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Semin Liver Dis 2016; 36(04): 349-353
DOI: 10.1055/s-0036-1594006
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Primary Biliary Cirrhosis and the Microbiome

Eamonn M. M. Quigley
1   Division of Gastroenterology and Hepatology, Lynda K. and David M. Underwood Center for Digestive Disorders, Houston Methodist Hospital, Houston, Texas
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Publication History

Publication Date:
20 December 2016 (online)

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Abstract

Primary biliary cirrhosis is a rather uncommon, slowly progressive, cholestatic liver disease that predominantly affects middle-aged women. Apart from the changes in the gut microbiome that have been described in liver disease in general, little is known of the composition of the microbiome in primary biliary cirrhosis. Nevertheless, epidemiological, clinical, and some experimental evidence points to the possible role of a bacterium (or bacteria) in the initiation of the autoimmune process that leads to the development of this unique clinical phenotype.

Keywords

Primary Biliary Cholangitis - Primary Biliary Cirrhosis - Microbiome - Microbiota - Biliary epithelium - Antimitochondrial antibody
 

  • References

  • 1 Poupon R. Primary biliary cirrhosis: a 2010 update. J Hepatol 2010; 52 (5) 745-758
    CrossrefPubMedGoogle Scholar
  • 2 Carey EJ, Ali AH, Lindor KD. Primary biliary cirrhosis. Lancet 2015; 386 (10003) 1565-1575
    CrossrefPubMedGoogle Scholar
  • 3 Floreani A, Franceschet I, Cazzagon N. Primary biliary cirrhosis: overlaps with other autoimmune disorders. Semin Liver Dis 2014; 34 (3) 352-360
    Article in Thieme ConnectPubMedGoogle Scholar
  • 4 Kurtovic J, Riordan SM, Williams R. The natural history of asymptomatic primary biliary cirrhosis. QJM 2005; 98 (5) 331-336
    CrossrefPubMedGoogle Scholar
  • 5 Imam MH, Lindor KD. The natural history of primary biliary cirrhosis. Semin Liver Dis 2014; 34 (3) 329-333
    Article in Thieme ConnectPubMedGoogle Scholar
  • 6 Pratt DS. Primary biliary cholangitis--a new name and a new treatment. N Engl J Med 2016; 375 (7) 685-687
    CrossrefPubMedGoogle Scholar
  • 7 Prince MI, James OF. The epidemiology of primary biliary cirrhosis. Clin Liver Dis 2003; 7 (4) 795-819
    CrossrefPubMedGoogle Scholar
  • 8 Gross RG, Odin JA. Recent advances in the epidemiology of primary biliary cirrhosis. Clin Liver Dis 2008; 12 (2) 289-303 , viii
    CrossrefPubMedGoogle Scholar
  • 9 Boonstra K, Beuers U, Ponsioen CY. Epidemiology of primary sclerosing cholangitis and primary biliary cirrhosis: a systematic review. J Hepatol 2012; 56 (5) 1181-1188
    CrossrefPubMedGoogle Scholar
  • 10 Podda M, Selmi C, Lleo A, Moroni L, Invernizzi P. The limitations and hidden gems of the epidemiology of primary biliary cirrhosis. J Autoimmun 2013; 46: 81-87
    CrossrefPubMedGoogle Scholar
  • 11 Griffiths L, Dyson JK, Jones DE. The new epidemiology of primary biliary cirrhosis. Semin Liver Dis 2014; 34 (3) 318-328
    Article in Thieme ConnectPubMedGoogle Scholar
  • 12 Rudic JS, Poropat G, Krstic MN, Bjelakovic G, Gluud C. Ursodeoxycholic acid for primary biliary cirrhosis. Cochrane Database Syst Rev 2012; 12: CD000551
    PubMedGoogle Scholar
  • 13 Metcalf J, James O. The geoepidemiology of primary biliary cirrhosis. Semin Liver Dis 1997; 17 (1) 13-22
    Article in Thieme ConnectPubMedGoogle Scholar
  • 14 Parikh-Patel A, Gold E, Mackay IR, Gershwin ME. The geoepidemiology of primary biliary cirrhosis: contrasts and comparisons with the spectrum of autoimmune diseases. Clin Immunol 1999; 91 (2) 206-218
    CrossrefPubMedGoogle Scholar
  • 15 Kim K-A, Ki M, Choi HY, Kim BH, Jang ES, Jeong S-H. Population-based epidemiology of primary biliary cirrhosis in South Korea. Aliment Pharmacol Ther 2016; 43 (1) 154-162
    CrossrefPubMedGoogle Scholar
  • 16 Selmi C, De Santis M, Cavaciocchi F, Gershwin ME. Infectious agents and xenobiotics in the etiology of primary biliary cirrhosis. Dis Markers 2010; 29 (6) 287-299
    CrossrefPubMedGoogle Scholar
  • 17 Triger DR. Primary biliary cirrhosis: an epidemiological study. BMJ 1980; 281 (6243) 772-775
    CrossrefPubMedGoogle Scholar
  • 18 Smyk D, Mytilinaiou MG, Rigopoulou EI, Bogdanos DP. PBC triggers in water reservoirs, coal mining areas and waste disposal sites: from Newcastle to New York. Dis Markers 2010; 29 (6) 337-344
    CrossrefPubMedGoogle Scholar
  • 19 Juran BD, Lazaridis KN. Environmental factors in primary biliary cirrhosis. Semin Liver Dis 2014; 34 (3) 265-272
    Article in Thieme ConnectPubMedGoogle Scholar
  • 20 Agmon-Levin N, Katz BS, Shoenfeld Y. Infection and primary biliary cirrhosis. Isr Med Assoc J 2009; 11 (2) 112-115
    PubMedGoogle Scholar
  • 21 Bogdanos DP, Vergani D. Bacteria and primary biliary cirrhosis. Clin Rev Allergy Immunol 2009; 36 (1) 30-39
    CrossrefPubMedGoogle Scholar
  • 22 Ortega-Hernandez OD, Levin NA, Altman A, Shoenfeld Y. Infectious agents in the pathogenesis of primary biliary cirrhosis. Dis Markers 2010; 29 (6) 277-286
    CrossrefPubMedGoogle Scholar
  • 23 Xu L, Sakalian M, Shen Z, Loss G, Neuberger J, Mason A. Cloning the human betaretrovirus proviral genome from patients with primary biliary cirrhosis. Hepatology 2004; 39 (1) 151-156
    CrossrefPubMedGoogle Scholar
  • 24 Wang W, Indik S, Wasilenko ST , et al. Frequent proviral integration of the human betaretrovirus in biliary epithelium of patients with autoimmune and idiopathic liver disease. Aliment Pharmacol Ther 2015; 41 (4) 393-405
    CrossrefPubMedGoogle Scholar
  • 25 Morshed SA, Nishioka M, Saito I, Komiyama K, Moro I. Increased expression of Epstein-Barr virus in primary biliary cirrhosis patients. Gastroenterol Jpn 1992; 27 (6) 751-758
    PubMedGoogle Scholar
  • 26 Haruta I, Kikuchi K, Hashimoto E , et al. A possible role of histone-like DNA-binding protein of Streptococcus intermedius in the pathogenesis of bile duct damage in primary biliary cirrhosis. Clin Immunol 2008; 127 (2) 245-251
    CrossrefPubMedGoogle Scholar
  • 27 Harada K, Tsuneyama K, Sudo Y, Masuda S, Nakanuma Y. Molecular identification of bacterial 16S ribosomal RNA gene in liver tissue of primary biliary cirrhosis: is Propionibacterium acnes involved in granuloma formation?. Hepatology 2001; 33 (3) 530-536
    CrossrefPubMedGoogle Scholar
  • 28 Mason AL, Farr GH, Xu L, Hubscher SG, Neuberger JM. Pilot studies of single and combination antiretroviral therapy in patients with primary biliary cirrhosis. Am J Gastroenterol 2004; 99 (12) 2348-2355
    CrossrefPubMedGoogle Scholar
  • 29 Selmi C, Ross SR, Ansari AA , et al. Lack of immunological or molecular evidence for a role of mouse mammary tumor retrovirus in primary biliary cirrhosis. Gastroenterology 2004; 127 (2) 493-501
    CrossrefPubMedGoogle Scholar
  • 30 Mason AL, Zhang G. Linking human beta retrovirus infection with primary biliary cirrhosis. Gastroenterol Clin Biol 2010; 34 (6–7) 359-366
    CrossrefPubMedGoogle Scholar
  • 31 Jones DE. A potential retroviral aetiology for mouse PBC: more answers or more questions?. J Hepatol 2011; 55 (4) 750-752
    CrossrefPubMedGoogle Scholar
  • 32 Bogdanos DP, Baum H, Vergani D, Burroughs AK. The role of E. coli infection in the pathogenesis of primary biliary cirrhosis. Dis Markers 2010; 29 (6) 301-311
    CrossrefPubMedGoogle Scholar
  • 33 Smyk D, Rigopoulou EI, Zen Y , et al. Role for mycobacterial infection in pathogenesis of primary biliary cirrhosis?. World J Gastroenterol 2012; 18 (35) 4855-4865
    CrossrefPubMedGoogle Scholar
  • 34 Liu HY, Deng AM, Zhang J , et al. Correlation of Chlamydia pneumoniae infection with primary biliary cirrhosis. World J Gastroenterol 2005; 11 (26) 4108-4110
    CrossrefPubMedGoogle Scholar
  • 35 Leung PS, Park O, Matsumura S, Ansari AA, Coppel RL, Gershwin ME. Is there a relation between Chlamydia infection and primary biliary cirrhosis?. Clin Dev Immunol 2003; 10 (2–4) 227-233
    CrossrefPubMedGoogle Scholar
  • 36 Abdulkarim AS, Petrovic LM, Kim WR, Angulo P, Lloyd RV, Lindor KD. Primary biliary cirrhosis: an infectious disease caused by Chlamydia pneumoniae?. J Hepatol 2004; 40 (3) 380-384
    CrossrefPubMedGoogle Scholar
  • 37 Saadah OI, Bokhary RY. Anti-mitochondrial antibody positive autoimmune hepatitis triggered by EBV infection in a young girl. Arab J Gastroenterol 2013; 14 (3) 130-132
    CrossrefPubMedGoogle Scholar
  • 38 Floreani A, Biagini MR, Zappalà F , et al. Chronic atrophic gastritis and Helicobacter pylori infection in primary biliary cirrhosis: a cross-sectional study with matching. Ital J Gastroenterol Hepatol 1997; 29 (1) 13-17
    PubMedGoogle Scholar
  • 39 Abenavoli L, Arena V, Giancotti F, Vecchio FM, Abenavoli S. Celiac disease, primary biliary cirrhosis and helicobacter pylori infection: one link for three diseases. Int J Immunopathol Pharmacol 2010; 23 (4) 1261-1265
    PubMedGoogle Scholar
  • 40 Feng H, Zhou X, Zhang G. Association between cirrhosis and Helicobacter pylori infection: a meta-analysis. Eur J Gastroenterol Hepatol 2014; 26 (12) 1309-1319
    PubMedGoogle Scholar
  • 41 Durazzo M, Rosina F, Premoli A , et al. Lack of association between seroprevalence of Helicobacter pylori infection and primary biliary cirrhosis. World J Gastroenterol 2004; 10 (21) 3179-3181
    CrossrefPubMedGoogle Scholar
  • 42 Shapira Y, Agmon-Levin N, Renaudineau Y , et al. Serum markers of infections in patients with primary biliary cirrhosis: evidence of infection burden. Exp Mol Pathol 2012; 93 (3) 386-390
    CrossrefPubMedGoogle Scholar
  • 43 Sakly W, Jeddi M, Ghedira I. Anti-Saccharomyces cerevisiae antibodies in primary biliary cirrhosis. Dig Dis Sci 2008; 53 (7) 1983-1987
    CrossrefPubMedGoogle Scholar
  • 44 Yamaguchi H, Miura H, Ohsumi K , et al. Detection and characterization of antibodies to bacterial heat-shock protein 60 in sera of patients with primary biliary cirrhosis. Microbiol Immunol 1994; 38 (6) 483-487
    CrossrefPubMedGoogle Scholar
  • 45 Stemerowicz R, Möller B, Martin P , et al. Antibody activity against lipopolysaccharides, lipid A and proteins from Enterobacteriaceae in patients with chronic inflammatory liver diseases. Autoimmunity 1990; 7 (4) 305-315
    CrossrefPubMedGoogle Scholar
  • 46 Bogdanos DP, Baum H, Sharma UC , et al. Antibodies against homologous microbial caseinolytic proteases P characterise primary biliary cirrhosis. J Hepatol 2002; 36 (1) 14-21
    CrossrefPubMedGoogle Scholar
  • 47 Miyakawa H, Tanaka A, Selmi C , et al. Serum reactivity against bacterial pyruvate dehydrogenase: increasing the specificity of anti-mitochondrial antibodies for the diagnosis of primary biliary cirrhosis. Clin Dev Immunol 2006; 13 (2–4) 289-294
    CrossrefPubMedGoogle Scholar
  • 48 Boomkens SY, de Rave S, Pot RG , et al. The role of Helicobacter spp. in the pathogenesis of primary biliary cirrhosis and primary sclerosing cholangitis. FEMS Immunol Med Microbiol 2005; 44 (2) 221-225
    CrossrefPubMedGoogle Scholar
  • 49 Aron JH, Bowlus CL. The immunobiology of primary sclerosing cholangitis. Semin Immunopathol 2009; 31 (3) 383-397
    CrossrefPubMedGoogle Scholar
  • 50 Selmi C, Meda F, Kasangian A , et al. Experimental evidence on the immunopathogenesis of primary biliary cirrhosis. Cell Mol Immunol 2010; 7 (1) 1-10
    CrossrefPubMedGoogle Scholar
  • 51 Wang J, Yang GX, Tsuneyama K, Gershwin ME, Ridgway WM, Leung PS. Animal models of primary biliary cirrhosis. Semin Liver Dis 2014; 34 (3) 285-296
    Article in Thieme ConnectPubMedGoogle Scholar
  • 52 Verdier J, Luedde T, Sellge G. Biliary mucosal barrier and microbiome. Viszeralmedizin 2015; 31 (3) 156-161
    CrossrefPubMedGoogle Scholar
  • 53 Haruta I, Kikuchi K, Hashimoto E , et al. Long-term bacterial exposure can trigger nonsuppurative destructive cholangitis associated with multifocal epithelial inflammation. Lab Invest 2010; 90 (4) 577-588
    CrossrefPubMedGoogle Scholar
  • 54 Butler P, Hamilton-Miller J, Baum H, Burroughs AK. Detection of M2 antibodies in patients with recurrent urinary tract infection using an ELISA and purified PBC specific antigens. Evidence for a molecular mimicry mechanism in the pathogenesis of primary biliary cirrhosis?. Biochem Mol Biol Int 1995; 35 (3) 473-485
    PubMedGoogle Scholar
  • 55 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 (1) 31-39
    PubMedGoogle Scholar
  • 56 Roesler KW, Schmider W, Kist M , et al. Identification of beta-subunit of bacterial RNA-polymerase--a non-species-specific bacterial protein--as target of antibodies in primary biliary cirrhosis. Dig Dis Sci 2003; 48 (3) 561-569
    CrossrefPubMedGoogle Scholar
  • 57 Stemerowicz R, Hopf U, Möller B , et al. Are antimitochondrial antibodies in primary biliary cirrhosis induced by R(rough)-mutants of Enterobacteriaceae?. Lancet 1988; 2 (8621) 1166-1170
    PubMedGoogle Scholar
  • 58 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 (8677) 1419-1422
    PubMedGoogle Scholar
  • 59 Fussey SP, Ali ST, Guest JR, James OF, Bassendine MF, Yeaman SJ. Reactivity of primary biliary cirrhosis sera with Escherichia coli dihydrolipoamide acetyltransferase (E2p): characterization of the main immunogenic region. Proc Natl Acad Sci U S A 1990; 87 (10) 3987-3991
    CrossrefPubMedGoogle Scholar
  • 60 Vilagut L, Parés A, Viñas O, Vila J, Jiménez de Anta MT, Rodés J. Antibodies to mycobacterial 65-kD heat shock protein cross-react with the main mitochondrial antigens in patients with primary biliary cirrhosis. Eur J Clin Invest 1997; 27 (8) 667-672
    CrossrefPubMedGoogle Scholar
  • 61 Bogdanos DP, Pares A, Baum H , et al. Disease-specific cross-reactivity between mimicking peptides of heat shock protein of Mycobacterium gordonae and dominant epitope of E2 subunit of pyruvate dehydrogenase is common in Spanish but not British patients with primary biliary cirrhosis. J Autoimmun 2004; 22 (4) 353-362
    CrossrefPubMedGoogle Scholar
  • 62 Berg CP, Kannan TR, Klein R , et al. Mycoplasma antigens as a possible trigger for the induction of antimitochondrial antibodies in primary biliary cirrhosis. Liver Int 2009; 29 (6) 797-809
    CrossrefPubMedGoogle Scholar
  • 63 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 (2) 458-465
    CrossrefPubMedGoogle Scholar
  • 64 Bogdanos D, Pusl T, Rust C, Vergani D, Beuers U. Primary biliary cirrhosis following Lactobacillus vaccination for recurrent vaginitis. J Hepatol 2008; 49 (3) 466-473
    CrossrefPubMedGoogle Scholar
  • 65 Bogdanos DP, Baum H, Gunsar F , et al. Extensive homology between the major immunodominant mitochondrial antigen in primary biliary cirrhosis and Helicobacter pylori does not lead to immunological cross-reactivity. Scand J Gastroenterol 2004; 39 (10) 981-987
    PubMedGoogle Scholar
  • 66 Olafsson S, Gudjonsson H, Selmi C , et al. Antimitochondrial antibodies and reactivity to N. aromaticivorans proteins in Icelandic patients with primary biliary cirrhosis and their relatives. Am J Gastroenterol 2004; 99 (11) 2143-2146
    CrossrefPubMedGoogle Scholar
  • 67 Kaplan MM. Novosphingobium aromaticivorans: a potential initiator of primary biliary cirrhosis. Am J Gastroenterol 2004; 99 (11) 2147-2149
    CrossrefPubMedGoogle Scholar
  • 68 Padgett KA, Selmi C, Kenny TP , et al. Phylogenetic and immunological definition of four lipoylated proteins from Novosphingobium aromaticivorans, implications for primary biliary cirrhosis. J Autoimmun 2005; 24 (3) 209-219
    CrossrefPubMedGoogle Scholar
  • 69 Tanimoto H, Shimoda S, Nakamura M , et al. Promiscuous T cells selected by Escherichia coli: OGDC-E2 in primary biliary cirrhosis. J Autoimmun 2003; 20 (3) 255-263
    CrossrefPubMedGoogle Scholar
  • 70 Mattner J, Savage PB, Leung P , et al. Liver autoimmunity triggered by microbial activation of natural killer T cells. Cell Host Microbe 2008; 3 (5) 304-315
    CrossrefPubMedGoogle Scholar
  • 71 Morita S, Joshita S, Umemura T , et al. Association analysis of toll-like receptor 4 polymorphisms in Japanese primary biliary cirrhosis. Hum Immunol 2013; 74 (2) 219-222
    CrossrefPubMedGoogle Scholar
  • 72 Haruta I, Hashimoto E, Kato Y , et al. Lipoteichoic acid may affect the pathogenesis of bile duct damage in primary biliary cirrhosis. Autoimmunity 2006; 39 (2) 129-135
    CrossrefPubMedGoogle Scholar
  • 73 Tsuneyama K, Harada K, Kono N , et al. Scavenger cells with gram-positive bacterial lipoteichoic acid infiltrate around the damaged interlobular bile ducts of primary biliary cirrhosis. J Hepatol 2001; 35 (2) 156-163
    CrossrefPubMedGoogle Scholar
  • 74 Palmer JM, Jones DE, Quinn J, McHugh A, Yeaman SJ. Characterization of the autoantibody responses to recombinant E3 binding protein (protein X) of pyruvate dehydrogenase in primary biliary cirrhosis. Hepatology 1999; 30 (1) 21-26
    CrossrefPubMedGoogle Scholar
  • 75 Dubel L, Tanaka A, Leung PS , et al. Autoepitope mapping and reactivity of autoantibodies to the dihydrolipoamide dehydrogenase-binding protein (E3BP) and the glycine cleavage proteins in primary biliary cirrhosis. Hepatology 1999; 29 (4) 1013-1018
    CrossrefPubMedGoogle Scholar
  • 76 Rieger R, Gershwin ME. The X and why of xenobiotics in primary biliary cirrhosis. J Autoimmun 2007; 28 (2–3) 76-84
    CrossrefPubMedGoogle Scholar
  • 77 Selmi C, Balkwill DL, Invernizzi P , et al. Patients with primary biliary cirrhosis react against a ubiquitous xenobiotic-metabolizing bacterium. Hepatology 2003; 38 (5) 1250-1257
    CrossrefPubMedGoogle Scholar
  • 78 Haruta I, Hashimoto E, Shibata N, Kato Y, Kobayashi M, Shiratori K. Lipoteichoic acid may affect the pathogenesis of PBC-like bile duct damage and might be involved in systemic multifocal epithelial inflammations in chronic colitis-harboring TCRalpha-/-xAIM-/- mice. Autoimmunity 2007; 40 (5) 372-379
    CrossrefPubMedGoogle Scholar
  • 79 Yanagisawa N, Haruta I, Kikuchi K, Shibata N, Yagi J. Are dysregulated inflammatory responses to commensal bacteria involved in the pathogenesis of hepatobiliary-pancreatic autoimmune disease? An analysis using mice models of primary biliary cirrhosis and autoimmune pancreatitis. ISRN Gastroenterol 2011; 2011: 513514
    PubMedGoogle Scholar
  • 80 Haruta I, Kikuchi K, Nakamura M , et al. Involvement of commensal bacteria may lead to dysregulated inflammatory and autoimmune responses in a mouse model for chronic nonsuppurative destructive cholangitis. J Clin Immunol 2012; 32 (5) 1026-1037
    CrossrefPubMedGoogle Scholar
  • 81 Wang JJ, Yang GX, Zhang WC , et al. Escherichia coli infection induces autoimmune cholangitis and anti-mitochondrial antibodies in non-obese diabetic (NOD).B6 (Idd10/Idd18) mice. Clin Exp Immunol 2014; 175 (2) 192-201
    CrossrefPubMedGoogle Scholar
  • 82 Abu-Shanab A, Quigley EM. The role of the gut microbiota in nonalcoholic fatty liver disease. Nat Rev Gastroenterol Hepatol 2010; 7 (12) 691-701
    CrossrefPubMedGoogle Scholar
  • 83 Quigley EM, Monsour HP. The gut microbiota and the liver: implications for clinical practice. Expert Rev Gastroenterol Hepatol 2013; 7 (8) 723-732
    CrossrefPubMedGoogle Scholar
  • 84 Chen Y, Yang F, Lu H , et al. Characterization of fecal microbial communities in patients with liver cirrhosis. Hepatology 2011; 54 (2) 562-572
    CrossrefPubMedGoogle Scholar
  • 85 Qin N, Yang F, Li A , et al. Alterations of the human gut microbiome in liver cirrhosis. Nature 2014; 513 (7516) 59-64
    CrossrefPubMedGoogle Scholar
  • 86 Yoshimoto S, Loo TM, Atarashi K , et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature 2013; 499 (7456) 97-101
    CrossrefPubMedGoogle Scholar
  • 87 Tomiyama Y, Takenaka K, Kodama T , et al. Risk factors for survival and the development of hepatocellular carcinoma in patients with primary biliary cirrhosis. Intern Med 2013; 52 (14) 1553-1559
    CrossrefPubMedGoogle Scholar
  • 88 Liang Y, Yang Z, Zhong R. Primary biliary cirrhosis and cancer risk: a systematic review and meta-analysis. Hepatology 2012; 56 (4) 1409-1417
    CrossrefPubMedGoogle Scholar
  • 89 Iqbal S, Quigley EM. Progress in our understanding of the gut microbiome: implications for the clinician. Curr Gastroenterol Rep 2016; 18 (9) 49
    CrossrefPubMedGoogle Scholar
  • 90 Lv LX, Fang DQ, Shi D , et al. Alterations and correlations of the gut microbiome, metabolism and immunity in patients with primary biliary cirrhosis. Environ Microbiol 2016; 18 (7) 2272-2286
    CrossrefPubMedGoogle Scholar