Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Gut microbiome, liver immunology, and liver diseases


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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1


  1. 1.

    World Health Organization. The Top 10 Causes of Death. WHO, https://www.whoint/en/news-room/fact-sheets/detail/the-top-10-causes-of-death (2018).

  2. 2.

    Younossi, Z. et al. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat. Rev. Gastroenterol. Hepatol. 15, 11–20 (2018).

    PubMed  Google Scholar 

  3. 3.

    Seitz, H. K. et al. Alcoholic liver disease. Nat. Rev. Dis. Prim. 4, 16 (2018).

    PubMed  Google Scholar 

  4. 4.

    Wong, M. C. S. et al. The changing epidemiology of liver diseases in the Asia-Pacific region. Nat. Rev. Gastroenterol. Hepatol. 16, 57–73 (2019).

    PubMed  Google Scholar 

  5. 5.

    Mieli-Vergani, G. et al. Autoimmune hepatitis. Nat. Rev. Dis. Primers. 4, 18018 (2018).

  6. 6.

    Lleo, A. & Colapietro, F. Changes in the epidemiology of primary biliary cholangitis. Clin. Liver Dis. 22, 429–441 (2018).

    PubMed  Google Scholar 

  7. 7.

    Tripathi, A. et al. The gut-liver axis and the intersection with the microbiome. Nat. Rev. Gastroenterol. Hepatol. 15, 397–411 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Chopyk, D. M. & Grakoui, A. Contribution of the intestinal microbiome and gut barrier to hepatic disorders. Gastroenterology 159, 849–863 (2020).

  9. 9.

    Albillos, A. et al. The gut-liver axis in liver disease: pathophysiological basis for therapy. J. Hepatol. 72, 558–577 (2020).

    CAS  PubMed  Google Scholar 

  10. 10.

    Eckburg, P. B. et al. Diversity of the human intestinal microbial flora. Science 308, 1635–1638 (2005).

    PubMed  PubMed Central  Google Scholar 

  11. 11.

    The Human Microbiome Project Consortium. et al. Structure, function and diversity of the healthy human microbiome. Nature. 486, 207–214 (2012).

  12. 12.

    Sender, R. et al. Revised estimates for the number of human and bacteria cells in the body. PLoS Biol. 14, e1002533 (2016).

    PubMed  PubMed Central  Google Scholar 

  13. 13.

    Cheng, J. et al. Discordant temporal development of bacterial phyla and the emergence of core in the fecal microbiota of young children. ISME J. 10, 1002–1014 (2016).

    PubMed  Google Scholar 

  14. 14.

    Mariat, D. et al. The Firmicutes/Bacteroidetes ratio of the human microbiota changes with age. BMC Microbiol. 9, 123 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Ni, J. et al. Gut microbiota and IBD: causation or correlation? Nat. Rev. Gastroenterol. Hepatol. 14, 573–584 (2017).

    PubMed  PubMed Central  Google Scholar 

  16. 16.

    Siljander, H. et al. Microbiome and type 1 diabetes. EBioMedicine 46, 512–521 (2019).

    PubMed  PubMed Central  Google Scholar 

  17. 17.

    Gomes, A. C. et al. The human gut microbiota: metabolism and perspective in obesity. Gut Microbes 9, 308–325 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Tang, W. H. W. et al. Intestinal microbiota in cardiovascular health and disease: JACC state-of-the-art review. J. Am. Coll. Cardiol. 73, 2089–2105 (2019).

    PubMed  PubMed Central  Google Scholar 

  19. 19.

    Fattorusso, A. et al. Autism spectrum disorders and the gut microbiota. Nutrients. 11, 521 (2019).

  20. 20.

    Gilbert, J. A. & Lynch, S. V. Community ecology as a framework for human microbiome research. Nat. Med. 25, 884–889 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Tanoue, T. et al. A defined commensal consortium elicits CD8 T cells and anti-cancer immunity. Nature 565, 600–605 (2019).

    CAS  PubMed  Google Scholar 

  22. 22.

    D’Haens, G. R. & Jobin, C. Fecal microbial transplantation for diseases beyond recurrent clostridium difficile infection. Gastroenterology 157, 624–636 (2019).

    PubMed  PubMed Central  Google Scholar 

  23. 23.

    Nash, A. K. et al. The gut mycobiome of the Human Microbiome Project healthy cohort. Microbiome 5, 153 (2017).

    PubMed  PubMed Central  Google Scholar 

  24. 24.

    Richard, M. L. & Sokol, H. The gut mycobiota: insights into analysis, environmental interactions and role in gastrointestinal diseases. Nat. Rev. Gastroenterol. Hepatol. 16, 331–345 (2019).

    PubMed  Google Scholar 

  25. 25.

    Standaert-Vitse, A. et al. Candida albicans is an immunogen for anti-Saccharomyces cerevisiae antibody markers of Crohn’s disease. Gastroenterology 130, 1764–1775 (2006).

    CAS  PubMed  Google Scholar 

  26. 26.

    Coker, O. O. et al. Enteric fungal microbiota dysbiosis and ecological alterations in colorectal cancer. Gut 68, 654–662 (2019).

    CAS  PubMed  Google Scholar 

  27. 27.

    Botschuijver, S. et al. Intestinal fungal dysbiosis is associated with visceral hypersensitivity in patients with irritable bowel syndrome and rats. Gastroenterology 153, 1026–1039 (2017).

    PubMed  Google Scholar 

  28. 28.

    Lang, S. et al. Intestinal fungal dysbiosis and systemic immune response to fungi in patients with alcoholic hepatitis. Hepatology 71, 522–538 (2020).

    CAS  PubMed  Google Scholar 

  29. 29.

    Lemoinne, S. et al. Fungi participate in the dysbiosis of gut microbiota in patients with primary sclerosing cholangitis. Gut 69, 92–102 (2020).

    CAS  PubMed  Google Scholar 

  30. 30.

    Shkoporov, A. N. & Hill, C. Bacteriophages of the human gut: The “Known Unknown” of the microbiome. Cell Host Microbe 25, 195–209 (2019).

    CAS  PubMed  Google Scholar 

  31. 31.

    Sausset, R. et al. New insights into intestinal phages. Mucosal Immunol. 13, 205–215 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Hoyles, L. et al. Characterization of virus-like particles associated with the human faecal and caecal microbiota. Res. Microbiol. 165, 803–812 (2014).

    CAS  PubMed  Google Scholar 

  33. 33.

    Breitbart, M. et al. Metagenomic analyses of an uncultured viral community from human feces. J. Bacteriol. 185, 6220–6223 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Shkoporov, A. N. et al. ΦCrAss001 represents the most abundant bacteriophage family in the human gut and infects Bacteroides intestinalis. Nat. Commun. 9, 4781 (2018).

    PubMed  PubMed Central  Google Scholar 

  35. 35.

    Zuo, T. et al. Gut mucosal virome alterations in ulcerative colitis. Gut 68, 1169–1179 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Gogokhia, L. et al. Expansion of bacteriophages is linked to aggravated intestinal inflammation and colitis. Cell Host Microbe 25, 285–99.e8 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Nakatsu, G. et al. Alterations in enteric virome are associated with colorectal cancer and survival outcomes. Gastroenterology 155, 529–41.e5 (2018).

    PubMed  Google Scholar 

  38. 38.

    Kramná, L. et al. Gut virome sequencing in children with early islet autoimmunity. Diabetes Care 38, 930–933 (2015).

    PubMed  Google Scholar 

  39. 39.

    Międzybrodzki, R. et al. In vivo studies on the influence of bacteriophage preparations on the autoimmune inflammatory process. Biomed. Res. Int. 2017, 3612015 (2017).

    PubMed  PubMed Central  Google Scholar 

  40. 40.

    Zuo, T. et al. Bacteriophage transfer during faecal microbiota transplantation in Clostridium difficile infection is associated with treatment outcome. Gut 67, 634–643 (2018).

    CAS  PubMed  Google Scholar 

  41. 41.

    Dong, X. et al. Bioinorganic hybrid bacteriophage for modulation of intestinal microbiota to remodel tumor-immune microenvironment against colorectal cancer. Sci. Adv. 6, eaba1590 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Zheng, D. W. et al. Phage-guided modulation of the gut microbiota of mouse models of colorectal cancer augments their responses to chemotherapy. Nat. Biomed. Eng. 3, 717–728 (2019).

    CAS  PubMed  Google Scholar 

  43. 43.

    Honda, K. & Littman, D. R. The microbiota in adaptive immune homeostasis and disease. Nature 535, 75–84 (2016).

    CAS  PubMed  Google Scholar 

  44. 44.

    Trompette, A. et al. Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis. Nat. Med. 20, 159–166 (2014).

    CAS  PubMed  Google Scholar 

  45. 45.

    Belkaid, Y. & Harrison, O. J. Homeostatic immunity and the microbiota. Immunity 46, 562–576 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Bunker, J. J. et al. Innate and adaptive humoral responses coat distinct commensal bacteria with immunoglobulin A. Immunity 43, 541–553 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Ivanov, I. I. et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139, 485–498 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Atarashi, K. et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science 331, 337–341 (2011).

    CAS  PubMed  Google Scholar 

  49. 49.

    Ansaldo, E. et al. Akkermansia muciniphila induces intestinal adaptive immune responses during homeostasis. Science 364, 1179–1184 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Ducarmon, Q. R. et al. Gut microbiota and colonization resistance against bacterial enteric infection. Microbiol Mol Biol Rev. 83 (2019).

  51. 51.

    Brown, E. M. et al. Gut microbiota regulation of T cells during inflammation and autoimmunity. Annu Rev. Immunol. 37, 599–624 (2019).

    CAS  PubMed  Google Scholar 

  52. 52.

    Shu, S. A. et al. Microbiota and food allergy. Clin. Rev. Allergy Immunol. 57, 83–97 (2019).

    CAS  PubMed  Google Scholar 

  53. 53.

    Roy, S. & Trinchieri, G. Microbiota: a key orchestrator of cancer therapy. Nat. Rev. Cancer 17, 271–285 (2017).

    CAS  PubMed  Google Scholar 

  54. 54.

    Racanelli, V. & Rehermann, B. The liver as an immunological organ. Hepatology 43, S54–S62 (2006).

    CAS  PubMed  Google Scholar 

  55. 55.

    Kolios, G. et al. Role of Kupffer cells in the pathogenesis of liver disease. World J. Gastroenterol. 12, 7413–7420 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Krenkel, O. & Tacke, F. Liver macrophages in tissue homeostasis and disease. Nat. Rev. Immunol. 17, 306–321 (2017).

    CAS  PubMed  Google Scholar 

  57. 57.

    Wu, X. et al. Oral ampicillin inhibits liver regeneration by breaking hepatic innate immune tolerance normally maintained by gut commensal bacteria. Hepatology 62, 253–264 (2015).

    CAS  PubMed  Google Scholar 

  58. 58.

    Rivera, C. A. et al. Toll-like receptor-4 signaling and Kupffer cells play pivotal roles in the pathogenesis of non-alcoholic steatohepatitis. J. Hepatol. 47, 571–579 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Vespasiani-Gentilucci, U. et al. Hepatic toll-like receptor 4 expression is associated with portal inflammation and fibrosis in patients with NAFLD. Liver Int. 35, 569–581 (2015).

    CAS  PubMed  Google Scholar 

  60. 60.

    Kawaratani, H. et al. Innate immune reactivity of the liver in rats fed a choline-deficient L-amino-acid-defined diet. World J. Gastroenterol. 14, 6655–6661 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61.

    Leroux, A. et al. Toxic lipids stored by Kupffer cells correlates with their pro-inflammatory phenotype at an early stage of steatohepatitis. J. Hepatol. 57, 141–149 (2012).

    CAS  PubMed  Google Scholar 

  62. 62.

    Kudo, H. et al. Lipopolysaccharide triggered TNF-alpha-induced hepatocyte apoptosis in a murine non-alcoholic steatohepatitis model. J. Hepatol. 51, 168–175 (2009).

    CAS  PubMed  Google Scholar 

  63. 63.

    Soderborg, T. K. et al. The gut microbiota in infants of obese mothers increases inflammation and susceptibility to NAFLD. Nat. Commun. 9, 4462 (2018).

    PubMed  PubMed Central  Google Scholar 

  64. 64.

    Dapito, D. H. et al. Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4. Cancer Cell 21, 504–516 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65.

    Mazagova, M. et al. Commensal microbiota is hepatoprotective and prevents liver fibrosis in mice. Faseb j. 29, 1043–1055 (2015).

    CAS  PubMed  Google Scholar 

  66. 66.

    Krishnan, S. et al. Gut microbiota-derived tryptophan metabolites modulate inflammatory response in hepatocytes and macrophages. Cell Rep. 23, 1099–1111 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67.

    Ma, L. et al. Indole alleviates diet-induced hepatic steatosis and inflammation in a manner involving myeloid cell 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3. Hepatology 72, 1191–1203 (2020).

  68. 68.

    Gong, S. et al. Intestinal microbiota mediates the susceptibility to polymicrobial sepsis-induced liver injury by granisetron generation in mice. Hepatology 69, 1751–1767 (2019).

    CAS  PubMed  Google Scholar 

  69. 69.

    McDonald, B. et al. Programing of an intravascular immune firewall by the gut microbiota protects against pathogen dissemination during infection. Cell Host Microbe 28, 660–668 (2020).

  70. 70.

    Hao, H. et al. Farnesoid X receptor regulation of the NLRP3 inflammasome underlies cholestasis-associated sepsis. Cell Metab. 25, 856–67.e5 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71.

    Isaacs-Ten, A. et al. Intestinal microbiome-macrophage crosstalk contributes to cholestatic liver disease by promoting intestinal permeability. Hepatology (2020).

  72. 72.

    Marrero, I. et al. Complex network of NKT cell subsets controls immune homeostasis in liver and gut. Front. Immunol. 9, 2082 (2018).

    PubMed  PubMed Central  Google Scholar 

  73. 73.

    Bandyopadhyay, K. et al. NKT cell subsets as key participants in liver physiology and pathology. Cell Mol. Immunol. 13, 337–346 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74.

    Chen, J. et al. Natural killer T cells play a necessary role in modulating of immune-mediated liver injury by gut microbiota. Sci. Rep. 4, 7259 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75.

    Wei, Y. et al. Enterogenous bacterial glycolipids are required for the generation of natural killer T cells mediated liver injury. Sci. Rep. 6, 36365 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76.

    Llopis, M. et al. Intestinal microbiota contributes to individual susceptibility to alcoholic liver disease. Gut 65, 830–839 (2016).

    CAS  PubMed  Google Scholar 

  77. 77.

    Ma, C. et al. Gut microbiome-mediated bile acid metabolism regulates liver cancer via NKT cells. Science. 360, eaan5931 (2018).

  78. 78.

    Bonneville, M. et al. Gammadelta T cell effector functions: a blend of innate programming and acquired plasticity. Nat. Rev. Immunol. 10, 467–478 (2010).

    CAS  PubMed  Google Scholar 

  79. 79.

    Martin, B. et al. Interleukin-17-producing gammadelta T cells selectively expand in response to pathogen products and environmental signals. Immunity 31, 321–330 (2009).

    CAS  PubMed  Google Scholar 

  80. 80.

    Paget, C. et al. CD3bright signals on γδ T cells identify IL-17A-producing Vγ6Vδ1+ T cells. Immunol. Cell Biol. 93, 198–212 (2015).

    CAS  PubMed  Google Scholar 

  81. 81.

    Li, F. et al. The microbiota maintain homeostasis of liver-resident γδT-17 cells in a lipid antigen/CD1d-dependent manner. Nat. Commun. 7, 13839 (2017).

    PubMed  Google Scholar 

  82. 82.

    Tedesco, D. et al. Alterations in intestinal microbiota lead to production of interleukin 17 by intrahepatic γδ T-cell receptor-positive cells and pathogenesis of cholestatic liver disease. Gastroenterology 154, 2178–2193 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83.

    Provine, N. M. & Klenerman, P. MAIT cells in health and disease. Annu. Rev. Immunol. 38, 203–228 (2020).

    CAS  PubMed  Google Scholar 

  84. 84.

    Kjer-Nielsen, L. et al. MR1 presents microbial vitamin B metabolites to MAIT cells. Nature. 491, 717–723 (2012).

    CAS  PubMed  Google Scholar 

  85. 85.

    Legoux, F. et al. Microbial metabolites control the thymic development of mucosal-associated invariant T cells. Science 366, 494–499 (2019).

    CAS  PubMed  Google Scholar 

  86. 86.

    Constantinides, M. G. et al. MAIT cells are imprinted by the microbiota in early life and promote tissue repair. Science. 366, eaax6624 (2019).

  87. 87.

    Lin, Q. et al. The dialogue between unconventional T cells and the microbiota. Mucosal Immunol. 13, 867–876 (2020).

  88. 88.

    Rha, M. S. et al. Human liver CD8(+) MAIT cells exert TCR/MR1-independent innate-like cytotoxicity in response to IL-15. J. Hepatol. 73, 640–650 (2020).

  89. 89.

    Niehaus, C. E. et al. MAIT cells are enriched and highly functional in ascites of patients with decompensated liver cirrhosis. Hepatology 72, 1378–1393 (2020).

  90. 90.

    Li, Y. et al. Mucosal-associated invariant T cells improve nonalcoholic fatty liver disease through regulating macrophage polarization. Front Immunol. 9, 1994 (2018).

    PubMed  PubMed Central  Google Scholar 

  91. 91.

    Jiang, X. et al. The immunobiology of mucosal-associated invariant T cell (MAIT) function in primary biliary cholangitis: regulation by cholic acid-induced Interleukin-7. J. Autoimmun. 90, 64–75 (2018).

    CAS  PubMed  Google Scholar 

  92. 92.

    Böttcher, K. et al. MAIT cells are chronically activated in patients with autoimmune liver disease and promote profibrogenic hepatic stellate cell activation. Hepatology 68, 172–186 (2018).

    PubMed  Google Scholar 

  93. 93.

    Wahlström, A. et al. Intestinal crosstalk between bile acids and microbiota and its impact on host metabolism. Cell Metab. 24, 41–50 (2016).

    PubMed  Google Scholar 

  94. 94.

    Jia, W. et al. Bile acid-microbiota crosstalk in gastrointestinal inflammation and carcinogenesis. Nat. Rev. Gastroenterol. Hepatol. 15, 111–128 (2018).

    CAS  PubMed  Google Scholar 

  95. 95.

    Li, Y. et al. Bile acids and intestinal microbiota in autoimmune cholestatic liver diseases. Autoimmun. Rev. 16, 885–896 (2017).

    CAS  PubMed  Google Scholar 

  96. 96.

    Tian, Y. et al. The microbiome modulating activity of bile acids. Gut Microbes 11, 979–996 (2020).

    PubMed  Google Scholar 

  97. 97.

    Sinha, S. R. et al. Dysbiosis-induced secondary bile acid deficiency promotes intestinal inflammation. Cell Host Microbe 27, 659–70.e5 (2020).

    CAS  PubMed  Google Scholar 

  98. 98.

    Song, X. et al. Microbial bile acid metabolites modulate gut RORγ(+) regulatory T cell homeostasis. Nature 577, 410–415 (2020).

    CAS  PubMed  Google Scholar 

  99. 99.

    Campbell, C. et al. Bacterial metabolism of bile acids promotes generation of peripheral regulatory T cells. Nature 581, 475–479 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100.

    Hang, S. et al. Bile acid metabolites control T(H)17 and T(reg) cell differentiation. Nature 576, 143–148 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101.

    Glaser, F. et al. Liver infiltrating T cells regulate bile acid metabolism in experimental cholangitis. J. Hepatol. 71, 783–792 (2019).

    CAS  PubMed  Google Scholar 

  102. 102.

    Zarrinpar, A. & Loomba, R. Review article: the emerging interplay among the gastrointestinal tract, bile acids and incretins in the pathogenesis of diabetes and non-alcoholic fatty liver disease. Aliment Pharmacol. Ther. 36, 909–921 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. 103.

    Mouries, J. et al. Microbiota-driven gut vascular barrier disruption is a prerequisite for non-alcoholic steatohepatitis development. J. Hepatol. 71, 1216–1228 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. 104.

    Copple, B. L. & Li, T. Pharmacology of bile acid receptors: evolution of bile acids from simple detergents to complex signaling molecules. Pharmacol. Res. 104, 9–21 (2016).

    CAS  PubMed  Google Scholar 

  105. 105.

    Nevens, F. et al. A placebo-controlled trial of obeticholic acid in primary biliary cholangitis. N. Engl. J. Med. 375, 631–643 (2016).

    CAS  PubMed  Google Scholar 

  106. 106.

    Gadaleta, R. M. et al. Fibroblast Growth Factor 19 modulates intestinal microbiota and inflammation in presence of Farnesoid X Receptor. EBioMedicine 54, 102719 (2020).

    PubMed  PubMed Central  Google Scholar 

  107. 107.

    Liu, Y. et al. Probiotic Lactobacillus rhamnosus GG prevents liver fibrosis through inhibiting hepatic bile acid synthesis and enhancing bile acid excretion in mice. Hepatology 71, 2050–2066 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. 108.

    Fiorucci, S. & Distrutti, E. Bile acid-activated receptors, intestinal microbiota, and the treatment of metabolic disorders. Trends Mol. Med. 21, 702–714 (2015).

    CAS  PubMed  Google Scholar 

  109. 109.

    Foley, M. H. et al. Bile salt hydrolases: gatekeepers of bile acid metabolism and host-microbiome crosstalk in the gastrointestinal tract. PLoS Pathog. 15, e1007581 (2019).

    PubMed  PubMed Central  Google Scholar 

  110. 110.

    Lang, S. & Schnabl, B. Microbiota and fatty liver disease-the known, the unknown, and the future. Cell Host Microbe 28, 233–244 (2020).

    CAS  PubMed  Google Scholar 

  111. 111.

    Philips, C. A. et al. Healthy donor fecal microbiota transplantation in steroid-ineligible severe alcoholic hepatitis: a pilot study. Clin. Gastroenterol. Hepatol. 15, 600–602 (2017).

    PubMed  Google Scholar 

  112. 112.

    Leclercq, S. et al. Intestinal permeability, gut-bacterial dysbiosis, and behavioral markers of alcohol-dependence severity. Proc. Natl Acad. Sci. USA 111, E4485–E4493 (2014).

    CAS  PubMed  Google Scholar 

  113. 113.

    Grander, C. et al. Recovery of ethanol-induced Akkermansia muciniphila depletion ameliorates alcoholic liver disease. Gut 67, 891–901 (2018).

    PubMed  Google Scholar 

  114. 114.

    Lang, S. et al. Changes in the fecal bacterial microbiota associated with disease severity in alcoholic hepatitis patients. Gut Microbes 12, 1785251 (2020).

    PubMed  PubMed Central  Google Scholar 

  115. 115.

    Mutlu, E. A. et al. Colonic microbiome is altered in alcoholism. Am. J. Physiol. Gastrointest. Liver Physiol. 302, G966–G978 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. 116.

    Duan, Y. et al. Bacteriophage targeting of gut bacterium attenuates alcoholic liver disease. Nature 575, 505–511 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. 117.

    Bode, J. C. et al. Jejunal microflora in patients with chronic alcohol abuse. Hepatogastroenterology 31, 30–34 (1984).

    CAS  PubMed  Google Scholar 

  118. 118.

    Wang, L. et al. Intestinal REG3 lectins protect against alcoholic steatohepatitis by reducing mucosa-associated microbiota and preventing bacterial translocation. Cell Host Microbe 19, 227–239 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. 119.

    Yang, A. M. et al. Intestinal fungi contribute to development of alcoholic liver disease. J. Clin. Investig 127, 2829–2841 (2017).

    PubMed  Google Scholar 

  120. 120.

    Chu, H. et al. The Candida albicans exotoxin candidalysin promotes alcohol-associated liver disease. J. Hepatol. 72, 391–400 (2020).

    CAS  PubMed  Google Scholar 

  121. 121.

    Jiang, L. et al. Intestinal virome in patients with alcoholic hepatitis. Hepatology 2020. Online ahead of print.

  122. 122.

    Bluemel, S. et al. Precision medicine in alcoholic and nonalcoholic fatty liver disease via modulating the gut microbiota. Am. J. Physiol. Gastrointest. Liver Physiol. 311, G1018–g36 (2016).

    PubMed  PubMed Central  Google Scholar 

  123. 123.

    Brenner, D. A. et al. Role of gut microbiota in liver disease. J. Clin. Gastroenterol. 49 Suppl 1, S25–S27 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. 124.

    Brandl, K. et al. Dysregulation of serum bile acids and FGF19 in alcoholic hepatitis. J. Hepatol. 69, 396–405 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. 125.

    Hendrikx, T. & Schnabl, B. Antimicrobial proteins: intestinal guards to protect against liver disease. J. Gastroenterol. 54, 209–217 (2019).

    PubMed  Google Scholar 

  126. 126.

    Inokuchi, S. et al. Toll-like receptor 4 mediates alcohol-induced steatohepatitis through bone marrow-derived and endogenous liver cells in mice. Alcohol Clin. Exp. Res. 35, 1509–1518 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. 127.

    Iracheta-Vellve, A. et al. Inhibition of sterile danger signals, uric acid and ATP, prevents inflammasome activation and protects from alcoholic steatohepatitis in mice. J. Hepatol. 63, 1147–1155 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. 128.

    Petrasek, J. et al. Metabolic danger signals, uric acid and ATP, mediate inflammatory cross-talk between hepatocytes and immune cells in alcoholic liver disease. J. Leukoc. Biol. 98, 249–256 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. 129.

    Petrasek, J. et al. IL-1 receptor antagonist ameliorates inflammasome-dependent alcoholic steatohepatitis in mice. J. Clin. Investig. 122, 3476–3489 (2012).

    CAS  PubMed  Google Scholar 

  130. 130.

    Lang, S. et al. Cytolysin-positive Enterococcus faecalis is not increased in patients with non-alcoholic steatohepatitis. Liver Int. 40, 860–865 (2020).

    CAS  PubMed  Google Scholar 

  131. 131.

    Hartmann, P. et al. Modulation of the intestinal bile acid/farnesoid X receptor/fibroblast growth factor 15 axis improves alcoholic liver disease in mice. Hepatology 67, 2150–2166 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. 132.

    Couch, R. D. et al. Alcohol induced alterations to the human fecal VOC metabolome. PLoS ONE 10, e0119362 (2015).

    PubMed  PubMed Central  Google Scholar 

  133. 133.

    Smirnova, E. et al. Fecal microbiome distinguishes alcohol consumption from alcoholic hepatitis but does not discriminate disease severity. Hepatology 72, 271–286 (2020).

    CAS  PubMed  Google Scholar 

  134. 134.

    Cresci, G. A. et al. Tributyrin supplementation protects mice from acute ethanol-induced gut injury. Alcohol Clin. Exp. Res. 38, 1489–1501 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. 135.

    Li, Z. et al. Probiotics and antibodies to TNF inhibit inflammatory activity and improve nonalcoholic fatty liver disease. Hepatology 37, 343–350 (2003).

    CAS  PubMed  Google Scholar 

  136. 136.

    Alferink, L. J. et al. Microbiomics, metabolomics, predicted metagenomics and hepatic steatosis in a population-based study of 1355 adults. Hepatology 2020. Online ahead of print.

  137. 137.

    Zhu, L. et al. Characterization of gut microbiomes in nonalcoholic steatohepatitis (NASH) patients: a connection between endogenous alcohol and NASH. Hepatology 57, 601–609 (2013).

    CAS  PubMed  Google Scholar 

  138. 138.

    Mouzaki, M. et al. Intestinal microbiota in patients with nonalcoholic fatty liver disease. Hepatology 58, 120–127 (2013).

    CAS  PubMed  Google Scholar 

  139. 139.

    Loomba, R. et al. Gut microbiome-based metagenomic signature for non-invasive detection of advanced fibrosis in human nonalcoholic fatty liver disease. Cell Metab. 25, 1054–62.e5 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. 140.

    Lang, S. et al. Intestinal virome signature associated with severity of nonalcoholic fatty liver disease. Gastroenterology 159, 1839–1852 (2020).

  141. 141.

    Scorletti, E. et al. Synbiotics alter fecal microbiomes, but not liver fat or fibrosis, in a randomized trial of patients with nonalcoholic fatty liver disease. Gastroenterology 158, 1597–610.e7 (2020).

    CAS  PubMed  Google Scholar 

  142. 142.

    Chong, C. Y. L. et al. Randomised double-blind placebo-controlled trial of inulin with metronidazole in non-alcoholic fatty liver disease (NAFLD). Nutrients 12, 937 (2020).

  143. 143.

    Aron-Wisnewsky, J. et al. Nonalcoholic fatty liver disease: modulating gut microbiota to improve severity? Gastroenterology 158, 1881–1898 (2020).

    CAS  PubMed  Google Scholar 

  144. 144.

    Tilg, H. et al. The intestinal microbiota fuelling metabolic inflammation. Nat. Rev. Immunol. 20, 40–54 (2020).

    CAS  PubMed  Google Scholar 

  145. 145.

    Gupta, B. et al. Western diet-induced increase in colonic bile acids compromises epithelial barrier in nonalcoholic steatohepatitis. FASEB J. 34, 7089–7102 (2020).

    CAS  PubMed  Google Scholar 

  146. 146.

    Craven, L. et al. Allogenic fecal microbiota transplantation in patients with nonalcoholic fatty liver disease improves abnormal small intestinal permeability: a randomized control trial. Am. J. Gastroenterol. 115, 1055–1065 (2020).

  147. 147.

    Chu, H. et al. Small metabolites, possible big changes: a microbiota-centered view of non-alcoholic fatty liver disease. Gut 68, 359–370 (2019).

    CAS  PubMed  Google Scholar 

  148. 148.

    Zhao, M. et al. TMAVA, a metabolite of intestinal microbes, is increased in plasma from patients with liver steatosis, inhibits γ-butyrobetaine hydroxylase, and exacerbates fatty liver in mice. Gastroenterology 158, 2266–81.e27 (2020).

    CAS  PubMed  Google Scholar 

  149. 149.

    Hoyles, L. et al. Molecular phenomics and metagenomics of hepatic steatosis in non-diabetic obese women. Nat. Med. 24, 1070–1080 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. 150.

    Goldstein, J. L. What makes a piece of art or science a masterpiece? Cell 175, 1–5 (2018).

    CAS  PubMed  Google Scholar 

  151. 151.

    Day, C. P. & James, O. F. Steatohepatitis: a tale of two “hits”? Gastroenterology 114, 842–845 (1998).

    CAS  PubMed  Google Scholar 

  152. 152.

    Fei, N. et al. Endotoxin producers overgrowing in human gut microbiota as the causative agents for nonalcoholic fatty liver disease. mBio. 11, e03263–19 (2020).

  153. 153.

    Carpino, G. et al. Increased liver localization of lipopolysaccharides in human and experimental NAFLD. Hepatology 159, 1715–1730 (2019).

  154. 154.

    Yuan, J. et al. Fatty liver disease caused by high-alcohol-producing Klebsiella pneumoniae. Cell Metab. 30, 675–88.e7 (2019).

    CAS  PubMed  Google Scholar 

  155. 155.

    Bajaj, J. S. et al. Serum levels of metabolites produced by intestinal microbes and lipid moieties independently associated with acute on chronic liver failure and death in patients with cirrhosis. Gastroenterology (2020).

  156. 156.

    Schierwagen, R. et al. Circulating microbiome in blood of different circulatory compartments. Gut 68, 578–580 (2019).

    CAS  PubMed  Google Scholar 

  157. 157.

    Sookoian, S. et al. Intrahepatic bacterial metataxonomic signature in non-alcoholic fatty liver disease. Gut 69, 1483–1491 (2020).

    CAS  PubMed  Google Scholar 

  158. 158.

    Anhê, F. F. et al. Type 2 diabetes influences bacterial tissue compartmentalisation in human obesity. Nat. Metab. 2, 233–242 (2020).

    PubMed  Google Scholar 

  159. 159.

    Wei, Y. et al. Alterations of gut microbiome in autoimmune hepatitis. Gut 69, 569–577 (2020).

    CAS  PubMed  Google Scholar 

  160. 160.

    Liwinski, T. et al. A disease-specific decline of the relative abundance of Bifidobacterium in patients with autoimmune hepatitis. Aliment Pharmacol Ther. 51, 1417–1428 (2020).

    CAS  PubMed  Google Scholar 

  161. 161.

    Lv, L. X. et al. Alterations and correlations of the gut microbiome, metabolism and immunity in patients with primary biliary cirrhosis. Environ. Microbiol. 18, 2272–2286 (2016).

    CAS  PubMed  Google Scholar 

  162. 162.

    Tang, R. et al. Gut microbial profile is altered in primary biliary cholangitis and partially restored after UDCA therapy. Gut 67, 534–541 (2018).

    CAS  PubMed  Google Scholar 

  163. 163.

    Chen, W. et al. Comprehensive analysis of serum and fecal bile acid profiles and interaction with gut microbiota in primary biliary cholangitis. Clin. Rev. Allergy Immunol. 58, 25–38 (2020).

    PubMed  Google Scholar 

  164. 164.

    Loomba, R. et al. The commensal microbe veillonella as a marker for response to an FGF19 analog in nonalcoholic steatohepatitis. Hepatology 2020. Online ahead of print.

  165. 165.

    Furukawa, M. et al. Gut dysbiosis associated with clinical prognosis of patients with primary biliary cholangitis. Hepatol. Res. 50, 840–852 (2020).

    CAS  PubMed  Google Scholar 

  166. 166.

    Kummen, M. et al. The gut microbial profile in patients with primary sclerosing cholangitis is distinct from patients with ulcerative colitis without biliary disease and healthy controls. Gut 66, 611–619 (2017).

    PubMed  Google Scholar 

  167. 167.

    Rühlemann, M. C. et al. Faecal microbiota profiles as diagnostic biomarkers in primary sclerosing cholangitis. Gut 66, 753–754 (2017).

    PubMed  Google Scholar 

  168. 168.

    Sabino, J. et al. Primary sclerosing cholangitis is characterised by intestinal dysbiosis independent from IBD. Gut 65, 1681–1689 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  169. 169.

    Pereira, P. et al. Bile microbiota in primary sclerosing cholangitis: Impact on disease progression and development of biliary dysplasia. PLoS ONE 12, e0182924 (2017).

    PubMed  PubMed Central  Google Scholar 

  170. 170.

    Rossen, N. G. et al. The mucosa-associated microbiota of PSC patients is characterized by low diversity and low abundance of uncultured Clostridiales II. J. Crohns Colitis 9, 342–348 (2015).

    PubMed  Google Scholar 

  171. 171.

    Kevans, D. et al. Characterization of intestinal microbiota in ulcerative colitis patients with and without primary sclerosing cholangitis. J. Crohns Colitis 10, 330–337 (2016).

    CAS  PubMed  Google Scholar 

  172. 172.

    Torres, J. et al. The features of mucosa-associated microbiota in primary sclerosing cholangitis. Aliment Pharmacol. Ther. 43, 790–801 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  173. 173.

    Quraishi, M. N. et al. The gut-adherent microbiota of PSC-IBD is distinct to that of IBD. Gut 66, 386–388 (2017).

    PubMed  Google Scholar 

  174. 174.

    Iwasawa, K. et al. Characterisation of the faecal microbiota in Japanese patients with paediatric-onset primary sclerosing cholangitis. Gut 66, 1344–1346 (2017).

    PubMed  Google Scholar 

  175. 175.

    Bajer, L. et al. Distinct gut microbiota profiles in patients with primary sclerosing cholangitis and ulcerative colitis. World J. Gastroenterol. 23, 4548–4558 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  176. 176.

    Torres, J. et al. The gut microbiota, bile acids and their correlation in primary sclerosing cholangitis associated with inflammatory bowel disease. United European Gastroenterol. J. 6, 112–122 (2018).

    CAS  PubMed  Google Scholar 

  177. 177.

    Ruff, W. E. et al. Host-microbiota interactions in immune-mediated diseases. Nat. Rev. Microbiol 18, 521–538 (2020).

    CAS  PubMed  Google Scholar 

  178. 178.

    Meng, X. et al. Microbe-metabolite-host axis, two-way action in the pathogenesis and treatment of human autoimmunity. Autoimmun. Rev. 18, 455–475 (2019).

    CAS  PubMed  Google Scholar 

  179. 179.

    Cai, W. et al. Intestinal microbiome and permeability in patients with autoimmune hepatitis. Best. Pract. Res Clin. Gastroenterol. 31, 669–673 (2017).

    CAS  PubMed  Google Scholar 

  180. 180.

    Fussey, S. P. et al. Reactivity of primary biliary cirrhosis sera with Escherichia coli dihydrolipoamide acetyltransferase (E2p): characterization of the main immunogenic region. Proc. Natl Acad. Sci. USA 87, 3987–3991 (1990).

    CAS  PubMed  Google Scholar 

  181. 181.

    Bogdanos, D. P. et al. Primary biliary cirrhosis is characterized by IgG3 antibodies cross-reactive with the major mitochondrial autoepitope and its Lactobacillus mimic. Hepatology 42, 458–465 (2005).

    CAS  PubMed  Google Scholar 

  182. 182.

    Terjung, B. et al. p-ANCAs in autoimmune liver disorders recognise human beta-tubulin isotype 5 and cross-react with microbial protein FtsZ. Gut 59, 808–816 (2010).

    CAS  PubMed  Google Scholar 

  183. 183.

    Manfredo Vieira, S. et al. Translocation of a gut pathobiont drives autoimmunity in mice and humans. Science 359, 1156–1161 (2018).

    CAS  PubMed  Google Scholar 

  184. 184.

    Nakamoto, N. et al. Gut pathobionts underlie intestinal barrier dysfunction and liver T helper 17 cell immune response in primary sclerosing cholangitis. Nat. Microbiol. 4, 492–503 (2019).

    CAS  PubMed  Google Scholar 

  185. 185.

    Trivedi, P. J. et al. Intestinal CCL25 expression is increased in colitis and correlates with inflammatory activity. J. Autoimmun. 68, 98–104 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  186. 186.

    Trivedi, P. J. et al. Vascular adhesion protein-1 is elevated in primary sclerosing cholangitis, is predictive of clinical outcome and facilitates recruitment of gut-tropic lymphocytes to liver in a substrate-dependent manner. Gut 67, 1135–1145 (2018).

    CAS  PubMed  Google Scholar 

  187. 187.

    Henriksen, E. K. et al. Gut and liver T-cells of common clonal origin in primary sclerosing cholangitis-inflammatory bowel disease. J. Hepatol. 66, 116–122 (2017).

    CAS  PubMed  Google Scholar 

  188. 188.

    Moro-Sibilot, L. et al. Mouse and human liver contain immunoglobulin A-secreting cells originating from Peyer’s patches and directed against intestinal antigens. Gastroenterology 151, 311–323 (2016).

    CAS  PubMed  Google Scholar 

  189. 189.

    Bajaj, J. S. & Khoruts, A. Microbiota changes and intestinal microbiota transplantation in liver diseases and cirrhosis. J. Hepatol. 72, 1003–1027 (2020).

    CAS  PubMed  Google Scholar 

  190. 190.

    Schwabe, R. F. & Greten, T. F. Gut microbiome in HCC—mechanisms, diagnosis and therapy. J. Hepatol. 72, 230–238 (2020).

    CAS  PubMed  Google Scholar 

  191. 191.

    Sehgal, R. et al. Role of microbiota in pathogenesis and management of viral hepatitis. Front. Cell Infect. Microbiol. 10, 341 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  192. 192.

    Lu, H. et al. Intestinal microbiota was assessed in cirrhotic patients with hepatitis B virus infection. Intestinal microbiota of HBV cirrhotic patients. Microb Ecol. 61, 693–703 (2011).

    PubMed  Google Scholar 

  193. 193.

    Cui, L. et al. The human mycobiome in health and disease. Genome Med. 5, 63 (2013).

    PubMed  PubMed Central  Google Scholar 

  194. 194.

    Xu, M. et al. Changes of fecal Bifidobacterium species in adult patients with hepatitis B virus-induced chronic liver disease. Microb. Ecol. 63, 304–313 (2012).

    PubMed  Google Scholar 

  195. 195.

    Chou, H. H. et al. Age-related immune clearance of hepatitis B virus infection requires the establishment of gut microbiota. Proc. Natl Acad. Sci. USA 112, 2175–2180 (2015).

    CAS  PubMed  Google Scholar 

  196. 196.

    Chauhan, A. et al. Fecal microbiota transplantation in hepatitis B e antigen-positive chronic hepatitis B patients: a pilot study. Dig. Dis. Sci. 2020. Online ahead of print.

  197. 197.

    Aly, A. M. et al. Gut microbiome alterations in patients with stage 4 hepatitis C. Gut Pathog. 8, 42 (2016).

    PubMed  PubMed Central  Google Scholar 

  198. 198.

    Heidrich, B. et al. Intestinal microbiota in patients with chronic hepatitis C with and without cirrhosis compared with healthy controls. Liver Int. 38, 50–58 (2018).

    PubMed  Google Scholar 

  199. 199.

    Inoue, T. et al. Gut dysbiosis associated with hepatitis C virus infection. Clin. Infect. Dis. 67, 869–877 (2018).

    CAS  PubMed  Google Scholar 

  200. 200.

    Wu, J. et al. Altered faecal microbiota on the expression of Th cells responses in the exacerbation of patients with hepatitis E infection. J. Viral Hepat. 27, 1243–1252 (2020).

    CAS  PubMed  Google Scholar 

  201. 201.

    Qin, N. et al. Alterations of the human gut microbiome in liver cirrhosis. Nature 513, 59–64 (2014).

    CAS  PubMed  Google Scholar 

  202. 202.

    Bajaj, J. S. et al. Altered profile of human gut microbiome is associated with cirrhosis and its complications. J. Hepatol. 60, 940–947 (2014).

    CAS  PubMed  Google Scholar 

  203. 203.

    Bajaj, J. S. et al. Colonic mucosal microbiome differs from stool microbiome in cirrhosis and hepatic encephalopathy and is linked to cognition and inflammation. Am. J. Physiol. Gastrointest. Liver Physiol. 303, G675–G685 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  204. 204.

    Santiago, A. et al. Alteration of the serum microbiome composition in cirrhotic patients with ascites. Sci. Rep. 6, 25001 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  205. 205.

    Bajaj, J. S. et al. Salivary microbiota reflects changes in gut microbiota in cirrhosis with hepatic encephalopathy. Hepatology 62, 1260–1271 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  206. 206.

    Bajaj, J. S. et al. Association between intestinal microbiota collected at hospital admission and outcomes of patients with cirrhosis. Clin. Gastroenterol. Hepatol. 17, 756–65.e3 (2019).

    PubMed  Google Scholar 

  207. 207.

    Albillos, A. et al. Cirrhosis-associated immune dysfunction: distinctive features and clinical relevance. J. Hepatol. 61, 1385–1396 (2014).

    CAS  PubMed  Google Scholar 

  208. 208.

    Muñoz, L. et al. Intestinal immune dysregulation driven by dysbiosis promotes barrier disruption and bacterial translocation in rats with cirrhosis. Hepatology 70, 925–938 (2019).

    PubMed  Google Scholar 

  209. 209.

    Lorenzo-Zúñiga, V. et al. Oral bile acids reduce bacterial overgrowth, bacterial translocation, and endotoxemia in cirrhotic rats. Hepatology 37, 551–557 (2003).

    PubMed  Google Scholar 

  210. 210.

    Sorribas, M. et al. FXR modulates the gut-vascular barrier by regulating the entry sites for bacterial translocation in experimental cirrhosis. J. Hepatol. 71, 1126–1140 (2019).

    CAS  PubMed  Google Scholar 

  211. 211.

    Oh, T. G. et al. A universal gut-microbiome-derived signature predicts cirrhosis. Cell Metab. (2020).

  212. 212.

    Tilg, H. et al. Gut microbiome and liver diseases. Gut 65, 2035–2044 (2016).

    CAS  PubMed  Google Scholar 

  213. 213.

    Ponziani, F. R. et al. Hepatocellular carcinoma is associated with gut microbiota profile and inflammation in nonalcoholic fatty liver disease. Hepatology 69, 107–120 (2019).

    CAS  PubMed  Google Scholar 

  214. 214.

    Ren, Z. et al. Gut microbiome analysis as a tool towards targeted non-invasive biomarkers for early hepatocellular carcinoma. Gut 68, 1014–1023 (2019).

    CAS  PubMed  Google Scholar 

  215. 215.

    Lin, R. S. et al. Endotoxemia in patients with chronic liver diseases: relationship to severity of liver diseases, presence of esophageal varices, and hyperdynamic circulation. J. Hepatol. 22, 165–172 (1995).

    CAS  PubMed  Google Scholar 

  216. 216.

    Bellot, P. et al. Bacterial DNA translocation is associated with systemic circulatory abnormalities and intrahepatic endothelial dysfunction in patients with cirrhosis. Hepatology 52, 2044–2052 (2010).

    CAS  PubMed  Google Scholar 

  217. 217.

    Routy, B. et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 359, 91–97 (2018).

    CAS  PubMed  Google Scholar 

  218. 218.

    Lagier, J. C. et al. Culture of previously uncultured members of the human gut microbiota by culturomics. Nat. Microbiol 1, 16203 (2016).

    CAS  PubMed  Google Scholar 

  219. 219.

    Metwaly, A. & Haller, D. Multi-omics in IBD biomarker discovery: the missing links. Nat. Rev. Gastroenterol. Hepatol. 16, 587–588 (2019).

    PubMed  Google Scholar 

  220. 220.

    Zhang, Q. et al. Integrated multiomic analysis reveals comprehensive tumour heterogeneity and novel immunophenotypic classification in hepatocellular carcinomas. Gut 68, 2019–2031 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  221. 221.

    Burberry, A. et al. C9orf72 suppresses systemic and neural inflammation induced by gut bacteria. Nature 582, 89–94 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  222. 222.

    Hu, S. et al. Whole exome sequencing analyses reveal gene-microbiota interactions in the context of IBD. Gut 2020;gutjnl-2019-319706. Online ahead of print.

  223. 223.

    Bober, J. R. et al. Synthetic biology approaches to engineer probiotics and members of the human microbiota for biomedical applications. Annu. Rev. Biomed. Eng. 20, 277–300 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  224. 224.

    Hendrikx, T. et al. Bacteria engineered to produce IL-22 in intestine induce expression of REG3G to reduce ethanol-induced liver disease in mice. Gut 68, 1504–1515 (2019).

    CAS  PubMed  Google Scholar 

Download references


This work was supported in part by the National Natural Science Foundation of China (grants #81830016, 81771732, and 81620108002 to X.M.; #81922010 and 81873561 to R.T.). This study was supported in part by services provided by the NIH centers P30 DK120515 and P50 AA011999. H.T. is supported by the excellence initiative VASCage (Centre for Promoting Vascular Health in the Ageing Community), an R&D K-Centre (COMET program—Competence Centers for Excellent Technologies) funded by the Austrian Ministry for Transport, Innovation and Technology, the Austrian Ministry for Digital and Economic Affairs and the federal states Tyrol, Salzburg and Vienna.

Author information




B.S. was responsible for writing the chapter “Contribution of the gut microbiota to alcohol-associated liver disease”. H.T. wrote the chapter “NAFLD and the Microbiome”. R.W., R.T. and X.M. wrote the chapters “The Gut Microbiome”, “The Gut Microbiome and Liver Immunology”, “The Gut Microbiome and AILD”, and “The Gut Microbiome and Other Types of Liver Diseases”. B.L. was responsible for draft calibration.

Corresponding authors

Correspondence to Xiong Ma or Bernd Schnabl or Herbert Tilg.

Ethics declarations

Competing interests

B.S. has been consulting for Ferring Research Institute, Intercept Pharmaceuticals, HOST Therabiomics, Mabwell Therapeutics and Patara Pharmaceuticals. B.S.’s institution (UC San Diego) has received grant support from BiomX, NGM Biopharmaceuticals, CymaBay Therapeutics, Synlogic Operating Company and Axial Biotherapeutics. H.T. and X.M. have no competing interests.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Wang, R., Tang, R., Li, B. et al. Gut microbiome, liver immunology, and liver diseases. Cell Mol Immunol 18, 4–17 (2021).

Download citation


  • Gut–liver axis
  • Alcohol liver disease
  • Nonalcoholic fatty liver disease
  • Autoimmune liver disease
  • Microbiome

Further reading


Quick links