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The Microbiota-Gut-Liver Axis: Implications for the Pathophysiology of Liver Disease

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Liver Immunology

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Abstract

Interactions between the gut and the liver in relation to immunological responses and metabolic functions have been recognized as central to homeostasis for decades. The roles of gut bacteria in the pathogenesis of certain complications of cirrhosis such as hepatic encephalopathy, spontaneous bacterial peritonitis, and systemic sepsis were also delineated decades ago – what is new is the idea that interactions between luminal bacteria in the gut (microbiota), the gut itself, and the liver may play a more fundamental role in the pathogenesis of a number of metabolic and immunological diseases. From basic animal research, as well as observations in human disease, a general hypothesis has emerged to explain how interplay between these factors might initiate or perpetuate alcoholic liver disease, nonalcoholic fatty liver disease, and even immunologically mediated liver diseases. In this framework, disrupted microbiota and their products gain access to the gut-associated immune system via a permeable gut barrier and generate inflammatory responses. Disruption of the gut vascular barrier then permits access for bacterial components as well as pro-inflammatory cytokines to the portal circulation and onto the liver where inflammatory and metabolic responses drive the genesis of various liver diseases. Cross-reactivity between bacterial antigens and biliary epitopes has also been invoked in relation to primary sclerosing cholangitis and primary biliary cholangitis. As we learn more of the details of these interactions and of the primacy, or otherwise, of the microbiota in this microbiota-gut-liver axis, new preventive strategies and therapeutic avenues may open up.

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References

  1. Simbrunner B, Mandorfer M, Trauner M, Reiberger T. Gut-liver axis signaling in portal hypertension. World J Gastroenterol. 2019;25:5897–917.

    CAS  Google Scholar 

  2. Broun GO, McMaster PD, Rous P. Studies on the total bile: IV. The enterohepatic circulation of bile pigment. J Exp Med. 1923;37:699–710.

    CAS  Google Scholar 

  3. Dowling RH, Mack E, Small DM. Effects of controlled interruption of the enterohepatic circulation of bile salts by biliary diversion and by ileal resection on bile salt secretion, synthesis, and pool size in the rhesus monkey. J Clin Invest. 1970;49:232–42.

    CAS  Google Scholar 

  4. Dowling RH. The enterohepatic circulation. Gastroenterology. 1972;62:122–40.

    CAS  Google Scholar 

  5. Emery FE, Joyce HE. Enterohepatic circulation of oestrogens. J Endocrinol. 1946;4:371–4.

    CAS  Google Scholar 

  6. Briggs FN, Taurog A, Chaikoff IL. The enterohepatic circulation of thyroxine in the rat. Endocrinology. 1953;52:559–67.

    CAS  Google Scholar 

  7. Lester R, Ostrow JD, Schmid R. Enterohepatic circulation of bilirubin. Nature. 1961;192:372.

    CAS  Google Scholar 

  8. Di Ciaula A, Garruti G, Lunardi Baccetto R, Molina-Molina E, Bonfrate L, Wang DQ, Portincasa P. Bile acid physiology. Ann Hepatol. 2017;16(Suppl. 1: s3–105):s4–s14.

    Google Scholar 

  9. Davis BC, Bajaj JS. The human gut microbiome in liver diseases. Semin Liver Dis. 2017;37:128–40.

    CAS  Google Scholar 

  10. Phillips GB, Schwartz R, Gabuzda GJ Jr, Davidson CS. The syndrome of impending hepatic coma in patients with cirrhosis of the liver given certain nitrogenous substances. N Engl J Med. 1952;247:239–46.

    CAS  Google Scholar 

  11. Martini GA, Phear EA, Ruebner B, Sherlock S. The bacterial content of the small intestine in normal and cirrhotic subjects: relation to methionine toxicity. Clin Sci. 1957;16:35–51.

    CAS  Google Scholar 

  12. Phear EA, Ruebner B, Sherlock S, Summerskill WH. Methionine toxicity in liver disease and its prevention by chlortetracycline. Clin Sci. 1956;15:93–117.

    CAS  Google Scholar 

  13. Quigley EMM. Gastrointestinal dysfunction in liver disease – gut-liver interactions revisited. Dig Dis Sci. 1996;41:557–61.

    CAS  Google Scholar 

  14. Thalheimer U, Triantos CK, Samonakis DN, Patch D, Burroughs AK. Infection, coagulation and variceal bleeding in cirrhosis. Gut. 2005;54:556–63.

    CAS  Google Scholar 

  15. Quigley EM, Abu-Shanab A, Murphy EF, Stanton C, Monsour HP Jr. The metabolic role of the microbiome: implications for NAFLD and the metabolic syndrome. Semin Liver Dis. 2016;36:312–6.

    CAS  Google Scholar 

  16. Brandl K, Kumar V, Eckmann L. Gut-liver axis at the frontier of host-microbial interactions. Am J Physiol Gastrointest Liver Physiol. 2017;312:G413–9.

    Google Scholar 

  17. Arab JP, Martin-Mateos RM, Shah VH. Gut-liver axis, cirrhosis and portal hypertension: the chicken and the egg. Hepatol Int. 2018;12(Suppl 1):24–33.

    Google Scholar 

  18. 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;15:397–411.

    CAS  Google Scholar 

  19. Wiest R, Albillos A, Trauner M, Bajaj JS, Jalan R. Targeting the gut-liver axis in liver disease. J Hepatol. 2017;67:1084–103.

    CAS  Google Scholar 

  20. Safari Z, Gérard P. The links between the gut microbiome and non-alcoholic fatty liver disease (NAFLD). Cell Mol Life Sci. 2019;76:1541–58.

    Article  CAS  Google Scholar 

  21. Quigley EM. Primary biliary cirrhosis and the microbiome. Semin Liver Dis. 2016;36:349–53.

    Article  CAS  Google Scholar 

  22. O’Hara SP, LaRusso NF. The gut-liver axis in primary sclerosing cholangitis: are pathobionts the missing link? Hepatology. 2019;70:1058–60.

    Article  Google Scholar 

  23. About the Human Microbiome. NIH Human Microbiome Project – About the Human Microbiome. https://hmpdacc.org/hmp/overview/. Accessed 2 Feb 2020.

  24. Eloe-Fadrosh EA, Rasko DA. The human microbiome: from symbiosis to pathogenesis. Annu Rev Med. 2013;64:145–63.

    Article  CAS  Google Scholar 

  25. Huang YJ, Boushey HA. The microbiome in asthma. J Allergy Clin Immunol. 2015;135:25–30.

    Article  Google Scholar 

  26. Costello ME, Robinson PC, Benham H, Brown MA. The intestinal microbiome in human disease and how it relates to arthritis and spondyloarthritis. Best Pract Res Clin Rheumatol. 2015;29:202–12.

    Article  Google Scholar 

  27. Mathur R, Barlow GM. Obesity and the microbiome. Expert Rev Gastroenterol Hepatol. 2015;9:1087–99.

    Article  CAS  Google Scholar 

  28. Tang WH, Kitai T, Hazen SL. Gut microbiota in cardiovascular health and disease. Circ Res. 2017;120:1183–96.

    CAS  Google Scholar 

  29. Fung TC, Olson CA, Hsiao EY. Interactions between the microbiota, immune and nervous systems in health and disease. Nat Neurosci. 2017;20:145–55.

    CAS  Google Scholar 

  30. Lynch SV, Pedersen O. The human intestinal microbiome in health and disease. N Engl J Med. 2016;375:2369–79.

    Article  CAS  Google Scholar 

  31. Claesson MJ, Clooney AG, O’Toole PW. A clinician’s guide to microbiome analysis. Nat Rev Gastroenterol Hepatol. 2017;14:585–95.

    Article  Google Scholar 

  32. Collado MC, Rautava S, Aakko J, Isolauri E, Salminen S. Human gut colonisation may be initiated in utero by distinct microbial communities in the placenta and amniotic fluid. Sci Rep. 2016;6:23129.

    Article  CAS  Google Scholar 

  33. Leiby JS, McCormick K, Sherrill-Mix S, et al. Lack of detection of a human placenta microbiome in samples from preterm and term deliveries. Microbiome. 2018;6(1):196.

    Article  Google Scholar 

  34. Neu J. The microbiome during pregnancy and early postnatal life. Semin Fetal Neonatal Med. 2016;21:373–9.

    Article  Google Scholar 

  35. Jakobsson HE, Abrahamsson TR, Jenmalm MC, Harris K, Quince C, Jernberg C, et al. Decreased gut microbiota diversity, delayed Bacteroidetes colonisation and reduced Th1 responses in infants delivered by caesarean section. Gut. 2014;63:559–66.

    Article  CAS  Google Scholar 

  36. Dogra S, Sakwinska O, Soh SE, Ngom-Bru C, Brück WM, Berger B, Brüssow H, Lee YS, Yap F, Chong YS, Godfrey KM, Holbrook JD, GUSTO Study Group. Dynamics of infant gut microbiota are influenced by delivery mode and gestational duration and are associated with subsequent adiposity. mBio. 2015;6:e02419–4.

    Article  Google Scholar 

  37. Cong X, Xu W, Janton S, Henderson WA, Matson A, McGrath JM, et al. Gut microbiome developmental patterns in early life of preterm infants: impacts of feeding and gender. PLoS One. 2016;11:e0152751.

    Article  CAS  Google Scholar 

  38. Bäckhed F, Roswall J, Peng Y, Feng Q, Jia H, Kovatcheva-Datchary P, et al. Dynamics and stabilization of the human gut microbiome during the first year of life. Cell Host Microbe. 2015;17:690–703.

    Article  CAS  Google Scholar 

  39. Yatsunenko T, Rey FE, Manary MJ, Trehan I, Dominguez-Bello MG, Contreras M, et al. Human gut microbiome viewed across age and geography. Nature. 2012;486:222–7.

    Article  CAS  Google Scholar 

  40. Pannaraj PS, Li F, Cerini C, et al. Association between breast milk bacterial communities and establishment and development of the infant gut microbiome. JAMA Pediatr. 2017;171:647–54.

    Article  Google Scholar 

  41. Tun HM, Bridgman SL, Chari R, et al. Roles of birth mode and infant gut microbiota in intergenerational transmission of overweight and obesity from mother to offspring. JAMA Pediatr. 2018;172:368–77.

    Article  Google Scholar 

  42. Lundgren SN, Madan JC, Emond JA, Morrison HG, Christensen BC, Karagas MR, et al. Maternal diet during pregnancy is related with the infant stool microbiome in a delivery mode-dependent manner. Microbiome. 2018;6:109.

    Article  Google Scholar 

  43. Cho I, Yamanishi S, Cox L, Methé BA, Zavadil J, Li K, et al. Antibiotics in early life alter the murine colonic microbiome and adiposity. Nature. 2012;488:621–6.

    Article  CAS  Google Scholar 

  44. Cox LM, Yamanishi S, Sohn J, Alekseyenko AV, Leung JM, Cho I, et al. Altering the intestinal microbiota during a critical developmental window has lasting metabolic consequences. Cell. 2014;158:705–21.

    Article  CAS  Google Scholar 

  45. Dawson-Hahn EE, Rhee KE. The association between antibiotics in the first year of life and child growth trajectory. BMC Pediatr. 2019;19:23.

    Article  Google Scholar 

  46. Saari A, Virta LJ, Sankilampi U, Dunkel L, Saxen H. Antibiotic exposure in infancy and risk of being overweight in the first 24 months of life. Pediatrics. 2015;135(4):617–26.

    Article  Google Scholar 

  47. Poulsen MN, Pollak J, Bailey-Davis L, Hirsch AG, Glass TA, Schwartz BS. Associations of prenatal and childhood antibiotic use with child body mass index at age 3 years. Obesity (Silver Spring). 2017;25:438–44.

    Article  CAS  Google Scholar 

  48. Block JP, Bailey LC, Gillman MW, Lunsford D, Daley MF, Eneli I, et al. Early antibiotic exposure and weight outcomes in young children. Pediatrics. 2018;142:e20180290.

    Article  Google Scholar 

  49. Diaz Heijtz R. Fetal, neonatal, and infant microbiome: perturbations and subsequent effects on brain development and behavior. Semin Fetal Neonatal Med. 2016;21:410–7.

    Article  Google Scholar 

  50. Forbes JD, Azad MB, Vehling L, Tun HM, Konya TB, Guttman DS, Canadian Healthy Infant Longitudinal Development (CHILD) Study Investigators, et al. Association of exposure to formula in the hospital and subsequent infant feeding practices with gut microbiota and risk of overweight in the first year of life. JAMA Pediatr. 2018;172:e181161.

    Article  Google Scholar 

  51. Tun HM, Bridgman SL, Chari R, Field CJ, Guttman DS, Becker AB, Canadian Healthy Infant Longitudinal Development (CHILD) Study Investigators, et al. Roles of birth mode and infant gut microbiota in intergenerational transmission of overweight and obesity from mother to offspring. JAMA Pediatr. 2018;172:368–77.

    Article  Google Scholar 

  52. Chelimo C, Camargo CA Jr, Morton SMB, Grant CC. Association of repeated antibiotic exposure up to age 4 years with body mass at age 4.5 years. JAMA Netw Open. 2020;3:e1917577.

    Article  Google Scholar 

  53. Arumugam M, Raes J, Pelletier E, Le Paslier D, Yamada T, Mende DR, et al. Enterotypes of the human gut microbiome. Nature. 2011;473:174–80.

    Article  CAS  Google Scholar 

  54. Santoro A, Ostan R, Candela M, Biagi E, Brigidi P, Capri M, Franceschi C. Gut microbiota changes in the extreme decades of human life: a focus on centenarians. Cell Mol Life Sci. 2018;75:129–48.

    Article  CAS  Google Scholar 

  55. Kumar M, Babaei P, Ji B, Nielsen J. Human gut microbiota and healthy aging: recent developments and future prospective. Nutr Healthy Aging. 2016;4:3–16.

    Article  Google Scholar 

  56. Claesson MJ, Jeffery IB, Conde S, Power SE, O’Connor EM, Cusack S, et al. Gut microbiota composition correlates with diet and health in the elderly. Nature. 2012;488:178–84.

    Article  CAS  Google Scholar 

  57. Odamaki T, Kato K, Sugahara H, Hashikura N, Takahashi S, **ao JZ, et al. Age-related changes in gut microbiota composition from newborn to centenarian: a cross-sectional study. BMC Microbiol. 2016;16:90.

    Article  CAS  Google Scholar 

  58. Kau AL, Ahern PP, Griffin NW, Goodman AL, Gordon JI. Human nutrition, the gut microbiome and the immune system. Nature. 2011;474:327–36.

    Article  CAS  Google Scholar 

  59. Surana NK, Kasper DL. Deciphering the tête-à-tête between the microbiota and the immune system. J Clin Invest. 2014;124:4197–203.

    CAS  Google Scholar 

  60. Wells JM, Brummer RJ, Derrien M, MacDonald TT, Troost F, Cani PD, et al. Homeostasis of the gut barrier and potential biomarkers. Am J Physiol Gastrointest Liver Physiol. 2017;312:G171–93.

    Google Scholar 

  61. Dey N, Wagner VE, Blanton LV, Cheng J, Fontana L, Haque R, et al. Regulators of gut motility revealed by a gnotobiotic model of diet-microbiome interactions related to travel. Cell. 2015;163:95–107.

    CAS  Google Scholar 

  62. Kabouridis PS, Lasrado R, McCallum S, Chng SH, Snippert HJ, Clevers H, et al. The gut microbiota keeps enteric glial cells on the move; prospective roles of the gut epithelium and immune system. Gut Microbes. 2015;6:398–403.

    CAS  Google Scholar 

  63. Savidge TC. Epigenetic regulation of enteric neurotransmission by gut bacteria. Front Cell Neurosci. 2016;9:503.

    Google Scholar 

  64. Turnbaugh PJ, Gordon JI. The core gut microbiome, energy balance and obesity. J Physiol. 2009;587:4153–8.

    CAS  Google Scholar 

  65. Carmody RN, Turnbaugh PJ. Host-microbial interactions in the metabolism of therapeutic and diet-derived xenobiotics. J Clin Invest. 2014;124:4173–81.

    CAS  Google Scholar 

  66. Vonk RJ, Reckman G. Progress in the biology and analysis of short chain fatty acids. J Physiol. 2017;595:419–20.

    CAS  Google Scholar 

  67. Yano JM, Yu K, Donaldson GP, Shastri GG, Ann P, Ma L, et al. Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell. 2015;161:264–76.

    CAS  Google Scholar 

  68. Wilson ID, Nicholson JK. Gut microbiome interactions with drug metabolism, efficacy and toxicity. Transl Res. 2017;179:204–22.

    CAS  Google Scholar 

  69. Shanahan F, van Sinderen D, O’Toole PW, Stanton C. Feeding the microbiota: transducer of nutrient signals for the host. Gut. 2017;66:1709–17.

    CAS  Google Scholar 

  70. Smith MI, Yatsunenko T, Manary MJ, Trehan I, Mkakosya R, Cheng J, et al. Gut microbiomes of Malawian twin pairs discordant for kwashiorkor. Science. 2013;339:548–54.

    CAS  Google Scholar 

  71. Subramanian S, Huq S, Yatsunenko T, Haque R, Mahfuz M, Alam MA, et al. Persistent gut microbiota immaturity in malnourished Bangladeshi children. Nature. 2014;510:417–21.

    CAS  Google Scholar 

  72. Sonnenburg ED, Sonnenburg JL. Starving our microbial self: the deleterious consequences of a diet deficient in microbiota-accessible carbohydrates. Cell Metab. 2014;20:779–86.

    CAS  Google Scholar 

  73. McIntosh K, Reed DE, Schneider T, Dang F, Keshteli AH, De Palma G, et al. FODMAPs alter symptoms and the metabolome of patients with IBS: a randomised controlled trial. Gut. 2017;66(7):1241–51.

    CAS  Google Scholar 

  74. Clarke SF, Murphy EF, O’Sullivan O, Lucey AJ, Humphreys M, Hogan A, et al. Exercise and associated dietary extremes impact on gut microbial diversity. Gut. 2014;63:1913–20.

    CAS  Google Scholar 

  75. Hildebrandt MA, Hoffmann C, Sherrill-Mix SA, Keilbaugh SA, Hamady M, Chen YY, et al. High-fat diet determines the composition of the murine gut microbiome independently of obesity. Gastroenterology. 2009;137:1716–24.

    CAS  Google Scholar 

  76. Heinritz SN, Weiss E, Eklund M, Aumiller T, Louis S, Rings A, et al. Intestinal microbiota and microbial metabolites are changed in a pig model fed a high-fat/low-fiber or a low-fat/high-fiber diet. PLoS One. 2016;11:e0154329.

    Google Scholar 

  77. Kovatcheva-Datchary P, Nilsson A, Akrami R, Lee YS, De Vadder F, Arora T, et al. Dietary fiber-induced improvement in glucose metabolism is associated with increased abundance of Prevotella. Cell Metab. 2015;22:971–82.

    CAS  Google Scholar 

  78. Sonnenburg ED, Smits SA, Tikhonov M, Higginbottom SK, Wingreen NS, Sonnenburg JL. Diet-induced extinctions in the gut microbiota compound over generations. Nature. 2016;529:212–5.

    CAS  Google Scholar 

  79. Degnan PH, Taga ME, Goodman AL. Vitamin B12 as a modulator of gut microbial ecology. Cell Metab. 2014;20:769–78.

    CAS  Google Scholar 

  80. Wu GD, Chen J, Hoffmann C, Bittinger K, Chen YY, Keilbaugh SA, et al. Linking long-term dietary patterns with gut microbial enterotypes. Science. 2011;334:105–8.

    CAS  Google Scholar 

  81. Halmos EP, Christophersen CT, Bird AR, Shepherd SJ, Gibson PR, Muir JG. Diets that differ in their FODMAP content alter the colonic luminal microenvironment. Gut. 2015;64:93–100.

    CAS  Google Scholar 

  82. Bonder MJ, Tigchelaar EF, Cai X, Trynka G, Cenit MC, Hrdlickova B, et al. The influence of a short-term gluten-free diet on the human gut microbiome. Genome Med. 2016;8:45.

    Google Scholar 

  83. David LA, Maurice CF, Carmody RN, Gootenberg DB, Button JE, Wolfe BE, et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature. 2014;505:559–63.

    CAS  Google Scholar 

  84. Luca F, Kupfer SS, Knights D, Khoruts A, Blekhman R. Functional genomics of host-microbiome interactions in humans. Trends Genet. 2017;34:30–40.

    Google Scholar 

  85. Dong TS, Gupta A. Influence of early life, diet, and the environment on the microbiome. Clin Gastroenterol Hepatol. 2019;17(2):231–42.

    Google Scholar 

  86. Mayer EA. Gut feelings: the emerging biology of gut-brain communication. Nat Rev Neurosci. 2011;12:453–66.

    CAS  Google Scholar 

  87. Modi SR, Collins JJ, Relman DA. Antibiotics and the gut microbiota. J Clin Invest. 2014;124:4212–8.

    CAS  Google Scholar 

  88. Blaser MJ. Antibiotic use and its consequences for the normal microbiome. Science. 2016;352:544–5.

    CAS  Google Scholar 

  89. Freedberg DE, Toussaint NC, Chen SP, Ratner AJ, Whittier S, Wang TC, Wang HH, Abrams JA. Proton pump inhibitors alter specific taxa in the human gastrointestinal microbiome: a crossover trial. Gastroenterology. 2015;149:883–5.

    CAS  Google Scholar 

  90. Jackson MA, Goodrich JK, Maxan ME, Freedberg DE, Abrams JA, Poole AC, et al. Proton pump inhibitors alter the composition of the gut microbiota. Gut. 2016;65:749–56.

    Google Scholar 

  91. Forslund K, Hildebrand F, Nielsen T, Falony G, Le Chatelier E, Sunagawa S, et al. Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature. 2015;528:262–6.

    CAS  Google Scholar 

  92. Quigley EMM. Gut microbiome as a clinical tool in gastrointestinal disease management: are we there yet? Nat Rev Gastroenterol Hepatol. 2017;14:315–20.

    Google Scholar 

  93. Hoefert B. Über die Bakterienbefunde im Duodenalsaft von Gesunden und Kranken. Zschr Klin Med. 1921;92:221–35.

    Google Scholar 

  94. Shah A, Shanahan E, Macdonald GA, Fletcher L, Ghasemi P, Morrison M, et al. Systematic review and meta-analysis: prevalence of small intestinal bacterial overgrowth in chronic liver disease. Semin Liver Dis. 2017;37:388–400.

    Google Scholar 

  95. Maslennikov R, Pavlov C, Ivashkin V. Small intestinal bacterial overgrowth in cirrhosis: systematic review and meta-analysis. Hepatol Int. 2018;12:567–76.

    Google Scholar 

  96. Augustyn M, Grys I, Kukla M. Small intestinal bacterial overgrowth and nonalcoholic fatty liver disease. Clin Exp Hepatol. 2019;5:1–10.

    Google Scholar 

  97. Ghosh G, Jesudian AB. Small intestinal bacterial overgrowth in patients with cirrhosis. J Clin Exp Hepatol. 2019;9:257–67.

    Google Scholar 

  98. Liu Chen Kiow J, Vincent C, Sidani S, Bouin M. High occurrence of small intestinal bacterial overgrowth in primary biliary cholangitis. Neurogastroenterol Motil. 2019;31:e13691.

    Google Scholar 

  99. Wijarnpreecha K, Lou S, Watthanasuntorn K, Kroner PT, Cheungpasitporn W, Lukens FJ, et al. Small intestinal bacterial overgrowth and nonalcoholic fatty liver disease: a systematic review and meta-analysis. Eur J Gastroenterol Hepatol. 2020;32(5):601–8.

    Google Scholar 

  100. Bode C, Kolepke R, Schafer K, Bode JC. Breath hydrogen excretion in patients with alcoholic liver disease–evidence of small intestinal bacterial overgrowth. Z Gastroenterol. 1993;31:3–7.

    CAS  Google Scholar 

  101. Teltschik Z, Wiest R, Beisner J, Nuding S, Hofmann C, Schoelmerich J, et al. Intestinal bacterial translocation in rats with cirrhosis is related to compromised Paneth cell antimicrobial host defense. Hepatology. 2012;55:1154–63.

    Article  Google Scholar 

  102. Purohit V, Bode JC, Bode C, Brenner DA, Choudhry MA, Hamilton F, et al. Alcohol, intestinal bacterial growth, intestinal permeability to endotoxin, and medical consequences: summary of a symposium. Alcohol. 2008;42:349–61.

    Article  CAS  Google Scholar 

  103. Bajaj JS. Alcohol, liver disease and the gut microbiota. Nat Rev Gastroenterol Hepatol. 2019;16:235–46.

    Article  Google Scholar 

  104. Wigg AJ, Roberts-Thomson IC, Dymock RB, McCarthy PJ, Grose RH, Cumming AG. The role of small intestinal bacterial overgrowth, intestinal permeability, endotoxemia, and tumor necrosis factor alpha in the pathogenesis of nonalcoholic steatohepatitis. Gut. 2001;48:206–11.

    Article  CAS  Google Scholar 

  105. Abu Shanab A, Scully P, Crosbie O, Buckley M, O’Mahony L, Shanahan F, et al. Small intestinal bacterial overgrowth in non-alcoholic steato-hepatitis; association with toll-like receptor 4 expression and plasma levels of interleukin 8. Dig Dis Sci. 2011;56:1524–34.

    Article  CAS  Google Scholar 

  106. Kolodziejczyk AA, Zheng D, Shibolet O, Elinav E. The role of the microbiome in NAFLD and NASH. EMBO Mol Med. 2019;11:pii: e9302.

    Article  CAS  Google Scholar 

  107. Vanderhoof JA, Tuma DJ, Antonson DL, Sorrell MF. Effect of antibiotics in the prevention of jejunoileal bypass-induced liver dysfunction. Digestion. 1982;23:9–15.

    Article  CAS  Google Scholar 

  108. Quigley EMM. The spectrum of small intestinal bacterial overgrowth (SIBO). Curr Gastroenterol Rep. 2019;21:3.

    Article  Google Scholar 

  109. Kastl AJ Jr, Terry NA, Albenberg LG, Wu GD. The structure and function of the human small intestinal microbiota: current understanding and future directions. Cell Mol Gastroenterol Hepatol. 2020;9:33–45.

    Article  Google Scholar 

  110. Quigley EMM. Symptoms and the small intestinal microbiome – the unknown explored. Nat Rev Gastroenterol Hepatol. 2019;16:457–8.

    CAS  Google Scholar 

  111. Bajaj JS, Hylemon PB, Ridlon JM, Heuman DM, Daita K, White MB, 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. 2012;303:G675–85.

    CAS  Google Scholar 

  112. Chen Y, Yang F, Lu H, Wang B, Chen Y, Lei D, Wang Y, Zhu B, Li L. Characterization of fecal microbial communities in patients with liver cirrhosis. Hepatology. 2011;54:562–72.

    Google Scholar 

  113. Bajaj JS, Ridlon JM, Hylemon PB, Thacker LR, Heuman DM, Smith S, et al. Linkage of gut microbiome with cognition in hepatic encephalopathy. Am J Physiol Gastrointest Liver Physiol. 2012;302:G168–75.

    CAS  Google Scholar 

  114. Lu H, Wu Z, Xu W, Yang J, Chen Y, Li L. Intestinal microbiota was assessed in cirrhotic patients with hepatitis B virus infection. Intestinal microbiota of HBV cirrhotic patients. Microb Ecol. 2011;61:693–703.

    Google Scholar 

  115. Liu J, Wu D, Ahmed A, Li X, Ma Y, Tang L, Mo D, Ma Y, **n Y. Comparison of the gut microbe profiles and numbers between patients with liver cirrhosis and healthy individuals. Curr Microbiol. 2012;65:7–13.

    CAS  Google Scholar 

  116. Machado MV, Cortez-Pinto H. Gut microbiota and nonalcoholic fatty liver disease. Ann Hepatol. 2012;11:440–9.

    CAS  Google Scholar 

  117. Chen X, Devaraj S. Gut microbiome in obesity, metabolic syndrome, and diabetes. Curr Diab Rep. 2018;18:129.

    CAS  Google Scholar 

  118. Cani PD. Microbiota and metabolites in metabolic diseases. Nat Rev Endocrinol. 2019;15:69–70.

    CAS  Google Scholar 

  119. Canfora EE, Meex RCR, Venema K, Blaak EE. Gut microbial metabolites in obesity, NAFLD and T2DM. Nat Rev Endocrinol. 2019;15:261–73.

    CAS  Google Scholar 

  120. Greenblum S, Turnbaugh PJ, Borenstein E. Metagenomic systems biology of the human gut microbiome reveals topological shifts associated with obesity and inflammatory bowel disease. PNAS. 2012;109:594–9.

    CAS  Google Scholar 

  121. Karlsson FH, Tremaroli V, Nookaew I, Bergström G, Behre CJ, Fagerberg B, et al. Gut metagenome in European women with normal, impaired and diabetic glucose control. Nature. 2013;498:99–103.

    CAS  Google Scholar 

  122. Zupancic ML, Cantarel BL, Liu Z, Drabek EF, Ryan KA, Cirimotich S, et al. Analysis of the gut microbiota in the old order Amish and its relation to the metabolic syndrome. PLoS One. 2012;7:e43052.

    CAS  Google Scholar 

  123. Penas-Steinhardt A, Barcos LS, Belforte FS, de Sereday M, Vilarino J, Gonzalez CD, et al. Functional characterization of TLR4 +3725G/C polymorphism and association with protection against overweight. PLoS One. 2012;7:e50992.

    CAS  Google Scholar 

  124. Kim K-A, Gu W, Lee I-A, Joh E-H, Kim D-H. High fat diet-induced gut microbiota exacerbates inflammation and obesity in mice via the TLR4 signaling pathway. PLoS One. 2012;7:347713.

    Google Scholar 

  125. Vijay-Kumar M, Aitken JD, Carvalho FA, Cullender TC, Mwangi S, Srinivasan S, et al. Metabolic syndrome and altered gut microbiota in mice lacking toll-like receptor 5. Science. 2010;328:228–31.

    CAS  Google Scholar 

  126. Fei N, Bruneau A, Zhang X, Wang R, Wang J, Rabot S, et al. Endotoxin producers overgrowing in human gut microbiota as the causative agents for nonalcoholic fatty liver disease. mBio. 2020;11:pii: e03263-19.

    Google Scholar 

  127. Schwimmer JB, Johnson JS, Angeles JE, Behling C, Belt PH, Borecki I, et al. Microbiome signatures associated with steatohepatitis and moderate to severe fibrosis in children with nonalcoholic fatty liver disease. Gastroenterology. 2019;157:1109–22.

    CAS  Google Scholar 

  128. Henao-Mejia J, Elinav E, ** C, Hao L, Mehal WZ, Strowig T, et al. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature. 2012;482:179–85.

    CAS  Google Scholar 

  129. Tilg H, Moschen AR, Szabo G. Interleukin-1 and inflammasomes in alcoholic liver disease/acute alcoholic hepatitis and nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Hepatology. 2016;64:955–65.

    CAS  Google Scholar 

  130. Meroni M, Longo M, Dongiovanni P. Alcohol or gut microbiota: who is the guilty? Int J Mol Sci. 2019;20:pii: E4568.

    Google Scholar 

  131. Yuan J, Chen C, Cui J, Lu J, Yan C, Wei X, et al. Fatty liver disease caused by high-alcohol-producing Klebsiella pneumoniae. Cell Metab. 2019;30:675–88.

    Article  CAS  Google Scholar 

  132. Zhu Y, Li F, Guo GL. Tissue-specific function of farnesoid X receptor in liver and intestine. Pharmacol Res. 2011;63:259–65.

    Article  CAS  Google Scholar 

  133. Porez G, Prawitt J, Gross B, et al. Bile acid receptors as targets for the treatment of dyslipidemia and cardiovascular disease. J Lipid Res. 2012;53:1723–37.

    Article  CAS  Google Scholar 

  134. Auwerx J, Messaddeq N, Sato H, Kodama T, Watanabe M, Ezaki O, et al. Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature. 2006;439(7075):484–9.

    Article  CAS  Google Scholar 

  135. Zhang Y, Lee FY, Lee H, Barrera G, Vales C, Gonzalez FJ, et al. Activation of the nuclear receptor FXR improves hyperglycemia and hyperlipidemia in diabetic mice. Proc Natl Acad Sci. 2006;103(4):1006–11.

    Article  CAS  Google Scholar 

  136. Sorribas M, Jakob MO, Yilmaz B, Li H, Stutz D, Noser Y, et al. FXR modulates the gut-vascular barrier by regulating the entry sites for bacterial translocation in experimental cirrhosis. J Hepatol. 2019;71:1126–40.

    Article  CAS  Google Scholar 

  137. Long SL, Gahan CGM, Joyce SA. Interactions between gut bacteria and bile in health and disease. Mol Asp Med. 2017;56:54–65.

    Article  CAS  Google Scholar 

  138. Jia W, **e G, Jia W. Bile acid-microbiota crosstalk in gastrointestinal inflammation and carcinogenesis. Nat Rev Gastroenterol Hepatol. 2018;15:111–28.

    Article  CAS  Google Scholar 

  139. Chen ML, Takeda K, Sundrud MS. Emerging roles of bile acids in mucosal immunity and inflammation. Mucosal Immunol. 2019;12:851–61.

    Article  CAS  Google Scholar 

  140. Thanissery R, Winston JA, Theriot CM. Inhibition of spore germination, growth, and toxin activity of clinically relevant C. difficile strains by gut microbiota derived secondary bile acids. Anaerobe. 2017;45:86–100.

    Article  CAS  Google Scholar 

  141. Jones BV, Begley M, Hill C, Gahan CG, Marchesi JR. Functional and comparative metagenomic analysis of bile salt hydrolase activity in the human gut microbiome. Proc Natl Acad Sci U S A. 2008;105:13580–5.

    Article  CAS  Google Scholar 

  142. Vetrano S, Rescigno M, Cera MR, et al. Unique role of junctional adhesion molecule-a in maintaining mucosal homeostasis in inflammatory bowel disease. Gastroenterology. 2008;135:173–84.

    CAS  Google Scholar 

  143. Gunzel D, Yu AS. Claudins and the modulation of tight junction permeability. Physiol Rev. 2013;93:525–69.

    Google Scholar 

  144. Takiishi T, Fenero CIM, Câmara NOS. Intestinal barrier and gut microbiota: sha** our immune responses throughout life. Tissue Barriers. 2017;5:e1373208.

    Google Scholar 

  145. Camilleri M. Leaky gut: mechanisms, measurement and clinical implications in humans. Gut. 2019;68:1516–26.

    CAS  Google Scholar 

  146. Blaschitz C, Raffatellu M. Th17 cytokines and the gut mucosal barrier. J Clin Immunol. 2010;30:196–203.

    CAS  Google Scholar 

  147. Pontarollo G, Mann A, Brandão I, Malinarich F, Schöpf M, Reinhardt C. Protease-activated receptor signaling in intestinal permeability regulation. FEBS J. 2020;287(4):645–58.

    CAS  Google Scholar 

  148. Nicoletti A, Ponziani FR, Biolato M, Valenza V, Marrone G, Sgagna G, et al. Intestinal permeability in the pathogenesis of liver damage: from non-alcoholic fatty liver disease to liver transplantation. World J Gastroenterol. 2019;25:4814–34.

    CAS  Google Scholar 

  149. Munford RS. Endotoxemia-menace, marker, or mistake? J Leukoc Biol. 2016;100:687–98.

    CAS  Google Scholar 

  150. Quigley E. Leaky gut – concept or clinical entity? Curr Opin Gastroenterol. 2016;32:74–9.

    Google Scholar 

  151. Glassner KL, Abraham BP, Quigley EMM. The microbiome and inflammatory bowel disease. J Allergy Clin Immunol. 2020;145:16–27.

    Article  CAS  Google Scholar 

  152. Spadoni I, Zagato E, Bertocchi A, Paolinelli R, Hot E, Di Sabatino A, et al. A gut-vascular barrier controls the systemic dissemination of bacteria. Science. 2015;350:830–4.

    CAS  Google Scholar 

  153. Bouziat R, Jabri B. IMMUNOLOGY. Breaching the gut-vascular barrier. Science. 2015;350(6262):742–3.

    Article  CAS  Google Scholar 

  154. Cheng C, Tan J, Qian W, Zhang L, Hou X. Gut inflammation exacerbates hepatic injury in the high-fat diet induced NAFLD mouse: attention to the gut-vascular barrier dysfunction. Life Sci. 2018;209:157–66.

    Article  CAS  Google Scholar 

  155. Huang J, Kelly CP, Bakirtzi K, Villafuerte Gálvez JA, Lyras D, Mileto SJ, et al. Clostridium difficile toxins induce VEGF-A and vascular permeability to promote disease pathogenesis. Nat Microbiol. 2019;4:269–79.

    Article  CAS  Google Scholar 

  156. Mouries J, Brescia P, Silvestri A, Spadoni I, Sorribas M, Wiest R, et al. Microbiota-driven gut vascular barrier disruption is a prerequisite for non-alcoholic steatohepatitis development. J Hepatol. 2019;71:1216–28.

    Article  CAS  Google Scholar 

  157. Liu P, Bian Y, Fan Y, Zhong J, Liu Z. Protective effect of naringin on in vitro gut-vascular barrier disruption of intestinal microvascular endothelial cells induced by TNF-α. J Agric Food Chem. 2020;68:168–75.

    Article  CAS  Google Scholar 

  158. Miyake Y, Yamammoto K. Role of gut microbiota in liver diseases. Hepatol Res. 2013;43:139–46.

    Article  CAS  Google Scholar 

  159. Chassaing B, Etienne-Mesmin L, Gewirtz AT. Microbiota-liver axis in hepatic disease. Hepatology. 2014;59(1):328–39.

    Article  CAS  Google Scholar 

  160. Seki E, Schnabl B. Role of innate immunity and the microbiota in liver fibrosis: crosstalk between the liver and gut. J Physiol. 2012;590:447–58.

    Article  CAS  Google Scholar 

  161. Crispe IN. The liver as a lymphoid organ. Annu Rev Immunol. 2009;27:147–63.

    Article  CAS  Google Scholar 

  162. Seo YS, Shah VH. The role of gut liver axis in the pathogenesis of liver cirrhosis and portal hypertension. Clin Mol Hepatol. 2012;18:337–46.

    Article  Google Scholar 

  163. Catala M, Anton A, Portoles MT. Characterization of the simultaneous binding of Escherichia coli endotoxin to Kupffer and endothelial liver cells by flow cytometry. Cytometry. 1999;36:123–30.

    Article  CAS  Google Scholar 

  164. Deng M, Scott MJ, Loughran P, Gibson G, Sodhi C, Watkins S, et al. Lipopolysaccharide clearance, bacterial clearance, and systemic inflammatory responses are regulated by cell type-specific functions of TLR4 during sepsis. J Immunol. 2013;190:5152–60.

    Article  CAS  Google Scholar 

  165. Hoque R, Vodovotz Y, Mehal W. Therapeutic strategies in inflammasome mediated diseases of the liver. J Hepatol. 2013;58:1047–52.

    Article  CAS  Google Scholar 

  166. Patel M, Watson AJM, Rushbrook S. A mechanistic insight into the role of gut microbiota in the pathogenesis of primary sclerosing cholangitis. Gastroenterology. 2019;157:1686–8.

    Article  Google Scholar 

  167. Pastor Rojo O, Lopez San Roman A, Albeniz Arbizu E, et al. Serum lipopolysaccharide–binding protein in endotoxemic patients with inflammatory bowel disease. Inflamm Bowel Dis. 2007;13:269–77.

    Article  Google Scholar 

  168. Terjung B, Spengler U. Atypical p-ANCA in PSC and AIH: a hint toward a “leaky gut”? Clin Rev Allergy Immunol. 2009;36:40–51.

    Article  CAS  Google Scholar 

  169. Terjung B, Söhne J, Lechtenberg B, Gottwein J, Muennich M, Herzog V, et al. p-ANCAs in autoimmune liver disorders recognise human beta-tubulin isotype 5 and cross-react with microbial protein FtsZ. Gut. 2010;59:808–16.

    Article  CAS  Google Scholar 

  170. Terziroli Beretta-Piccoli B, Mieli-Vergani G, Vergani D, Vierling JM, Adams D, Alpini G, et al. The challenges of primary biliary cholangitis: what is new and what needs to be done. J Autoimmun. 2019;105:102328.

    Article  Google Scholar 

  171. Wang AP, Migita K, Ito M, et al. Hepatic expression of toll–like receptor 4 in primary biliary cirrhosis. J Autoimmun. 2005;25:85–91.

    Article  CAS  Google Scholar 

  172. Hopf U, Möller B, Stemerowicz R, et al. Relation between Escherichia coli R (rough)-forms in gut, lipid A in liver, and primary biliary cirrhosis. Lancet. 1989;2:1419–22.

    Article  CAS  Google Scholar 

  173. Bogdanos DP, Baum H, Grasso A, et al. Microbial mimics are major targets of crossreactivity with human pyruvate dehydrogenase in primary biliary cirrhosis. J Hepatol. 2004;40:31–9.

    Article  CAS  Google Scholar 

  174. Bogdanos DP, Baum H, Okamoto M, et al. Primary biliary cirrhosis is characterized by IgG3 antibodies cross-reactive with the major mitochondrial autoepitope and its Lactobacillus mimic. Hepatology. 2005;42:458–65.

    Article  CAS  Google Scholar 

  175. Schwabe RF, Greten TF. Gut microbiome in HCC. J Hepatol. 2020;72:230–8.

    CAS  Google Scholar 

  176. Fox JG, Feng Y, Theve EJ, Raczynski AR, Fiala JL, Doernte AL, et al. Gut microbes define liver cancer risk in mice exposed to chemical and viral transgenic heptocarcinogenesis. Gut. 2010;59:88–97.

    CAS  Google Scholar 

  177. Yoshimoto S, Loo TM, Atarashi K, Kanda H, Sato S, Oyadomari S, et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature. 2013;499:97–101.

    CAS  Google Scholar 

  178. Bindels IB, Porporato P, Dewulf EM, Verrax J, Neyrinck AM, Martin JC, et al. Gut microbiota-derives propionate reduces cancer cell proliferation in the liver. Br J Cancer. 2012;107:1337–44.

    CAS  Google Scholar 

  179. Ponziani FR, Bhoori S, Castelli C, Putignani L, Rivoltini L, Del Chierico F, et al. Hepatocellular carcinoma is associated with gut microbiota profile and inflammation in nonalcoholic fatty liver disease. Hepatology. 2019;69:107–20.

    CAS  Google Scholar 

  180. Ponziani FR, Nicoletti A, Gasbarrini A, Pompili M. Diagnostic and therapeutic potential of the gut microbiota in patients with early hepatocellular carcinoma. Ther Adv Med Oncol. 2019;11:1758835919848184.

    CAS  Google Scholar 

  181. Orci LA, Lacotte S, Delaune V, Slits F, Oldani G, Lazarevic V, et al. Effects of the gut-liver axis on ischaemia-mediated hepatocellular carcinoma recurrence in the mouse liver. J Hepatol. 2018;68:978–85.

    CAS  Google Scholar 

  182. Li B, Selmi C, Tang R, Gershwin ME, Ma X. The microbiome and autoimmunity: a paradigm from the gut-liver axis. Cell Mol Immunol. 2018;15:595–609.

    Google Scholar 

  183. Ma HD, Zhao ZB, Ma WT, Liu QZ, Gao CY, Li L, et al. Gut microbiota translocation promotes autoimmune cholangitis. J Autoimmun. 2018;95:47–57.

    CAS  Google Scholar 

  184. Denton C, Price A, Friend J, Manithody C, Blomenkamp K, Westrich M, et al. Role of the gut-liver axis in driving parenteral nutrition-associated injury. Children (Basel). 2018;5:pii: E136.

    Google Scholar 

  185. Kummen M, Hov JR. The gut microbial influence on cholestatic liver disease. Liver Int. 2019;39:1186–96.

    Google Scholar 

  186. Wei Y, Li Y, Yan L, Sun C, Miao Q, Wang Q, et al. Alterations of gut microbiome in autoimmune hepatitis. Gut. 2020;69:569–77.

    Article  CAS  Google Scholar 

  187. Szabo G. Gut-liver axis beyond the microbiome: how the fungal mycobiome contributes to alcoholic liver disease. Hepatology. 2018;68:2426–8.

    Article  Google Scholar 

  188. Bolte FJ, Rehermann B. Mucosal-invariant T cells in chronic inflammatory liver disease. Semin Liver Dis. 2018;38:60–5.

    Article  CAS  Google Scholar 

  189. Marrero I, Maricic I, Feldstein AE, Loomba R, Schnabl B, Rivera-Nieves J, et al. Complex network of NKT cell subsets controls immune homeostasis in liver and gut. Front Immunol. 2018;9:2082.

    Article  CAS  Google Scholar 

  190. Biolato M, Manca F, Marrone G, Cefalo C, Racco S, Miggiano GA, et al. Intestinal permeability after Mediterranean diet and low-fat diet in non-alcoholic fatty liver disease. World J Gastroenterol. 2019;25:509–20.

    Article  CAS  Google Scholar 

  191. Nakamura K, Kageyama S, Ito T, Hirao H, Kadono K, Aziz A, et al. Antibiotic pretreatment alleviates liver transplant damage in mice and humans. J Clin Invest. 2019;129:3420–34.

    Article  Google Scholar 

  192. Bajaj JS, Hays RA. Manipulation of the gut-liver axis using microbiome restoration therapy in primary sclerosing cholangitis. Am J Gastroenterol. 2019;114:1027–9.

    Article  Google Scholar 

  193. Liu R, Kang JD, Sartor RB, Sikaroodi M, Fagan A, Gavis EA, et al. Neuroinflammation in murine cirrhosis is dependent on the gut microbiome and is attenuated by fecal transplant. Hepatology. 2020;71(2):611–26.

    Article  CAS  Google Scholar 

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Acknowledgments

To Conor McGrann for develo** Figs. 8.1 and 8.3.

Dr. Quigley is supported in part by a bequest from the Hughes Sterling Foundation and by the Underwood Center for Digestive Disorders.

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  1. Lynda K. and David M. Underwood Center for Digestive Disorders, Houston Methodist Hospital and Weill Cornell Medical College, Houston, TX, USA

    Eamonn M. M. Quigley

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  1. Division of Rheumatology, Allergy and Clinical Immunology, The University of California School of Medicine, Davis, CA, USA

    M. Eric Gershwin

  2. Departments of Medicine and Surgery, Baylor College of Medicine, Houston, TX, USA

    John M. Vierling

  3. Department of Medicine, Teikyo University School of Medicine, Itabashi, Tokyo, Japan

    Atsushi Tanaka

  4. President, Hannover Medical School, Hannover, Germany

    Michael P. Manns

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Quigley, E.M.M. (2020). The Microbiota-Gut-Liver Axis: Implications for the Pathophysiology of Liver Disease. In: Gershwin, M.E., M. Vierling, J., Tanaka, A., P. Manns, M. (eds) Liver Immunology . Springer, Cham. https://doi.org/10.1007/978-3-030-51709-0_8

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