Gut Microbiota Alterations Associated with Viral Activity in Chronic Hepatitis B
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Abstract
Background: The gut–liver axis plays a pivotal role in chronic liver diseases, and increasing evidence links gut microbiota dysbiosis to disease progression in chronic hepatitis B (CHB). However, data comparing microbiota features between patients with active and inactive HBV infection remain limited.
Methods: We performed a retrospective analysis of gut microbiota composition and functional potential in patients with chronic HBV infection, stratified according to viral activity as defined by current EASL guidelines. Microbial diversity, taxonomic composition, enterotypes, pathobiont prevalence, and predicted metabolic pathways were compared between active and inactive HBV infection.
Results: Patients with active HBV infection exhibited significantly reduced microbial α-diversity, lower phylogenetic diversity, and decreased evenness compared with inactive carriers, despite virological suppression under antiviral therapy. Active HBV was associated with Prevotella-dominated enterotypes, expansion of pathobionts (Escherichia coli, Klebsiella pneumoniae, Bacteroides fragilis), and depletion of beneficial symbionts, particularly short-chain fatty acid– and indole-producing taxa, including Faecalibacterium prausnitzii, Roseburia intestinalis, Blautia wexlerae, and Alistipes spp. Functional profiling revealed reduced production of butyrate, propionate, acetate, and indole derivatives, alongside increased synthesis of ethanol, secondary bile acids, and lipopolysaccharides.
Conclusion: Active CHB is characterized by a distinct dysbiotic and pro-inflammatory gut microbiota profile that persists despite effective antiviral therapy. These findings support a contributory role of gut microbiota in immune dysregulation and disease activity in CHB and provide a rationale for microbiota-targeted interventions as complementary therapeutic strategies.
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Kang Y, Cai Y. Gut microbiota and hepatitis-B-virus-induced chronic liver disease: implications for faecal microbiota transplantation therapy. J Hosp Infect. 2017;96(4):342-348. Available from: https://doi.org/10.1016/j.jhin.2017.04.007
Tranah TH, Edwards LA, Schnabl B, Shawcross DL. Targeting the gut-liver-immune axis to treat cirrhosis. Gut. 2020;70(5):982-994. Available from: https://doi.org/10.1136/gutjnl-2020-320786
Fukui H. Gut microbiome-based therapeutics in liver cirrhosis: basic consideration for the next step. J Clin Transl Hepatol. 2017;5(3):249-260. Available from: https://doi.org/10.14218/jcth.2017.00008
Yang J, He Q, Lu F, Chen K, Ni Z, Wang H, et al. A distinct microbiota signature precedes the clinical diagnosis of hepatocellular carcinoma. Gut Microbes. 2023;15(1):2201159. Available from: https://doi.org/10.1080/19490976.2023.2201159
Zeng Y, Chen S, Fu Y, Wu W, Chen T, Chen J, et al. Gut microbiota dysbiosis in patients with hepatitis B virus-induced chronic liver disease, covering chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. J Viral Hepat. 2020;27(2):143-155. Available from: https://doi.org/10.1111/jvh.13216
Chen Z, Xie Y, Zhou F, Zhang B, Wu J, Yang L, et al. Featured gut microbiomes associated with the progression of chronic hepatitis B disease. Front Microbiol. 2020;11:383. Available from: https://doi.org/10.3389/fmicb.2020.00383
Lu H, Wu Z, Xu W, Yang J, Chen Y, Li L. Intestinal microbiota was assessed in cirrhotic patients with hepatitis B virus infection. Microb Ecol. 2011;61(3):693-703. Available from: https://doi.org/10.1007/s00248-010-9801-8
Chou HH, Chien WH, Wu LL, Cheng CH, Chung CH, Horng JH, et al. Age-related immune clearance of hepatitis B virus infection requires the establishment of gut microbiota. Proc Natl Acad Sci U S A. 2015;112(7):2175-2180. Available from: https://doi.org/10.1073/pnas.1424775112
Xu L, Yin W, Sun R, Wei H, Tian Z. Kupffer cell-derived IL-10 plays a key role in maintaining humoral immune tolerance in hepatitis B virus-persistent mice. Hepatology. 2014;59(2):443-452. Available from: https://doi.org/10.1002/hep.26668
Wu T, Li F, Chen Y, Wei H, Tian Z, Sun C, et al. CD4(+) T cells play a critical role in microbiota-maintained anti-HBV immunity in a mouse model. Front Immunol. 2019;10:927. Available from: https://doi.org/10.3389/fimmu.2019.00927
Wang G, Huang S, Wang Y, Cai S, Yu H, Liu H, et al. Bridging intestinal immunity and gut microbiota by metabolites. Cell Mol Life Sci. 2019;76(20):3917-3937. Available from: https://doi.org/10.1007/s00018-019-03190-6
Wang X, Li MM, Niu Y, Zhang X, Yin JB, Zhao CJ, et al. Serum zonulin in HBV-associated chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. Dis Markers. 2019;2019:5945721. Available from: https://doi.org/10.1155/2019/5945721
Calgin MK, Cetinkol Y. Decreased levels of serum zonulin and copeptin in chronic hepatitis B patients. Pak J Med Sci. 2019;35(3):847-851. Available from: https://doi.org/10.12669/pjms.35.3.144
Liu Q, Li F, Zhuang Y, Xu J, Wang J, Mao X, et al. Alteration in gut microbiota associated with hepatitis B and non-hepatitis virus related hepatocellular carcinoma. Gut Pathog. 2019;11:1. Available from: https://doi.org/10.1186/s13099-018-0281-6
Caussy C, Hsu C, Singh S, Bassirian S, Kolar J, Faulkner C, et al. Serum bile acid patterns are associated with the presence of NAFLD in twins, and dose-dependent changes with increase in fibrosis stage in patients with biopsy-proven NAFLD. Aliment Pharmacol Ther. 2019;49(2):183-193. Available from: https://agris.fao.org/search/en/providers/122439/records/6798e03ad6a63682f045f442
Chen Y, Ji F, Guo J, Shi D, Fang D, Li L. Dysbiosis of small intestinal microbiota in liver cirrhosis and its association with etiology. Sci Rep. 2016;6:34055. Available from: https://doi.org/10.1038/srep34055
Pan C, Gu Y, Zhang W, Zheng Y, Peng L, Deng H, et al. Dynamic changes of lipopolysaccharide levels in different phases of acute-on-chronic hepatitis B liver failure. PLoS One. 2012;7(11):e49460. Available from: https://doi.org/10.1371/journal.pone.0049460
Deng YD, Peng XB, Zhao RR, Ma CQ, Li JN, Yao LQ. The intestinal microbial community dissimilarity in hepatitis B virus-related liver cirrhosis patients with and without alcohol consumption. Gut Pathog. 2019;11:58. Available from: https://doi.org/10.1186/s13099-019-0337-2
European Association for the Study of the Liver. EASL Clinical Practice Guidelines on the management of hepatitis B virus infection. J Hepatol. 2025;83(2):502-583. Available from: https://doi.org/10.1016/j.jhep.2025.03.018
Shen Y, Wu SD, Chen Y, Li XY, Zhu Q, Nakayama K, et al. Alterations in gut microbiome and metabolomics in chronic hepatitis B infection-associated liver disease and their impact on peripheral immune response. Gut Microbes. 2023;15(1):2155018. Available from: https://doi.org/10.1080/19490976.2022.2155018
Yan F, Zhang Q, Shi K, Zhang Y, Zhu B, Bi Y, et al. Gut microbiota dysbiosis with hepatitis B virus liver disease and association with immune response. Front Cell Infect Microbiol. 2023;13:1152987. Available from: https://doi.org/10.3389/fcimb.2023.1152987
Rautio M, Eerola E, Väisänen-Tunkelrott ML, Molitoris D, Lawson P, Collins MD, et al. Reclassification of Bacteroides putredinis in a new genus Alistipes gen. nov., as Alistipes putredinis comb. nov., and description of Alistipes finegoldii sp. nov., from human sources. Syst Appl Microbiol. 2003;26(2):182-188. Available from: https://doi.org/10.1078/072320203322346029
Shkoporov AN, Chaplin AV, Khokhlova EV, Shcherbakova VA, Motuzova OV, Bozhenko VK, et al. Alistipes inops sp. nov. and Coprobacter secundus sp. nov., isolated from human feces. Int J Syst Evol Microbiol. 2015;65:4580-4588. Available from: https://doi.org/10.1099/ijsem.0.000617
Iebba V, Guerrieri F, Di Gregorio V, Levrero M, Gagliardi A, Santangelo F, et al. Combining amplicon sequencing and metabolomics in cirrhotic patients highlights distinctive microbiota features involved in bacterial translocation, systemic inflammation and hepatic encephalopathy. Sci Rep. 2018;8:8210. Available from: https://doi.org/10.1038/s41598-018-26509-y
Shao L, Ling Z, Chen D, Liu Y, Yang F, Li L. Disorganized gut microbiome contributed to liver cirrhosis progression: a meta-omics-based study. Front Microbiol. 2018;9:3166. Available from: https://doi.org/10.3389/fmicb.2018.03166
Sung CM, Lin YF, Chen KF, Ke HM, Huang HY, Gong YN, et al. Predicting clinical outcomes of cirrhosis patients with hepatic encephalopathy from the fecal microbiome. Cell Mol Gastroenterol Hepatol. 2019;8:301-318.e2. Available from: https://doi.org/10.1016/j.jcmgh.2019.04.008
Rau M, Rehman A, Dittrich M, Groen AK, Hermanns HM, Seyfried F, et al. Fecal SCFAs and SCFA-producing bacteria in gut microbiome of human NAFLD as a putative link to systemic T-cell activation and advanced disease. United Eur Gastroenterol J. 2018;6:1496-1507. Available from: https://doi.org/10.1177/2050640618804444
Oliphant K, Allen-Vercoe E. Macronutrient metabolism by the human gut microbiome: major fermentation by-products and their impact on host health. Microbiome. 2019;7:91. Available from: https://doi.org/10.1186/s40168-019-0704-8
Li J, Sung CY, Lee N, Ni Y, Pihlajamäki J, Panagiotou G, et al. Probiotics modulate gut microbiota suppresses hepatocellular carcinoma growth in mice. Proc Natl Acad Sci U S A. 2016;113:E1306-E1315. Available from: https://doi.org/10.1073/pnas.1518189113
Bindels LB, Porporato P, Dewulf EM, Verrax J, Neyrinck AM, Martin JC, et al. Gut microbiota-derived propionate reduces cancer cell proliferation in the liver. Br J Cancer. 2012;107:1337-1344. Available from: https://doi.org/10.1038/bjc.2012.409
Koh A, De Vadder F, Kovatcheva-Datchary P, Bäckhed F. From dietary fiber to host physiology: short-chain fatty acids as key bacterial metabolites. Cell. 2016;165(6):1332-1345. Available from: https://doi.org/10.1016/j.cell.2016.05.041
Magdy Wasfy R, Mbaye B, Borentain P, Tidjani Alou M, Murillo Ruiz ML, Caputo A, Andrieu C, Armstrong N, Million M, Gerolami R. Ethanol-producing Enterocloster bolteae is enriched in chronic hepatitis B-associated gut dysbiosis: a case-control culturomics study. Microorganisms. 2023;11(10):2437. Available from: https://doi.org/10.3390/microorganisms11102437
Min BH, Devi S, Kwon GH, Gupta H, Jeong JJ, Sharma SP, et al. Gut microbiota-derived indole compounds attenuate metabolic dysfunction-associated steatotic liver disease by improving fat metabolism and inflammation. Gut Microbes. 2024;16(1):2307568. Available from: https://doi.org/10.1080/19490976.2024.2307568
Chou YC, Chen CL, Sheen IS. The gut ecosystem and the pathogenesis of chronic hepatitis B virus infection. Clin Microbiol Infect. 2015;21(6):548-553.
Yan F, Zhang Q, Shi K, Zhang Y, Zhu B, Bi Y, Wang X. Gut microbiota dysbiosis with hepatitis B virus liver disease and association with immune response. Front Cell Infect Microbiol. 2023;13:1152987. Available from: https://doi.org/10.3389/fcimb.2023.1152987
Seki E, Schnabl B. Role of innate immunity and the microbiota in liver fibrosis: crosstalk between the liver and gut. J Physiol. 2012;590(3):447-458. Available from: https://doi.org/10.1113/jphysiol.2011.219691
Wiest R, Albillos A, Trauner M, Bajaj JS, Jalan R. Targeting the gut-liver axis in liver disease. J Hepatol. 2017;67(5):1084-1103. Available from: https://doi.org/10.1016/j.jhep.2017.05.007
Dapito DH, Mencin A, Gwak GY, Pradere JP, Jang MK, Mederacke I, et al. Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4. Cancer Cell. 2012;21(4):504-516. Available from: https://doi.org/10.1016/j.ccr.2012.02.007
Parada Venegas D, De la Fuente MK, Landskron G, González MJ, Quera R, Dijkstra G, Harmsen HJM, et al. Short-chain fatty acids (SCFAs)-mediated gut epithelial and immune regulation and its relevance for inflammatory bowel diseases. Front Immunol. 2019;10:277. Available from: https://doi.org/10.3389/fimmu.2019.00277
Tripathi A, Debelius J, Brenner DA, Karin M, Loomba R, Schnabl B, Knight R. The gut-liver axis and the intersection with the microbiome. Nat Rev Gastroenterol Hepatol. 2018;15(7):397-411. Available from: https://doi.org/10.1038/s41575-018-0011-z
Lynch SV, Pedersen O. The human intestinal microbiome in health and disease. N Engl J Med. 2016;375(24):2369-2379. Available from: https://doi.org/10.1056/nejmra1600266