Lan
- The Second Clinical Medical College, Southern Medical University, Guangzhou, China
| | - Yaling Wen
- School of Mathematics and Computational Science, Guilin University of Electronic Technology, Guangxi, China
| | - Chanjiao Zheng
- Modern Service Industry Department, Guangzhou Technician College, Guangzhou, China
| | - Zuhua Rong
- Guangdong Provincial Institute of Public Health, Guangdong Provincial Center for Disease Control and Prevention, Guangzhou, China
| | - Tao Liu
- Guangdong Provincial Institute of Public Health, Guangdong Provincial Center for Disease Control and Prevention, Guangzhou, China
| | - Siyi Chen
- Guangdong Provincial Institute of Public Health, Guangdong Provincial Center for Disease Control and Prevention, Guangzhou, China
| | - Xingfen Yang
- School of Public Health, Southern Medical University, Guangzhou, China
| | - Huimin Zheng
- Guangdong Provincial Institute of Public Health, Guangdong Provincial Center for Disease Control and Prevention, Guangzhou, China
| | - Wei Wu
- Guangdong Provincial Institute of Public Health, Guangdong Provincial Center for Disease Control and Prevention, Guangzhou, China
- School of Public Health, Southern Medical University, Guangzhou, China
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Yilmaz B, Ruckstuhl L, Müllhaupt B, Magenta L, Kuster MH, Clerc O, Torgler R, Semmo N. Pilot Sub-Study of the Effect of Hepatitis C Cure by Glecaprevir/Pibrentasvir on the Gut Microbiome of Patients with Chronic Hepatitis C Genotypes 1 to 6 in the Mythen Study. Pharmaceuticals (Basel) 2021; 14:931. [PMID: 34577631 PMCID: PMC8472424 DOI: 10.3390/ph14090931] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 09/10/2021] [Accepted: 09/13/2021] [Indexed: 12/12/2022] Open
Abstract
In this small pilot sub-study, longitudinal gut microbiota composition changes, after successful treatment of hepatitis C virus (HCV) with the co-formulated glecaprevir/pibrentasvir (GLE/PIB), were analyzed before treatment (baseline) and 12 weeks post-treatment. Participating patients provided a fresh stool sample the week before their study visit, from which microbial DNA was extracted and sequenced for the 16S rRNA region in an Illumina MiSeq2 platform. Microbial and statistical analyses were conducted to determine the alpha-diversity (number of different taxa within a sample) and beta-diversity (number of overlapping taxa between samples). Stool samples from 58 patients were eligible for analysis. There were 27 patients with HCV genotype 1, 10 with genotype 2, 16 with genotype 3, and 5 with genotype 4. No statistically significant differences in gut microbiota diversity, species richness, or microbial community pattern were found at baseline and at post-treatment Week 12. Lack of statistically significant differences remained consistent in further analysis by demographic and baseline disease characteristics. Surprisingly, no statistically significant changes in alpha- and beta-diversity were seen in the microbiota after GLE/PIB treatment, though there was a trend toward less richness over time. Further investigation is needed into this unexpected outcome to better understand the role of HCV treatment and the gut microbiota.
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Affiliation(s)
- Bahtiyar Yilmaz
- Department for Biomedical Research, Inselspital, University of Bern, 3008 Bern, Switzerland
| | - Lisa Ruckstuhl
- AbbVie Schweiz AG, 6330 Cham, Switzerland; (L.R.); (M.H.K.); (R.T.)
| | - Beat Müllhaupt
- Department of Gastroenterology & Hepatology, University Hospital Zurich, 8091 Zurich, Switzerland;
| | | | | | - Olivier Clerc
- Infectious Diseases Department, Hospital Pourtalès, 2000 Neuchâtel, Switzerland;
| | - Ralph Torgler
- AbbVie Schweiz AG, 6330 Cham, Switzerland; (L.R.); (M.H.K.); (R.T.)
| | - Nasser Semmo
- Hepatology, Department for BioMedical Research, University of Bern, 3008 Bern, Switzerland
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Milosevic I, Russo E, Vujovic A, Barac A, Stevanovic O, Gitto S, Amedei A. Microbiota and viral hepatitis: State of the art of a complex matter. World J Gastroenterol 2021; 27:5488-5501. [PMID: 34588747 PMCID: PMC8433613 DOI: 10.3748/wjg.v27.i33.5488] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 03/26/2021] [Accepted: 07/21/2021] [Indexed: 02/06/2023] Open
Abstract
Changes in gut microbiota influence both the gut and liver, which are strictly connected by the so-called "gut-liver axis". The gut microbiota acts as a major determinant of this relationship in the onset and clinical course of liver diseases. According to the results of several studies, gut dysbiosis is linked to viral hepatitis, mainly hepatitis C virus and hepatitis B virus infection. Gut bacteria-derived metabolites and cellular components are key molecules that affect liver function and modulate the pathology of viral hepatitis. Recent studies showed that the gut microbiota produces various molecules, such as peptidoglycans, lipopolysaccharides, DNA, lipoteichoic acid, indole-derivatives, bile acids, and trimethylamine, which are translocated to the liver and interact with liver immune cells causing pathological effects. Therefore, the existence of crosstalk between the gut microbiota and the liver and its implications on host health and pathologic status are essential factors impacting the etiology and therapeutic approach. Concrete mechanisms behind the pathogenic role of gut-derived components on the pathogenesis of viral hepatitis remain unclear and not understood. In this review, we discuss the current findings of research on the bidirectional relationship of the components of gut microbiota and the progression of liver diseases and viral hepatitis and vice versa. Moreover, this paper highlights the current therapeutic and preventive strategies, such as fecal transplantation, used to restore the gut microbiota composition and so improve host health.
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Affiliation(s)
- Ivana Milosevic
- Clinic for Infectious and Tropical Diseases, Clinical Centre of Serbia Faculty of Medicine, University of Belgrade, Belgrade 101801, Serbia
| | - Edda Russo
- Department of Experimental and Clinical Medicine, University of Florence, Firenze 50100, Italy
| | - Ankica Vujovic
- Clinic for Infectious and Tropical Diseases, Clinical Centre of Serbia Faculty of Medicine, University of Belgrade, Belgrade 101801, Serbia
| | - Aleksandra Barac
- Clinic for Infectious and Tropical Diseases, Clinical Centre of Serbia Faculty of Medicine, University of Belgrade, Belgrade 101801, Serbia
| | - Olja Stevanovic
- Clinic for Infectious and Tropical Diseases, Clinical Centre of Serbia Faculty of Medicine, University of Belgrade, Belgrade 101801, Serbia
| | - Stefano Gitto
- Department of Experimental and Clinical Medicine, University of Florence, Firenze 50100, Italy
| | - Amedeo Amedei
- Department of Experimental and Clinical Medicine, University of Florence, Firenze 50100, Italy
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Wellhöner F, Döscher N, Woelfl F, Vital M, Plumeier I, Kahl S, Potthoff A, Manns MP, Pieper DH, Cornberg M, Wedemeyer H, Heidrich B. Eradication of Chronic HCV Infection: Improvement of Dysbiosis Only in Patients Without Liver Cirrhosis. Hepatology 2021; 74:72-82. [PMID: 33411981 DOI: 10.1002/hep.31700] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Revised: 11/14/2020] [Accepted: 12/13/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS It is well accepted that liver diseases and their outcomes are associated with intestinal microbiota, but causality is difficult to establish. The intestinal microbiota are altered in patients with hepatitis C. As chronic HCV infection can now be cured in almost all patients, it is an ideal model to study the influence of liver disease on the microbiota. APPROACH AND RESULTS We aimed to prospectively analyze the changes in the gut microbiome in patients who received direct-acting antivirals (DAA) and achieved sustained virological response (SVR). Amplicon sequencing of the V1-V2 region in the 16S ribosomal RNA gene was performed in stool samples of patients with chronic hepatitis C. Patients in the treatment group received DAA (n = 65), whereas in the control group, no DAA were given (n = 33). Only patients achieving SVR were included. The alpha diversity increased numerically but not significantly from baseline to SVR at week 24 or 48 (SVR24/48; 2.784 ± 0.248 vs. 2.846 ± 0.224; P = 0.057). When stratifying for the presence of liver cirrhosis, a significant increase in diversity was only seen in patients without cirrhosis. Differences in the microbial community structure induced by the achievement of SVR were only observed in patients without liver cirrhosis. In patients with liver cirrhosis and in the control group, no significant differences were observed. CONCLUSIONS In conclusion, the achievement of SVR24/48 in patients with chronic HCV was associated with changes in the intestinal microbiota. However, these changes were only seen in patients without liver cirrhosis. A major role of liver remodeling on the intestinal microbiota is indicated by the dynamics of the intestinal microbial community structure depending on the stage of fibrosis in patients resolving chronic hepatitis C.
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Affiliation(s)
- Freya Wellhöner
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Nico Döscher
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Franziska Woelfl
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Marius Vital
- Microbial Interactions and Processes Research Group, Helmholtz Center for Infection Research, Braunschweig, Germany
| | - Iris Plumeier
- Microbial Interactions and Processes Research Group, Helmholtz Center for Infection Research, Braunschweig, Germany
| | - Silke Kahl
- Microbial Interactions and Processes Research Group, Helmholtz Center for Infection Research, Braunschweig, Germany
| | - Andrej Potthoff
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Michael Peter Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Braunschweig, Germany
| | - Dietmar Helmut Pieper
- Microbial Interactions and Processes Research Group, Helmholtz Center for Infection Research, Braunschweig, Germany.,German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Braunschweig, Germany
| | - Markus Cornberg
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Braunschweig, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Braunschweig, Germany
| | - Benjamin Heidrich
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,Microbial Interactions and Processes Research Group, Helmholtz Center for Infection Research, Braunschweig, Germany.,German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Braunschweig, Germany
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Sultan S, El-Mowafy M, Elgaml A, El-Mesery M, El Shabrawi A, Elegezy M, Hammami R, Mottawea W. Alterations of the Treatment-Naive Gut Microbiome in Newly Diagnosed Hepatitis C Virus Infection. ACS Infect Dis 2021; 7:1059-1068. [PMID: 33119247 DOI: 10.1021/acsinfecdis.0c00432] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Gut microbiota dysbiosis has been linked to many heath disorders including hepatitis C virus (HCV) infection. However, profiles of the gut microbiota alterations in HCV are inconsistent in the literature and are affected by the treatment regimens. Using samples collected prior to treatment from newly diagnosed patients, we characterized the gut microbiota structure in HCV patients as compared to healthy controls. Treatment-naive HCV microbiota showed increased diversity, an increased abundance of Prevotella, Succinivibrio, Catenibacterium, Megasphaera, and Ruminococcaceae, and a lower abundance of Bacteroides, Dialister, Bilophila, Streptococcus, parabacteroides, Enterobacteriaceae, Erysipelotrichaceae, Rikenellaceae, and Alistipes. Predicted community metagenomic functions showed a depletion of carbohydrate and lipid metabolism in HCV microbiota along with perturbations of amino acid metabolism. Receiver-operating characteristic analysis identified five disease-specific operational taxonomic units (OTUs) as potential biomarkers of HCV infections. Collectively, our findings reveal the alteration of gut microbiota in treatment naive HCV patients and suggest that gut microbiota may hold diagnostic promise in HCV infection.
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Affiliation(s)
- Salma Sultan
- Faculty of Health Sciences, School of Nutrition Sciences, University of Ottawa, Ottawa, Ontario K1H8M5, Canada
| | | | - Abdelaziz Elgaml
- Faculty of Pharmacy, Department of Microbiology and Immunology, Horus University, New Damietta 34518, Egypt
| | | | | | | | - Riadh Hammami
- Faculty of Health Sciences, School of Nutrition Sciences, University of Ottawa, Ottawa, Ontario K1H8M5, Canada
| | - Walid Mottawea
- Faculty of Health Sciences, School of Nutrition Sciences, University of Ottawa, Ottawa, Ontario K1H8M5, Canada
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Moreno-Gonzalez M, Beraza N. The Role of the Microbiome in Liver Cancer. Cancers (Basel) 2021; 13:2330. [PMID: 34066064 PMCID: PMC8150469 DOI: 10.3390/cancers13102330] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 04/30/2021] [Accepted: 05/03/2021] [Indexed: 12/11/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common malignancy occuring in the context of chronic liver disease and is one of the main causes of cancer-derived death worldwide. The lack of effective treatments, together with the poor prognosis, underlines the urge to develop novel and multidisciplinary therapeutics. An increasing body of evidence shows that HCC associates with changes in intestinal microbiota abundance and composition as well as with impaired barrier function, leading to the release of bacteria and their metabolites to the liver. These factors trigger a cascade of inflammatory responses contributing to liver cirrhosis and constituting an ideal environment for the progression of HCC. Interestingly, the use of bacteriotherapy in human and preclinical studies of chronic liver disease and HCC has been shown to successfully modify the microbiota composition, reducing overall inflammation and fibrosis. In this review, we explore the existing knowledge on the characterisation of the intestinal microbial composition in humans and experimental murine chronic liver disease and HCC, as well as the use of antibiotics and bacteriotherapy as therapeutic options.
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Affiliation(s)
- Mar Moreno-Gonzalez
- Gut Microbes and Health Institute Strategic Programme, Quadram Institute Bioscience, Norwich Research Park, Norwich NR4 7UQ, UK;
| | - Naiara Beraza
- Gut Microbes and Health Institute Strategic Programme, Quadram Institute Bioscience, Norwich Research Park, Norwich NR4 7UQ, UK;
- Food Innovation and Health Institute Strategic Programme, Quadram Institute Bioscience, Norwich Research Park, Norwich NR4 7UQ, UK
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Hupa-Breier KL, Dywicki J, Hartleben B, Wellhöner F, Heidrich B, Taubert R, Mederacke YSE, Lieber M, Iordanidis K, Manns MP, Wedemeyer H, Hardtke-Wolenski M, Jaeckel E. Dulaglutide Alone and in Combination with Empagliflozin Attenuate Inflammatory Pathways and Microbiome Dysbiosis in a Non-Diabetic Mouse Model of NASH. Biomedicines 2021; 9:biomedicines9040353. [PMID: 33808404 PMCID: PMC8066839 DOI: 10.3390/biomedicines9040353] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 03/22/2021] [Accepted: 03/25/2021] [Indexed: 12/15/2022] Open
Abstract
Dysregulation of glucose homeostasis plays a major role in the pathogenesis of non-alcoholic steatohepatitis (NASH) as it activates proinflammatory and profibrotic processes. Beneficial effects of antiglycemic treatments such as GLP-1 agonist or SGLT-2 inhibitor on NASH in patients with diabetes have already been investigated. However, their effect on NASH in a non-diabetic setting remains unclear. With this aim, we investigated the effect of long-acting GLP1-agonist dulaglutide and SGLT-2 inhibitor empagliflozin and their combination in a non-diabetic mouse model of NASH. C57BL/6 mice received a high-fat-high-fructose (HFHC) diet with a surplus of cholesterol for 16 weeks. After 12 weeks of diet, mice were treated with either dulaglutide, empagliflozin or their combination. Dulaglutide alone and in combination with empagliflozin led to significant weight loss, improved glucose homeostasis and diminished anti-inflammatory and anti-fibrotic pathways. Combination of dulaglutide and empagliflozin further decreased MoMFLy6CHigh and CD4+Foxp3+ T cells. No beneficial effects for treatment with empagliflozin alone could be shown. While no effect of dulaglutide or its combination with empaglifozin on hepatic steatosis was evident, these data demonstrate distinct anti-inflammatory effects of dulaglutide and their combination with empagliflozin in a non-diabetic background, which could have important implications for further treatment of NASH.
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Affiliation(s)
- Katharina Luise Hupa-Breier
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, 30625 Hannover, Germany; (J.D.); (F.W.); (B.H.); (R.T.); (Y.S.M.); (M.L.); (K.I.); (M.P.M.); (H.W.); (M.H.-W.); (E.J.)
- Correspondence: ; Tel.: +49-(0)-511-532-6992
| | - Janine Dywicki
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, 30625 Hannover, Germany; (J.D.); (F.W.); (B.H.); (R.T.); (Y.S.M.); (M.L.); (K.I.); (M.P.M.); (H.W.); (M.H.-W.); (E.J.)
| | - Björn Hartleben
- Department of Pathology, Hannover Medical School, 30625 Hannover, Germany;
| | - Freya Wellhöner
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, 30625 Hannover, Germany; (J.D.); (F.W.); (B.H.); (R.T.); (Y.S.M.); (M.L.); (K.I.); (M.P.M.); (H.W.); (M.H.-W.); (E.J.)
| | - Benjamin Heidrich
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, 30625 Hannover, Germany; (J.D.); (F.W.); (B.H.); (R.T.); (Y.S.M.); (M.L.); (K.I.); (M.P.M.); (H.W.); (M.H.-W.); (E.J.)
| | - Richard Taubert
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, 30625 Hannover, Germany; (J.D.); (F.W.); (B.H.); (R.T.); (Y.S.M.); (M.L.); (K.I.); (M.P.M.); (H.W.); (M.H.-W.); (E.J.)
| | - Young-Seon Elisabeth Mederacke
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, 30625 Hannover, Germany; (J.D.); (F.W.); (B.H.); (R.T.); (Y.S.M.); (M.L.); (K.I.); (M.P.M.); (H.W.); (M.H.-W.); (E.J.)
| | - Maren Lieber
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, 30625 Hannover, Germany; (J.D.); (F.W.); (B.H.); (R.T.); (Y.S.M.); (M.L.); (K.I.); (M.P.M.); (H.W.); (M.H.-W.); (E.J.)
| | - Konstantinos Iordanidis
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, 30625 Hannover, Germany; (J.D.); (F.W.); (B.H.); (R.T.); (Y.S.M.); (M.L.); (K.I.); (M.P.M.); (H.W.); (M.H.-W.); (E.J.)
| | - Michael P. Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, 30625 Hannover, Germany; (J.D.); (F.W.); (B.H.); (R.T.); (Y.S.M.); (M.L.); (K.I.); (M.P.M.); (H.W.); (M.H.-W.); (E.J.)
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, 30625 Hannover, Germany; (J.D.); (F.W.); (B.H.); (R.T.); (Y.S.M.); (M.L.); (K.I.); (M.P.M.); (H.W.); (M.H.-W.); (E.J.)
| | - Matthias Hardtke-Wolenski
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, 30625 Hannover, Germany; (J.D.); (F.W.); (B.H.); (R.T.); (Y.S.M.); (M.L.); (K.I.); (M.P.M.); (H.W.); (M.H.-W.); (E.J.)
- Department of Gastroenterology and Hepatology, Essen University Hospital, University Duisburg-Essen, 45147 Essen, Germany
| | - Elmar Jaeckel
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, 30625 Hannover, Germany; (J.D.); (F.W.); (B.H.); (R.T.); (Y.S.M.); (M.L.); (K.I.); (M.P.M.); (H.W.); (M.H.-W.); (E.J.)
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41
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Gui QF, Jin HL, Zhu F, Lu HF, Zhang Q, Xu J, Yang YM, Xiao C. Gut microbiota signatures in Schistosoma japonicum infection-induced liver cirrhosis patients: a case-control study. Infect Dis Poverty 2021; 10:43. [PMID: 33771232 PMCID: PMC8004463 DOI: 10.1186/s40249-021-00821-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Accepted: 03/08/2021] [Indexed: 12/15/2022] Open
Abstract
Background Several studies have assessed the role of gut microbiota in various cirrhosis etiologies, however, none has done so in the context of Schistosoma japonicum infection in humans. We, therefore, sought to determine whether gut microbiota is associated with S. japonicum infection-induced liver cirrhosis. Methods From December 2017 to November 2019, 24 patients with S. japonicum infection-induced liver cirrhosis, as well as 25 age- and sex-matched controls from the Zhejiang Province, China, were enrolled. Fecal samples were collected and used for 16S rRNA gene sequencing (particularly, the hypervariable V4 region) using the Illumina MiSeq system. Wilcoxon Rank-Sum and PERMANOVA tests were used for analysis. Results Eight hundred and seven operational taxonomic units (OTUs) were detected, of which, 491 were common between the two groups, whereas 123 and 193 were unique to the control and cirrhosis groups, respectively. Observed species, Chao, ACE, Shannon, Simpson, and Good’s coverage indexes, used for alpha diversity analysis, showed values of 173.4 ± 63.8, 197.7 ± 73.0, 196.3 ± 68.9, 2.96 ± 0.57, 0.13 ± 0.09, and 1.00 ± 0.00, respectively, in the control group and 154.0 ± 68.1, 178.6 ± 75.1, 179.9 ± 72.4, 2.68 ± 0.76, 0.19 ± 0.18, and 1.00 ± 0.00, respectively, in the cirrhosis group, with no significant differences observed between the groups. Beta diversity was evaluated by weighted UniFrac distances, with values of 0.40 ± 0.13 and 0.40 ± 0.11 in the control and cirrhosis groups, respectively (P > 0.05). PCA data also confirmed this similarity (P > 0.05). Meanwhile, the relative abundance of species belonging to the Bacilli class was higher in cirrhosis patients [median: 2.74%, interquartile range (IQR): 0.18–7.81%] than healthy individuals (median: 0.15%, IQR: 0.47–0.73%; P < 0.01), and that of Lactobacillales order was also higher in cirrhosis patients (median: 2.73%, IQR: 0.16–7.80%) than in healthy individuals (median: 0.12%, IQR: 0.03–0.70%; P < 0.05). Conclusions Cumulatively, our results suggest that the gut microbiota of S. japonicum infection-induced liver cirrhosis patients is similar to that of healthy individuals, indicating that bacterial taxa cannot be used as non-invasive biomarkers for S. japonicum infection-induced liver cirrhosis. ![]()
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Affiliation(s)
- Qi-Feng Gui
- Department of Geriatrics, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.,Zhejiang Provincial Key Laboratory for Diagnosis and Treatment of Aging and Physic-Chemical Injury Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Hui-Lin Jin
- Department of Geriatrics, Wangdian People's Hospital, Jiaxing, Zhejiang, People's Republic of China
| | - Feng Zhu
- Department of Geriatrics, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.,Zhejiang Provincial Key Laboratory for Diagnosis and Treatment of Aging and Physic-Chemical Injury Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Hai-Feng Lu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People's Republic of China
| | - Qin Zhang
- Department of Geriatrics, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.,Zhejiang Provincial Key Laboratory for Diagnosis and Treatment of Aging and Physic-Chemical Injury Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Jia Xu
- Zhejiang Provincial Key Laboratory for Diagnosis and Treatment of Aging and Physic-Chemical Injury Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.,Department of Emergency Medicine, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Yun-Mei Yang
- Department of Geriatrics, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China. .,Zhejiang Provincial Key Laboratory for Diagnosis and Treatment of Aging and Physic-Chemical Injury Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.
| | - Chi Xiao
- School of Basic Medical Sciences & Forensic Medicine, Hangzhou Medical College, Hangzhou, Zhejiang, People's Republic of China.
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Goeser F, Münch P, Lesker TR, Lutz PL, Krämer B, Kaczmarek DJ, Finnemann C, Nischalke HD, Geffers R, Parcina M, McHardy A, Strassburg C, Hoerauf A, Nattermann J, Bekeredjian-Ding I, Spengler U. Neither black nor white: do altered intestinal microbiota reflect chronic liver disease severity? Gut 2021; 70:438-440. [PMID: 32503844 DOI: 10.1136/gutjnl-2020-321424] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Revised: 05/14/2020] [Accepted: 05/15/2020] [Indexed: 12/21/2022]
Affiliation(s)
- Felix Goeser
- Department of Internal Medicine I, University Hospital Bonn, Bonn, Germany .,Partner Site Bonn/Cologne, German Center for Infection Research (DZIF), Bonn, Germany
| | - Philipp Münch
- Computational Biology for Infection Research, Helmholtz-Zentrum fur Infektionsforschung GmbH, Braunschweig, Niedersachsen, Germany.,Partner Site Hannover-Braunschweig, German Centre for Infection Research (DZIF), Braunschweig, Germany
| | - Till Robin Lesker
- Computational Biology for Infection Research, Helmholtz-Zentrum fur Infektionsforschung GmbH, Braunschweig, Niedersachsen, Germany.,Microbial Immune Regulation, Helmholtz-Zentrum fur Infektionsforschung GmbH, Braunschweig, Niedersachsen, Germany
| | - Philipp Ludwig Lutz
- Department of Internal Medicine I, University Hospital Bonn, Bonn, Germany.,Partner Site Bonn/Cologne, German Center for Infection Research (DZIF), Bonn, Germany
| | - Benjamin Krämer
- Department of Internal Medicine I, University Hospital Bonn, Bonn, Germany.,Partner Site Bonn/Cologne, German Center for Infection Research (DZIF), Bonn, Germany
| | | | - Claudia Finnemann
- Department of Internal Medicine I, University Hospital Bonn, Bonn, Germany.,Partner Site Bonn/Cologne, German Center for Infection Research (DZIF), Bonn, Germany
| | | | - Robert Geffers
- Institute for Genomanalytik, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Marijo Parcina
- Institute of Medical Microbiology, Immunology and Parasitology, University Hospital Bonn, Bonn, Germany
| | - Alice McHardy
- Computational Biology for Infection Research, Helmholtz-Zentrum fur Infektionsforschung GmbH, Braunschweig, Niedersachsen, Germany.,Partner Site Hannover-Braunschweig, German Centre for Infection Research (DZIF), Braunschweig, Germany
| | | | - Achim Hoerauf
- Partner Site Bonn/Cologne, German Center for Infection Research (DZIF), Bonn, Germany.,Institute of Medical Microbiology, Immunology and Parasitology, University Hospital Bonn, Bonn, Germany
| | - Jacob Nattermann
- Department of Internal Medicine I, University Hospital Bonn, Bonn, Germany.,Partner Site Bonn/Cologne, German Center for Infection Research (DZIF), Bonn, Germany
| | - Isabelle Bekeredjian-Ding
- Partner Site Bonn/Cologne, German Center for Infection Research (DZIF), Bonn, Germany.,Division of Microbiology, Paul-Ehrlich-Institut, Langen, Hessen, Germany
| | - Ulrich Spengler
- Department of Internal Medicine I, University Hospital Bonn, Bonn, Germany.,Partner Site Bonn/Cologne, German Center for Infection Research (DZIF), Bonn, Germany
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Changes of Gut-Microbiota-Liver Axis in Hepatitis C Virus Infection. BIOLOGY 2021; 10:biology10010055. [PMID: 33451143 PMCID: PMC7828638 DOI: 10.3390/biology10010055] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Revised: 01/02/2021] [Accepted: 01/08/2021] [Indexed: 12/12/2022]
Abstract
Simple Summary Gut microbiota alteration is linked to many health disorders including hepatitis C virus (HCV) infection. This dysbiosis in turn impacts the coordination between the gut and the liver that is known as the gut–liver-axis. Here, we discuss the latest findings regarding the changes in gut microbiota structure and functionality post HCV infection and its treatment regimens. In addition, we underline the contribution of the microbiota alterations to HCV associated liver complications. Abstract The gut–liver-axis is a bidirectional coordination between the gut, including microbial residents, the gut microbiota, from one side and the liver on the other side. Any disturbance in this crosstalk may lead to a disease status that impacts the functionality of both the gut and the liver. A major cause of liver disorders is hepatitis C virus (HCV) infection that has been illustrated to be associated with gut microbiota dysbiosis at different stages of the disease progression. This dysbiosis may start a cycle of inflammation and metabolic disturbance that impacts the gut and liver health and contributes to the disease progression. This review discusses the latest literature addressing this interplay between the gut microbiota and the liver in HCV infection from both directions. Additionally, we highlight the contribution of gut microbiota to the metabolism of antivirals used in HCV treatment regimens and the impact of these medications on the microbiota composition. This review sheds light on the potential of the gut microbiota manipulation as an alternative therapeutic approach to control the liver complications post HCV infection.
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Acharya C, Bajaj JS. Chronic Liver Diseases and the Microbiome-Translating Our Knowledge of Gut Microbiota to Management of Chronic Liver Disease. Gastroenterology 2021; 160:556-572. [PMID: 33253686 PMCID: PMC9026577 DOI: 10.1053/j.gastro.2020.10.056] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Revised: 10/13/2020] [Accepted: 10/21/2020] [Indexed: 02/07/2023]
Abstract
Chronic liver disease is reaching epidemic proportions with the increasing prevalence of obesity, nonalcoholic liver disease, and alcohol overuse worldwide. Most patients are not candidates for liver transplantation even if they have end-stage liver disease. There is growing evidence of a gut microbial basis for many liver diseases, therefore, better diagnostic, prognostic, and therapeutic approaches based on knowledge of gut microbiota are needed. We review the questions that need to be answered to successfully translate our knowledge of the intestinal microbiome and the changes associated with liver disease into practice.
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Wang R, Tang R, Li B, Ma X, Schnabl B, Tilg H. Gut microbiome, liver immunology, and liver diseases. Cell Mol Immunol 2021; 18:4-17. [PMID: 33318628 PMCID: PMC7852541 DOI: 10.1038/s41423-020-00592-6] [Citation(s) in RCA: 252] [Impact Index Per Article: 63.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Accepted: 11/08/2020] [Indexed: 02/08/2023] Open
Abstract
The gut microbiota is a complex and plastic consortium of microorganisms that are intricately connected with human physiology. The liver is a central immunological organ that is particularly enriched in innate immune cells and constantly exposed to circulating nutrients and endotoxins derived from the gut microbiota. The delicate interaction between the gut and liver prevents accidental immune activation against otherwise harmless antigens. Work on the interplay between the gut microbiota and liver has assisted in understanding the pathophysiology of various liver diseases. Of immense importance is the step from high-throughput sequencing (correlation) to mechanistic studies (causality) and therapeutic intervention. Here, we review the gut microbiota, liver immunology, and the interaction between the gut and liver. In addition, the impairment in the gut-liver axis found in various liver diseases is reviewed here, with an emphasis on alcohol-associated liver disease (ALD), nonalcoholic fatty liver disease (NAFLD), and autoimmune liver disease (AILD). On the basis of growing evidence from these preclinical studies, we propose that the gut-liver axis paves the way for targeted therapeutic modalities for liver diseases.
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Affiliation(s)
- Rui Wang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, 200001, Shanghai, China
| | - Ruqi Tang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, 200001, Shanghai, China
| | - Bo Li
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, 200001, Shanghai, China
| | - Xiong Ma
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, 200001, Shanghai, China.
| | - Bernd Schnabl
- Department of Medicine, University of California, San Diego, La Jolla, CA, USA.
- Department of Medicine, VA San Diego Healthcare System, San Diego, CA, USA.
| | - Herbert Tilg
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & Metabolism, Medical University Innsbruck, Innsbruck, Austria.
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Grąt M, Grąt K, Krawczyk M, Lewandowski Z, Krasnodębski M, Masior Ł, Patkowski W, Zieniewicz K. Post-hoc analysis of a randomized controlled trial on the impact of pre-transplant use of probiotics on outcomes after liver transplantation. Sci Rep 2020; 10:19944. [PMID: 33204004 PMCID: PMC7672052 DOI: 10.1038/s41598-020-76994-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Accepted: 11/04/2020] [Indexed: 01/14/2023] Open
Abstract
Perioperative use of probiotics serves as efficient prophylaxis against postoperative infections after liver transplantation, yet data on long-term effects of pre-transplant probiotic intake is lacking. The aim of this study was to assess the effects of pre-transplant probiotic administration on long-term results of liver transplantation. This was secondary analysis of a randomized trial. Patients were randomized to receive either 4-strain probiotic or placebo before liver transplantation. Five year graft survival was set as the primary end-point. Secondary end-points comprised serum bilirubin and C-reactive protein (CRP) concentration, international normalized ratio (INR), serum transaminases and gamma-glutamyl transferase (GGT) activity. Study group comprised 44 patients, of whom 21 received probiotics and 23 received placebo with 5-year graft survival of 81.0% and 87.0%, respectively (p = 0.591). Patients in the probiotic arm exhibited lower INR (p = 0.001) and CRP (p = 0.030) over the first 6 post-transplant months. In the absence of hepatitis B or C virus infection, pre-transplant administration of probiotics also reduced aspartate transaminase activity (p = 0.032). In the intervention arm, patients receiving probiotics for under and over 30 days had 5-year graft survival rates of 100% and 66.7%, respectively (p = 0.061). Duration of probiotic intake > 30 days was additionally associated with increased INR (p = 0.031), GGT (p = 0.032) and a tendency towards increased bilirubin (p = 0.074) over first 6 post-transplant months. Pre-transplant administration of probiotics has mild positive influence on 6-month allograft function, yet should not exceed 30 days due to potential negative effects on long-term outcomes. (ClinicalTrials.gov Identifier: NCT01735591).
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Affiliation(s)
- M Grąt
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - K Grąt
- Second Department of Clinical Radiology, Medical University of Warsaw, Banacha 1A, 02-097, Warsaw, Poland.
| | - M Krawczyk
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Z Lewandowski
- Department of Epidemiology and Biostatistics, Medical University of Warsaw, Warsaw, Poland
| | - M Krasnodębski
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Ł Masior
- Second Department of General, Vascular and Oncological Surgery, Medical University of Warsaw, Warsaw, Poland
| | - W Patkowski
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - K Zieniewicz
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
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The Gut Microbiota: How Does It Influence the Development and Progression of Liver Diseases. Biomedicines 2020; 8:biomedicines8110501. [PMID: 33207562 PMCID: PMC7697996 DOI: 10.3390/biomedicines8110501] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 11/06/2020] [Accepted: 11/13/2020] [Indexed: 02/07/2023] Open
Abstract
The gut–liver axis plays important roles in both the maintenance of a healthy liver and the pathogenesis of liver diseases, where the gut microbiota acts as a major determinant of this relationship. Gut bacteria-derived metabolites and cellular components are key molecules that affect the function of the liver and modulate the pathology of liver diseases. Accumulating evidence showed that gut microbiota produces a myriad of molecules, including lipopolysaccharide, lipoteichoic acid, peptidoglycan, and DNA, as well as short-chain fatty acids, bile acids, trimethylamine, and indole derivatives. The translocation of these components to the liver exerts beneficial or pathogenic effects by interacting with liver immune cells. This is a bidirectional relationship. Therefore, the existence of crosstalk between the gut and liver and its implications on host health and diseases are essential for the etiology and treatment of diseases. Several mechanisms have been proposed for the pathogenesis of liver diseases, but still, the mechanisms behind the pathogenic role of gut-derived components on liver pathogenesis remain elusive and not understandable. This review discusses the current progress on the gut microbiota and its components in terms of the progression of liver diseases, and in turn, how liver diseases indirectly affect the intestinal function and induce intestinal inflammation. Moreover, this paper highlights the current therapeutic and preventive strategies used to restore the gut microbiota composition and improve host health.
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Plaza-Díaz J, Solís-Urra P, Rodríguez-Rodríguez F, Olivares-Arancibia J, Navarro-Oliveros M, Abadía-Molina F, Álvarez-Mercado AI. The Gut Barrier, Intestinal Microbiota, and Liver Disease: Molecular Mechanisms and Strategies to Manage. Int J Mol Sci 2020; 21:8351. [PMID: 33171747 PMCID: PMC7664383 DOI: 10.3390/ijms21218351] [Citation(s) in RCA: 75] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 10/31/2020] [Accepted: 11/05/2020] [Indexed: 02/06/2023] Open
Abstract
Liver disease encompasses pathologies as non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, alcohol liver disease, hepatocellular carcinoma, viral hepatitis, and autoimmune hepatitis. Nowadays, underlying mechanisms associating gut permeability and liver disease development are not well understood, although evidence points to the involvement of intestinal microbiota and their metabolites. Animal studies have shown alterations in Toll-like receptor signaling related to the leaky gut syndrome by the action of bacterial lipopolysaccharide. In humans, modifications of the intestinal microbiota in intestinal permeability have also been related to liver disease. Some of these changes were observed in bacterial species belonging Roseburia, Streptococcus, and Rothia. Currently, numerous strategies to treat liver disease are being assessed. This review summarizes and discusses studies addressed to determine mechanisms associated with the microbiota able to alter the intestinal barrier complementing the progress and advancement of liver disease, as well as the main strategies under development to manage these pathologies. We highlight those approaches that have shown improvement in intestinal microbiota and barrier function, namely lifestyle changes (diet and physical activity) and probiotics intervention. Nevertheless, knowledge about how such modifications are beneficial is still limited and specific mechanisms involved are not clear. Thus, further in-vitro, animal, and human studies are needed.
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Affiliation(s)
- Julio Plaza-Díaz
- Children’s Hospital of Eastern Ontario Research Institute, Ottawa, ON K1H 8L1, Canada;
- Department of Biochemistry and Molecular Biology II, School of Pharmacy, University of Granada, 18071 Granada, Spain
- Instituto de Investigación Biosanitaria IBS.GRANADA, Complejo Hospitalario Universitario de Granada, 18071 Granada, Spain
| | - Patricio Solís-Urra
- Faculty of Education and Social Sciences, Universidad Andres Bello, Viña del Mar 2531015, Chile;
| | - Fernando Rodríguez-Rodríguez
- IRyS Research Group, School of Physical Education, Pontificia Universidad Católica de Valparaíso, Valparaíso 2374631, Chile; (F.R.-R.); (J.O.-A.)
| | - Jorge Olivares-Arancibia
- IRyS Research Group, School of Physical Education, Pontificia Universidad Católica de Valparaíso, Valparaíso 2374631, Chile; (F.R.-R.); (J.O.-A.)
- Escuela de Pedagogía en Educación Física, Facultad de Educación, Universidad de las Américas, Santiago 8370035, Chile
| | - Miguel Navarro-Oliveros
- BioCritic. Group for Biomedical Research in Critical Care Medicine, 47005 Valladolid, Spain;
| | - Francisco Abadía-Molina
- Institute of Nutrition and Food Technology “José Mataix”, Center of Biomedical Research, University of Granada, Avda. del Conocimiento s/n. 18016 Armilla, Granada, Spain;
- Department of Cell Biology, School of Sciences, University of Granada, 18071 Granada, Spain
| | - Ana I. Álvarez-Mercado
- Department of Biochemistry and Molecular Biology II, School of Pharmacy, University of Granada, 18071 Granada, Spain
- Instituto de Investigación Biosanitaria IBS.GRANADA, Complejo Hospitalario Universitario de Granada, 18071 Granada, Spain
- Institute of Nutrition and Food Technology “José Mataix”, Center of Biomedical Research, University of Granada, Avda. del Conocimiento s/n. 18016 Armilla, Granada, Spain;
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49
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Jia W, Rajani C, Xu H, Zheng X. Gut microbiota alterations are distinct for primary colorectal cancer and hepatocellular carcinoma. Protein Cell 2020; 12:374-393. [PMID: 32797354 PMCID: PMC8106555 DOI: 10.1007/s13238-020-00748-0] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Accepted: 06/15/2020] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer (CRC) and hepatocellular carcinoma (HCC) are the second and third most common causes of death by cancer, respectively. The etiologies of the two cancers are either infectious insult or due to chronic use of alcohol, smoking, diet, obesity and diabetes. Pathological changes in the composition of the gut microbiota that lead to intestinal inflammation are a common factor for both HCC and CRC. However, the gut microbiota of the cancer patient evolves with disease pathogenesis in unique ways that are affected by etiologies and environmental factors. In this review, we examine the changes that occur in the composition of the gut microbiota across the stages of the HCC and CRC. Based on the idea that the gut microbiota are an additional "lifeline" and contribute to the tumor microenvironment, we can observe from previously published literature how the microbiota can cause a shift in the balance from normal → inflammation → diminished inflammation from early to later disease stages. This pattern leads to the hypothesis that tumor survival depends on a less pro-inflammatory tumor microenvironment. The differences observed in the gut microbiota composition between different disease etiologies as well as between HCC and CRC suggest that the tumor microenvironment is unique for each case.
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Affiliation(s)
- Wei Jia
- Center for Translational Medicine and Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China. .,Hong Kong Tranditional Chinese Medicine Phenome Research Center, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, 999077, Hong Kong, China.
| | - Cynthia Rajani
- University of Hawaii Cancer Center, Honolulu, HI, 96813, USA
| | - Hongxi Xu
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Xiaojiao Zheng
- Center for Translational Medicine and Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China.
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50
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Giuffrè M, Campigotto M, Campisciano G, Comar M, Crocè LS. A story of liver and gut microbes: how does the intestinal flora affect liver disease? A review of the literature. Am J Physiol Gastrointest Liver Physiol 2020; 318:G889-G906. [PMID: 32146836 DOI: 10.1152/ajpgi.00161.2019] [Citation(s) in RCA: 85] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Each individual is endowed with a unique gut microbiota (GM) footprint that mediates numerous host-related physiological functions, such as nutrient metabolism, maintenance of the structural integrity of the gut mucosal barrier, immunomodulation, and protection against microbial pathogens. Because of increased scientific interest in the GM, its central role in the pathophysiology of many intestinal and extraintestinal conditions has been recognized. Given the close relationship between the gastrointestinal tract and the liver, many pathological processes have been investigated in the light of a microbial-centered hypothesis of hepatic damage. In this review we introduce to neophytes the vast world of gut microbes, including prevalent bacterial distribution in healthy individuals, how the microbiota is commonly analyzed, and the current knowledge of the role of GM in liver disease pathophysiology. Also, we highlight the potentials and downsides of GM-based therapy.
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Affiliation(s)
- Mauro Giuffrè
- Dipartimento Universitario Clinico di Scienze Mediche Chirurgiche e della Salute, Università degli Studi di Trieste, Italy
| | - Michele Campigotto
- Dipartimento Universitario Clinico di Scienze Mediche Chirurgiche e della Salute, Università degli Studi di Trieste, Italy
| | - Giuseppina Campisciano
- Istituto di Ricovero e Cura a Carattere Scientifico Materno Infantile Burlo Garofolo, Trieste, Italy
| | - Manola Comar
- Dipartimento Universitario Clinico di Scienze Mediche Chirurgiche e della Salute, Università degli Studi di Trieste, Italy.,Istituto di Ricovero e Cura a Carattere Scientifico Materno Infantile Burlo Garofolo, Trieste, Italy
| | - Lory Saveria Crocè
- Dipartimento Universitario Clinico di Scienze Mediche Chirurgiche e della Salute, Università degli Studi di Trieste, Italy.,Clinica Patologie del Fegato, Azienda Sanitaria Universitaria Integrata di Trieste, Italy.,Fondazione Italiana Fegato, Trieste, Italy
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