Gut microbial profiling as a therapeutic and diagnostic target for managing primary biliary cholangitis.

References

• De Luca F, Shoenfeld Y. The microbiome in autoimmune diseases. Clin Exp Immunol. 2019;195:74–85.
   PubMed Web of Science ®Google Scholar
• Zheng D, Liwinski T, Elinav E. Interaction between microbiota and immunity in health and disease. Cell Res. 2020;30:492–506.
   PubMed Web of Science ®Google Scholar
• Maroni L, Ninfole E, Pinto C, et al. Gut-liver axis and inflammasome activation in cholangiocyte pathophysiology. Cells. 2020;9:736.
   Web of Science ®Google Scholar
• Brenner DA, Paik YH, Schnabl B. Role of gut microbiota in liver disease. J Clin Gastroenterol. 2015;49:S25–7.
   PubMed Web of Science ®Google Scholar
• Chopyk DM, Grakoui A. Contribution of the intestinal microbiome and gut barrier to hepatic disorders. Gastroenterology. 2020;159:S0016–5085(20)34839–3. Online ahead of print.
   PubMed Web of Science ®Google Scholar
• Alvaro D, Carpino G, Craxi A, et al. Primary Biliary Cholangitis management: controversies, perspectives, and daily practice implications from an expert panel. Liver Int. 2020;40:2590–2601. Online ahead of print.
   Web of Science ®Google Scholar
• Selmi C, De Santis M, Cavaciocchi F, et al. Infectious agents and xenobiotics in the aetiology of primary biliary cirrhosis. Dis Markers. 2010;29:287–299.
   PubMed Web of Science ®Google Scholar
• Floreani A, Leung PSC, Gershwin ME. Environmental basis of autoimmunity. Clin Rev Allerg Immunol. 2016;50:287–300.
   PubMed Web of Science ®Google Scholar
• Mattner J, Savage PB, Leung P, et al. Liver autoimmunity triggered by microbial activation of natural killers T cells. Cell Host Microbe. 2008;3:304–315.
   PubMed Web of Science ®Google Scholar
• 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;42:458–465.
   PubMed Web of Science ®Google Scholar
• Burroughs AK, Rosenstein IJ, Epstein O, et al. Bacteriuria and primary biliary cirrhosis. Gut. 1984;25:133–137.
   PubMed Web of Science ®Google Scholar
• Bogdanos DP, Baum H, Butler P, et al. Association between the primary biliary cirrhosis specific anti-sp100 antibodies and recurrent urinary tract infection. Dig Liver Dis. 2003;35:801–805.
   PubMedGoogle Scholar
• Gershwin ME, Selmi C, Worman HJ, et al. The USA PBC Epidemiology Group. Risk factors and comorbidities in primary biliary cirrhosis: a controlled interview-based study of 1032 patients. Hepatology. 2005;42:1194–1202.
   PubMed Web of Science ®Google Scholar
• Daniels JA, Torbenson M, Anders RA, et al. Immunostaining of plasma cells in primary biliary cirrhosis. Am J Clin Pathol. 2009;131:243–249.
   PubMed Web of Science ®Google Scholar
• Moreira RK, Revetta F, Koehler E, et al. Diagnostic utility of IgG and IgM immunohistochemistry in autoimmune liver disease. World J Gastroenterol. 2010;16:453–457.
   PubMed Web of Science ®Google Scholar
• Feld JJ, Meddings J, Heathcote EJ. Abnormal intestine permeability in primary biliary cirrhosis. Dig Dis Sci. 2006;51:1607–1613.
   PubMed Web of Science ®Google Scholar
• Floreani A, Baragiotta A, Pizzuti D, et al. Mucosal IgA defect in primary biliary cirrhosis. Am J Gastroenterol. 2002;97:508–510.
   PubMed Web of Science ®Google Scholar
• Sheth P, Delos Santos N, Seth A, et al. Lipopolysaccharide disrupts tight junctions in cholangiocyte monolayers by c-Src-, TLR4-, and LBP-dependent mechanism. Am J Physiol Gastrointest Liver Physiol. 2007;293:G308–G318.
   PubMed Web of Science ®Google Scholar
• Tabibian JH, O’Hara SP, Splinter PL, et al. Cholangiocyte senescence by way of N-ras activation is characteristic of primary sclerosing cholangitis. Hepatology. 2014;59:2263–2275.
   PubMed Web of Science ®Google Scholar
• Maldonado R, Sa-Correira I, Valvano M. Lipopolysaccharide modification in gram-negative bacteria during chronic infection. FEMS Microbiol Rev. 2016;40:480–493.
   PubMed Web of Science ®Google Scholar
• Wang A-P, Migita K, Ito M, et al. Hepatic expression of toll-like receptor 4 in primary biliary cirrhosis. J Autoimmun. 2005;25:85–91.
   PubMed Web of Science ®Google Scholar
• Seki E, Brenner DA. Toll-like receptors and adaptor molecules in liver disease: update. Hepatology. 2008;48:322–335.
   PubMed Web of Science ®Google Scholar
• Wahlstrom A, Sayin SI, Marschall H-U, et al. Intestinal crosstalk between bile acids and microbiota and its impact on host metabolism. Cell Metab. 2016;24:41–50.
   PubMed Web of Science ®Google Scholar
• Sayin SI, Wahlstrom A, Felin J, et al. Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist. Cell Metab. 2013;17:225–235.
   PubMed Web of Science ®Google Scholar
• Pean N, Doignon I, Tordjmann T. Gut microbiota and bile acids: an old story revisited (again). Clin Res Hepatol Gastroenterol. 2014;38:129–131.
   PubMed Web of Science ®Google Scholar
• Isaacs-Ten A, Echeandia M, Moreno-Gonzalez M, et al. Intestinal microbiome-macrophage crosstalk contributes to cholestatic liver disease by promoting intestinal permeability. Hepatology. 2020. in press. DOI:10.1002/hep.31228
   PubMed Web of Science ®Google Scholar
• Sato K, Meng F, Fava G, et al. Functional roles of gut bacteria imbalance in cholangiopathies. Liver Res. 2019;3:40–45.
   Google Scholar
• Sabino J, Vieira-Silva S, Machiels K, et al. Primary sclerosing cholangitis is characterised by intestinal dysbiosis independent from IBD. Gut. 2016;65:1681–1689.
   PubMed Web of Science ®Google Scholar
• Kummen M, Holm K, Anmarkrud JA, 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. 2017;66:611–619.
   PubMed Web of Science ®Google Scholar
• Ruhlemann M, Liwinski T, Heinsen F-A, et al. Consistent alterations in faecal microbiomes of patients with primary sclerosing cholangitis independent of associated colitis. Aliment Pharmacol Ther. 2019;50:580–589.
   PubMed Web of Science ®Google Scholar
• Lv L-X, Fang D-Q, Shi D, et al. Alterations and correlations of the gut microbiome, metabolism and immunity in patients with primary biliary cirrhosis. Environ Microbiol. 2016;18:2272–2286.
   PubMed Web of Science ®Google Scholar
• Tang R, Wei Y, Li Y, et al. Gut microbial profile is altered in primary biliary cholangitis and partially restored after UDCA therapy. Gut. 2018;67:534–541.
   PubMed Web of Science ®Google Scholar
• Hiramatsu K, Harada K, Tsuneyama K, et al. Amplification and sequence analysis of partial bacterial 16S ribosomal RNA gene in gallbladder bile from patients with primary biliary cirrhosis. J Hepatol. 2000;33:9–18.
   PubMed Web of Science ®Google Scholar
• Pereira P, Aho V, Arola J, et al. Bile microbiota in primary sclerosing cholangitis: impact on disease progression and development of biliary dysplasia. Plos One. 2017;12:e0182924.
   PubMed Web of Science ®Google Scholar
• Kong L, Lu Y, Zhang S, et al. Role of nutrition, gene polymorphism, and gut microbiota in non-alcoholic fatty liver disease. Discov Med. 2017;24:95–106.
   PubMed Web of Science ®Google Scholar
• Zhao L-N, Yu T, Lan S-Y, et al. Probiotics can improve the clinical outcomes of hepatic encephalopathy: an update meta-analysis. Clin Res Hepatol Gastroenterol. 2015;39:674–682.
   PubMed Web of Science ®Google Scholar
• Shukla S, Shukla A, Mehboob S, et al. Meta-analysis: the effect of gut flora modulation using prebiotics, probiotics and symbiotics on minimal hepatic encephalopathy. Aliment Pharmacol Ther. 2011;33:662–671.
   PubMed Web of Science ®Google Scholar
• Kuiper EM, Hansen BE, de Vries RA, et al. Improved prognosis of patients with primary biliary cirrhosis that have a biochemical response to ursodeoxycholic acid. Gastroenterology. 2009;136:1281–1287.
   PubMed Web of Science ®Google Scholar
• Zhang D-Y, Zhu L, Tseng Y-J, et al. The protective effect and mechanism of the FXR agonist obeticholic acid via targeting gut microbiota in non-alcoholic fatty liver disease. Drug Des Devel Ther. 2019;13:2249–2270.
   PubMed Web of Science ®Google Scholar
• Ubeda M, Lazio M, Munoz L, et al. Obeticholic acid reduces bacterial translocation and inhibits intestinal inflammation in cirrhotic rats. J Hepatol. 2016;64:1049–1957.
   PubMed Web of Science ®Google Scholar
• Parmer C, Hung A, Yan KG, et al. Changes in intestinal microbiome in rats with cirrhosis and ascites: comparison between obeticholic acid (OCA) and placebo. Hepatology. 2019;70(suppl. 1):1098A (Abs 1821).
   Google Scholar
• Verkebe L, Farre R, Verbinnen B, et al. The FXR agonist obeticholic acid prevents gut barrier dysfunction and bacterial translocation in cholestatic rats. Am J Pathol. 2015;185:409–419.
   PubMed Web of Science ®Google Scholar
• Kang SH, Lee YB, Lee J-H, et al. Rifaximin treatment is associated with reduced risk of cirrhotic complications and prolonged overall survival in patients experiencing hepatic encephalopathy. Aliment Pharmacol Ther. 2017;46:845–855.
   PubMed Web of Science ®Google Scholar
• Farkkila M, Karvonen AL, Nurmi H, et al. Metronidazole and ursodeoxycholic acid for primary sclerosing cholangitis: a randomized placebo-controlled trial. Hepatology. 2004;40:1379–1386.
   PubMed Web of Science ®Google Scholar
• Silveira MG, Torok NJ, Gassard AA, et al. Minocycline in the treatment of patients with primary sclerosing cholangitis: results of a pilot study. Am J Gastroenterol. 2009;104:83–88.
   PubMed Web of Science ®Google Scholar
• Tabibian JH, Weeding E, Jorgensen RA, et al. Randomised clinical trial: vancomycin or metronidazole in patients with primary sclerosing cholangitis – a pilot study. Aliment Pharmacol Ther. 2013;37:604–612.
   PubMed Web of Science ®Google Scholar
• Bajaj JS, Khoruts A. Microbiota changes and intestinal microbiota transplantation in liver disease and cirrhosis. J Hepatol. 2020;72:1003–1027.
   PubMed Web of Science ®Google Scholar
• Bajaj JS, Salzman N, Acharya C, et al. Microbial functional change is linked with clinical outcomes after capsular fecal transplant in cirrhosis. JCI Insight. 2019;4:e133410.
   PubMed Web of Science ®Google Scholar
• Allegretti JB, Kassam Z, Carrellas M, et al. Fecal microbiota transplantation in patients with primary sclerosing cholangitis: a pilot clinical trial. Am J Gastroenterol. 2019;114:1071–1079.
   PubMed Web of Science ®Google Scholar
• Fraher MH, O’Toole PW, Quigley EMM. Techniques used to characterize the microbiota: a guide for clinicians. Nat Rev Gastroenterol Hepatol. 2012;9:312–322.
   PubMed Web of Science ®Google Scholar
• Handelsman J, Rondon MR, Brady SF, et al. Molecular biological access to the chemistry of unknown soil microbes: a new frontier for natural products. Chem Biol. 1998;5:R245–R249.
   PubMed Web of Science ®Google Scholar
• Breitbart M, Hewson I, Felts B, et al. Metagenomic analyses of an uncultured viral community from human feces. J Bacteriol. 2003;185:6220–6223.
   PubMed Web of Science ®Google Scholar
• Hiramatsu K, Harada K, Tsuneyama K, et al. Amplification and sequence analysis of partial bacterial 16S ribosomal gene in gallbladder bile from patients with primary biliary cirrhosis. J Hepatol. 2000;33:9–18.
   PubMed Web of Science ®Google Scholar
• Chen Y, Ji F, Shi D, et al. Dysbiosis of small intestinal microbiota in liver cirrhosis and its association with aetiology. Sci Rep. 2016;6:34055.
   PubMed Web of Science ®Google Scholar
• Nakamoto N, Sasaki N, Aoki R, et al. Gut pathobionts underlie intestinal barrier dysfunction and liver T helper 17 cell immune response in primary sclerosing cholangitis. Nat Microbiol. 2019;4:492–503.
   PubMed Web of Science ®Google Scholar
• Liwinski T, Zenouzi R, John C. Alterations of the bile microbiome in primary sclerosing cholangitis. Gut. 2020;69:665–672.
   PubMed Web of Science ®Google Scholar
• Olsson R, Boberg KM, Schaffalistky De Mickadell O, et al. High-dose ursodeoxycholic acid in primary sclerosing cholangitis: a 5-year multicenter, randomized, controlled study. Gastroenterology. 2005;129:1464–1472.
   PubMed Web of Science ®Google Scholar
• Lindor KD, Kowdley KV, Luketic VAC, et al. High dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis. Hepatology. 2009;50:808–814.
   PubMed Web of Science ®Google Scholar
• Tabibian JH, Lindon KD. Ursodeoxycholic acid in primary sclerosing cholangitis: if withdrawal is bad, then administration is good (right?). Hepatology. 2014;60:785–788.
   PubMed Web of Science ®Google Scholar
• Arizumi T, Tazuma S, Nakazawa T, et al. The association of UDCA treatment with long-term outcome and biliary tract cancer in patients with primary sclerosing cholangitis. Hepatology. 2020;72(Suppl 1):Abs 100.
   Google Scholar
• Kulkarni AV, Tevethia HV, Da PK, et al. Obeticholic acid in liver disease – a systematic review and meta-analysis. Hepatology. 2020;72(Suppl. 1):Abs 1685.
   Google Scholar
• Gadaleta RM, Garcia-Irigoyen O, Cariello M, et al. Fibroblast growth factor 19 modulates intestinal microbiota and inflammation in presence of farnesoid X receptor. EBiomedicine. 2020;52:102719.
   Google Scholar
• Russell DW. Fifty years of advanced in the bile acid synthesis and metabolism. J Lipid Res. 2009;50(Suppl):S120–S125.
   PubMedGoogle Scholar
• May MJ, Wigg AJ, Leggett BA, et al. NGM282 for treatment of patients with primary biliary cholangitis: a multicenter, randomized, double-blind, placebo-controlled trial. Hepatol Commun. 2018;2:1–14.
   Web of Science ®Google Scholar
• Avila MA, Moschetta A. The FXR-FGF19 gut-liver axis as a novel “hepatostat”. Gastroenterology. 2015;149:536–540.
   Web of Science ®Google Scholar
• Trivedi HD, Lizaola B, Tapper EB, et al. Management of pruritus in primary biliary cholangitis: a narrative review. Am J Med. 2017;130:744.e1–744.e7.
   Web of Science ®Google Scholar
• Namasivayan S, Maiga M, Yan W, et al. Longitudinal profiling reveals a persistent intestinal dysbiosis triggered by conventional anti-tuberculosis therapy. Microbioma. 2017;5:71–88.
   PubMed Web of Science ®Google Scholar
• Henao-Mejia J, Elinav E, Thaiss CA, et al. Role of the intestinal microbioma in liver disease. J Autoimmun. 2013;46:66–73.
   PubMed Web of Science ®Google Scholar
• Ruhlemann MC, Heinsen F-A, Zenouzi R, et al. Faecal microbiota profiles as diagnostic biomarkers in primary sclerosing cholangitis. Gut. 2017;66:753–754.
   PubMed Web of Science ®Google Scholar