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Autoimmune liver disease and the enteric microbiome

1 Lynda K and David M Underwood Center for Digestive Disorders, Division of Gastroenterology and Hepatology, Houston Methodist Hospital, Weill Cornell Medical College, 6550 Fannin Street, SM 1201, Houston, TX 77030, USA
2 Sherrie and Alan Conover Center for Liver Disease, Houston Methodist Hospital, Weill Cornell Medical College, 6550 Fannin Street, SM 1201, Houston, TX 77030, USA

Topical Section: Gut bacteria in human health and diseases

The human enteric microbiome is highly complex and has more than 150 times more genes within it than its host. The host and the microbiome have a commensurate relationship that can evolve over time. The typically symbiotic relationship between the two can become pathogenic. The microbiome composition in adults reflects their history of exposure to bacteria and environmental factors during early life, their genetic background, age, interactions with the immune system, geographical location, and, most especially, their diet. Similarly, these factors are thought to contribute to the development of autoimmune disease. It is possible that alterations in the intestinal microbiome could lead to liver disease. There is emerging data for the contribution of the microbiome in development of primary sclerosing cholangitis, primary biliary cholangitis, and autoimmune hepatitis; liver disorders associated with aberrant immune function in genetically susceptible individuals.
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Keywords primary sclerosing cholangitis; primary biliary cholangitis; autoimmune hepatitis; microbiome; PSC; PBC

Citation: Kerri Glassner, Eamonn MM Quigley, Lissa Franco, David W Victor III. Autoimmune liver disease and the enteric microbiome. AIMS Microbiology, 2018, 4(2): 334-346. doi: 10.3934/microbiol.2018.2.334


  • 1. Huttenhower C, Gevers D, Knight R, et al. (2012) Structure, function and diversity of the healthy human microbiome. Nature 486: 207–214.    
  • 2. Backhed F (2011) Programming of host metabolism by the gut microbiota. Ann Nutr Metab 58: 44–52.    
  • 3. Cani P, Everard A (2015) Talking microbes: when gut bacteria interact with diet and host organs. Mol Nutr Food Res 60: 58–66.
  • 4. Cotillard A, Kennedy S, Kong L, et al. (2013) Dietary intervention impact on gut microbial gene richness. Nature 500: 585–588.    
  • 5. Wu G, Compher C, Chen E, et al. (2014) Comparative metabolomics in vegans and omnivores reveal constraints on diet-dependent gut microbiota metabolite production. Gut 65: 63–72.
  • 6. Lim M, Rho M, Song Y, et al. (2014) Stability of gut enterotypes in korean monozygotic twins and their association with biomarkers and diet. Sci Rep 4: 7348.
  • 7. Org E, Parks B, Joo J, et al. (2015) Genetic and environmental control of host-gut microbiota interactions. Genome Res 25: 1558–1569.    
  • 8. Tilg H, Cani P, Mayer E, et al. (2016) Gut microbiome and liver diseases. Gut 65: 2035–2044.    
  • 9. Tabibian J, Varghese C, LaRusso N, et al. (2015) The enteric microbiome in hepatobiliary health and disease. Liver Int 36: 480–487.
  • 10. Lazaridis K, LaRusso N (2016) Primary sclerosing cholangitis. New Engl J Med 375: 2500–2502.    
  • 11. Trivedi P, Adams D (2016) Gut-liver immunity. J Hepatol 64: 1187–1189.    
  • 12. Kummen M, Holm K, Anmarkrud J, et al. (2016) 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.
  • 13. Bajer L, Kverka M, Kostovcik M, et al. (2017) Distinct gut microbiota profiles in patients with primary sclerosing cholangitis and ulcerative colitis. World J Gastroentero 23: 4548.    
  • 14. Sabino J, Vieira-Silva S, Machiels K, et al. (2016) Primary sclerosing cholangitis is characterised by intestinal dysbiosis independent from IBD. Gut 65: 1681–1689.    
  • 15. Tabibian J, O-Hara S, Trussoni C, et al. (2015) Absence of the intestinal microbiota exacerbates hepatobiliary disease in a murine model of primary sclerosing cholangitis. Hepatology 63: 185–196.
  • 16. Tabibian J, O'Hara S, Splinter P, et al. (2014) Cholangiocyte senescence by way of n-ras activation is a characteristic of primary sclerosing choalngitis. Hepatology 59: 2263–2275.    
  • 17. Tabibian J, O'Hara S, Lindor K (2014) Primary sclerosing cholangitis and the microbiota: current knowledge and perspectives on etiopathogenesis and emerging therapies. Scand J Gastroentero 49: 901–908.
  • 18. Eaton J, Juran B, Atkinson E, et al. (2015) A comprehensive assessment of environmental exposures among 1000 north american patients with primary sclerosing cholangitis, with and without inflammatory bowel disease. Aliment Pharm Therap 41: 980–990.    
  • 19. Lichtman S, Keku J, Schwab J, et al. (1991) Hepatic injury associated with small bowel bacterial overgrowth in rats is prevented by metronidazole and tetracycline. Gastroenterology 100: 513–519.    
  • 20. Tabibian J, Talwalkar J, Lindor K (2013) Role of the microbiota and antibiotics in primary sclerosing cholangitis. Biomed Res Int 2013: 1–7.
  • 21. Tabibian J, Weeding E, Jorgensen R, et al. (2013) Randomised clinical trial: vancomycin or metronidazole in patients with primary sclerosing cholangitis-a pilot study. Aliment Pharm Therap 37: 604–612.    
  • 22. Mistilis S, Skyring A, Goulston S (1965) Effect of long-term tetracycline therapy, steroid therapy and colectomy in pericholangitis associated with ulcerative colitis. Australas Ann Med 14: 286–294.    
  • 23. Färkkilä M, Karvonen A, Nurmi H, et al. (2004) Metronidazole and ursodeoxycholic acid for primary sclerosing cholangitis: a randomized placebo-controlled trial. Hepatology 40: 1379–1386.    
  • 24. Silveira M, Torok N, Gossard A, et al. (2009) Minocycline in the treatment of patients with primary sclerosing cholangitis: results of a pilot study. Am J Gastroenterol 104: 83–88.    
  • 25. Rankin J, Sydney M, Boden R, et al. (1959) The liver in ulcerative colitis; treatment of pericholangitis with tetracycline. Lancet 274: 1110–1112.    
  • 26. Mathew K (1983) Metronidazole in primary cholangitis. J Indian Med Assoc 80: 31–33.
  • 27. Kozaiwa K, Tajiri H, Sawada A, et al. (1998) Case report: three paediatric cases of primary sclerosing cholangitis treated with ursodeoxycholic acid and sulphasalazine. J Gastroen Hepatol 13: 825–829.    
  • 28. Cox KL, Cox KM (1998) Oral vancomycin: treatment of primary sclerosing cholangitis in children with inflammatory bowel disease. J Pediatr Gastr Nutr 27: 580–583.    
  • 29. Broccoletti T, Ciccimarra E, Spaziano M, et al. (2002) Refractory primary sclerosing cholangitis becoming responsive after sulphasalazine treatment of an underlying silent colitis. Ital J Pediatr 28: 515–517.
  • 30. Tada S, Ebinuma H, Saito H, et al. (2006) Therapeutic benefit of sulfasalazine for patients with primary sclerosing cholangitis. J Gastroenterol 41: 388–389.    
  • 31. Boner A, Peroni D, Bodini A, et al. (2007) Azithromycin may reduce cholestasis in primary sclerosing cholangitis: a case report and serendipitous observation. Int J Immunopath Ph 20: 847–849.    
  • 32. Davies Y, Cox K, Abdullah B, et al. (2008) Long-term treatment of primary sclerosing cholangitis in children with oral vancomycin: an immunomodulating antibiotic. J Pediatr Gastr Nutr 47: 61–67.    
  • 33. Pohl J, Ring A, Stremmel W, et al. (2006) The role of dominant stenoses in bacterial infections of bile ducts in primary sclerosing cholangitis. Eur J Gastroen Hepat 18: 69–74.    
  • 34. Hiramatsu K, Harada K, Tsuneyama K, et al. (2000) Amplification and sequence analysis of partial bacterial 16S ribosomal RNA gene in gallbladder bile from patients with primary biliary cirrhosis. J Hepatol 33: 9–18.    
  • 35. Olsson R, Bjornsson E, Backman L, et al. (1998) Bile duct bacterial isolates in primary sclerosing cholangitis: a study of explanted livers. J Hepatol 28: 426–432.    
  • 36. Sasatomi K, Noguchi K, Sakisaka S (1998) Abnormal accumulation of endotoxin in biliary epithelial cells in primary biliary cirrhosis and primary sclerosing cholangitis. J Hepatol 29: 409–416.    
  • 37. Vleggaar F, Monkelbaan J, Van Erpecum K (2008) Probiotics in primary sclerosing cholangitis: a randomized placebo-controlled crossover pilot study. Eur J Gastroen Hepat 20: 688–692.    
  • 38. Allegretti J, Kassam Z, Carrellas M, et al. (2017) Fecal microbiota transplantation improves microbiome diversity and liver enzyme profile in primary sclerosing cholangitis. World Congress of Gastroenterology at ACG2017 Meeting Abstracts.
  • 39. David L, Maurice C, Carmody R, et al (2013) Diet rapidly and reproducibly alters the human gut microbiome. Nature 505: 559–563.
  • 40. Andersen I, Tengesdal G, Lie B, et al. (2014) Effects of coffee consumption, smoking, and hormones on risk for primary sclerosing cholangitis. Clin Gastroenterol H 12: 1019–1028.    
  • 41. Lammert C, Juran B, Schlicht E, et al. (2014) Reduced coffee consumption among individuals with primary sclerosing cholangitis but not primary biliary cirrhosis. Clin Gastroenterol H 12: 1562–1568.    
  • 42. Torres J, Palmela C, Bao X, et al. (2016) The gut microbiota in primary sclerosing cholangitis and inflammatory bowel disease: correlations with disease and diet. Microbiology 150: S583–S584.
  • 43. Boonstra K, Beuers U, Ponsioen C (2012) Epidemiology of primary sclerosing cholangitis and primary biliary cirrhosis: a systematic review. J Hepatol 56: 1181–1188.    
  • 44. Dyson J, Hirschfield G, Adams D, et al. (2015) Novel therapeutic targets in primary biliary cirrhosis. Nat Rev Gastro Hepat 12: 147–158.    
  • 45. Mattner J (2016) Impact of microbes on the pathogenesis of primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). Int J Mol Sci 17: 1864.    
  • 46. Kaplan M, Gershwin E (2005) Primary biliary cirrhosis. New Engl J Med 353: 1261–1273.    
  • 47. Selmi C, Bowlus C, Gershwin E, et al. (2011) Primary biliary cirrhosis. Lancet 377: 1600–1609.    
  • 48. Chassaing B, Etienne-Mesmin L, Bonnet R, et al. (2013) Bile salts induce long polar fimbriae expression favouring crohn's disease-associated adherent-invasive escherichia coli interaction with peyer's patches. Environ Microbiol 15: 355–371.    
  • 49. Kakiyama G, Pandak W, Gillevet P, et al. (2013) Modulation of the fecal bile acid profile by gut microbiota in cirrhosis. J Hepatol 58: 949–955.    
  • 50. Lv L, Fang D, Shi D, et al. (2016) Alterations and correlations of the gut microbiome, metabolism and immunity in patients with primary biliary cirrhosis. Environ Microbiol 18: 2272–2286.    
  • 51. Sasatomi K, Noguchi K, Sakisaka S, et al. (1998) Abnormal accumulation of endotoxin in biliary epithelial cells in primary biliary cirrhosis and primary sclerosing cholangitis. J Hepatol 29: 409–416.    
  • 52. Maldonado R, Sa-Correia I, Valvano M (2016) Lipopolysaccharide modification in gram-negative bacteria during chronic infection. FEMS Microbiol Rev 40: 480–493.    
  • 53. Wang A, Migita K, Ito M, et al. (2005) Hepatic expression of toll-like receptor 4 in primary biliary cirrhosis. J Autoimmun 25: 85–91.    
  • 54. Benias P, Gopal K, Bodenheimer H, et al. (2012) Hepatic expression of toll-like receptors 3, 4, and 9 in primary biliary cirrhosis and chronic hepatitis c. Clin Res Hepatol Gas 36: 448–454.    
  • 55. Seki E, Brenner D (2008) Toll-like receptors and adaptor molecules in liver disease: update. Hepatology 48: 322–335.    
  • 56. Wahlström A, Sayin S, Marschall H, et al. (2016) Intestinal crosstalk between bile acids and microbiota and its impact on host metabolism. Cell Metab 24: 41–50.    
  • 57. Visschers R, Luyer M, Schaap F, et al. (2013) The gut-liver axis. Curr Opin Clin Nutr 16: 576–581.    
  • 58. Lindor K, Gershwin E, Poupon R, et al. (2009) Primary biliary cirrhosis. Hepatology 50: 291–308.    
  • 59. Beuers U, Boberg K, Chapman R (2009) EASL clinical practice guidelines: management of cholestatic liver diseases. J Hepatol 51: 237–267.    
  • 60. Lee J, Arai H, Nakamura Y, et al. (2013) Contribution of the 7β-hydroxysteroid dehydrogenase from ruminococcus gnavus N53 to ursodeoxycholic acid formation in the human colon. J Lipid Res 54: 3062–3069.    
  • 61. Tang R, Wei Y, Che W, et al. (2017) Gut microbial profile is altered in primary biliary cholangitis and partially restored after UDCA therapy. Gut 67: 534–541.
  • 62. Hopf U, Moller B, Stemerowicz R, et al. (1989) Relation between Escherichia coli R(rough)-forms in gut, lipid A in liver, and primary biliary cirrhosis. Lancet 334: 1419–1422.    
  • 63. Bogdanos D, Baum H, Grasso A, et al. (2004) Microbial mimics are major targets of crossreactivity with human pyruvate dehydrogenase in primary biliary cirrhosis. J Hepatol 40: 31–39.
  • 64. Olafsson S, Gudjonsson H, Selmi C, et al. (2004) Antimitochondrial antibodies and reactivity to N. aromaticivorans proteins in icelandic patients with primary biliary cirrhosis and their relatives. Am J Gastroenterol 99: 2143–2146.
  • 65. Mattner J, Savage P, Leung P, et al. (2008) Liver autoimmunity triggered by microbial activation of natural killer T cells. Cell Host Microbe 3: 304–315.    
  • 66. Smyk D, Bogdanos D, Kriese S, et al. (2012) Urinary tract infection as a risk factor for autoimmune liver disease: from bench to bedside. Clin Res Hepatol Gas 36: 110–121.    
  • 67. Rashid T, Ebringer A (2012) Autoimmunity in rheumatic diseases is induced by microbial infections via crossreactivity or molecular mimicry. Autoimmune Dis: 1–9.
  • 68. Stemerowicz R, Hopf U, Moller B, et al. (1988) Are antimitochondrial antibodies in primary biliary cirrhosis induced by R(rough)-mutants of enterobacteriaceae? Lancet 332: 1166–1170.    
  • 69. Gossard A, Lindor K (2012) Autoimmune hepatitis: a review. J Gastroenterol 47: 498–503.    
  • 70. Boberg K, Aadland E, Jahnse J, et al. (1998) Incidence and prevalence of brimary biliary cirrhosis, primary sclerosing cholangitis, and autoimmune hepatitis in a norwegian population. Scand J Gastroentero 33: 99–103.    
  • 71. Lee Y, Teo E, Ng T, et al. (2001) Autoimmune hepatitis in singapore: a rare syndrome affecting middle-aged women. J Gastroen Hepatol 16: 1384–1389.    
  • 72. Hurlburt K, McMahon B, Deubner H, et al. (2002) Prevalence of autoimmune liver disease in Alaska natives. Am J Gastroenterol 97: 2402–2407.    
  • 73. Primo J, Merino C, Fernandez J, et al. (2004) Incidence and prevalence of autoimmune hepatitis in the area of the Hospital de Sagunto (spain). Gastroent Hepat-Barc 27: 239–243.    
  • 74. Ngu J, Bechly K, Chapman B, et al. (2010) Population-based epidemiology study of autoimmune hepatitis: a disease of older women? J Gastroen Hepatol 25: 1681–1686.    
  • 75. Delgado J, Vodonos A, Malnick S, et al. (2013) Autoimmune hepatitis in southern Israel: a multicenter study of 15 years. J Digest Dis 14: 611–618.
  • 76. Czaja A (2016) Factoring the intestinal microbiome into the pathogenesis of autoimmune hepatitis. World J Gastroentero 22: 9257–9278.    
  • 77. Czaja A (1998) Frequency and nature of the variant syndromes of autoimmune liver disease. Hepatology 28: 360–365.    
  • 78. Czaja A (2013) The overlap syndromes of autoimmune hepatitis. Digest Dis Sci 58: 326–343.
  • 79. Lin R, Zhou L, Zhang J, et al. (2015) Abnormal intestinal permeability and microbiota in patients with autoimmune hepatitis. Int J Clin Exp Patho 8: 5153–5160.
  • 80. Cai W, Ran Y, Li Y, et al. (2017) Intestinal microbiome and permeability in patients with autoimmune hepatitis. Best Pract Res Cl Ga 31: 669–673.    
  • 81. Yuksel M, Wang Y, Tai N, et al. (2015) A novel humanized mouse model for autoimmune hepatitis and the association of gut microbiota with liver inflammation. Hepatology 62: 1536–1550.    
  • 82. Reumaux D, Duthilleul P, Roos D (2004) Pathogenesis of diseases associated with antineutrophil cytoplasm autoantibodies. Hum Immunol 65: 1–12.    
  • 83. Terjung B, Sohne J, Lechtenberg B, et al. (2010) p-ANCAs in autoimmune liver disorders recognise human beta-tubulin isotype 5 and cross-react with microbial protein FtsZ. Gut 59: 808–816.    


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