Semin Liver Dis 2016; 36(04): 340-348
DOI: 10.1055/s-0036-1594007
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

The Microbiome and Primary Sclerosing Cholangitis

Ahmad H. Ali
1   Division of Gastroenterology and Hepatology, Mayo Clinic, Phoenix, Arizona
,
Elizabeth J. Carey
1   Division of Gastroenterology and Hepatology, Mayo Clinic, Phoenix, Arizona
,
Keith D. Lindor
1   Division of Gastroenterology and Hepatology, Mayo Clinic, Phoenix, Arizona
2   College of Health Solutions, Arizona State University, Tempe, Arizona
› Author Affiliations
Further Information

Publication History

Publication Date:
20 December 2016 (online)

Abstract

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease with detrimental sequela. In many patients, PSC progresses to end-stage liver disease and hepatobiliary cancer. There is no medical therapy that is proven to halt or reverse the progression of PSC. Approximately 70 to 80% of PSC patients have inflammatory bowel disease, usually ulcerative colitis. The etiology of PSC is poorly understood. Several lines of evidence suggest that the intestinal microbiota plays an important role in the etiopathogenesis of PSC. Stemming from this theory, several antibiotics have been tried in PSC, some of which had shown promising results. Fecal microbiota transplantation is a novel therapy, and is currently being investigated as a potential therapeutic strategy in PSC along with probiotics. In this article, the authors discuss the current knowledge of the intestinal microbiota in PSC.

 
  • References

  • 1 Hirschfield GM, Karlsen TH, Lindor KD, Adams DH. Primary sclerosing cholangitis. Lancet 2013; 382 (9904) 1587-1599
  • 2 Bambha K, Kim WR, Talwalkar J , et al. Incidence, clinical spectrum, and outcomes of primary sclerosing cholangitis in a United States community. Gastroenterology 2003; 125 (5) 1364-1369
  • 3 Brandsaeter B, Broomé U, Isoniemi H , et al. Liver transplantation for primary sclerosing cholangitis in the Nordic countries: outcome after acceptance to the waiting list. Liver Transpl 2003; 9 (9) 961-969
  • 4 Bjøro K, Brandsaeter B, Foss A, Schrumpf E. Liver transplantation in primary sclerosing cholangitis. Semin Liver Dis 2006; 26 (1) 69-79
  • 5 Olsson R, Boberg KM, de Muckadell OS , et al. High-dose ursodeoxycholic acid in primary sclerosing cholangitis: a 5-year multicenter, randomized, controlled study. Gastroenterology 2005; 129 (5) 1464-1472
  • 6 Lindor KD, Kowdley KV, Luketic VA , et al. High-dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis. Hepatology 2009; 50 (3) 808-814
  • 7 Chapman R, Fevery J, Kalloo A , et al; American Association for the Study of Liver Diseases. Diagnosis and management of primary sclerosing cholangitis. Hepatology 2010; 51 (2) 660-678
  • 8 European Association for the Study of the Liver. EASL Clinical Practice Guidelines: management of cholestatic liver diseases. J Hepatol 2009; 51 (2) 237-267
  • 9 Bergquist A, Montgomery SM, Bahmanyar S , et al. Increased risk of primary sclerosing cholangitis and ulcerative colitis in first-degree relatives of patients with primary sclerosing cholangitis. Clin Gastroenterol Hepatol 2008; 6 (8) 939-943
  • 10 Henriksen EK, Melum E, Karlsen TH. Update on primary sclerosing cholangitis genetics. Curr Opin Gastroenterol 2014; 30 (3) 310-319
  • 11 Liu JZ, Hov JR, Folseraas T , et al; UK-PSCSC Consortium; International PSC Study Group; International IBD Genetics Consortium. Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis. Nat Genet 2013; 45 (6) 670-675
  • 12 Ellinghaus D, Folseraas T, Holm K , et al. Genome-wide association analysis in primary sclerosing cholangitis and ulcerative colitis identifies risk loci at GPR35 and TCF4. Hepatology 2013; 58 (3) 1074-1083
  • 13 Jacobs JP, Braun J. Immune and genetic gardening of the intestinal microbiome. FEBS Lett 2014; 588 (22) 4102-4111
  • 14 Folseraas T, Melum E, Rausch P , et al. Extended analysis of a genome-wide association study in primary sclerosing cholangitis detects multiple novel risk loci. J Hepatol 2012; 57 (2) 366-375
  • 15 Koenig JE, Spor A, Scalfone N , et al. Succession of microbial consortia in the developing infant gut microbiome. Proc Natl Acad Sci U S A 2011; 108 (Suppl. 01) 4578-4585
  • 16 Krajmalnik-Brown R, Ilhan ZE, Kang DW, DiBaise JK. Effects of gut microbes on nutrient absorption and energy regulation. Nutr Clin Pract 2012; 27 (2) 201-214
  • 17 Cantarel BL, Coutinho PM, Rancurel C, Bernard T, Lombard V, Henrissat B. The Carbohydrate-Active EnZymes database (CAZy): an expert resource for glycogenomics. Nucleic Acids Res 2009; 37 (Database issue) D233-D238
  • 18 LeBlanc JG, Milani C, de Giori GS, Sesma F, van Sinderen D, Ventura M. Bacteria as vitamin suppliers to their host: a gut microbiota perspective. Curr Opin Biotechnol 2013; 24 (2) 160-168
  • 19 Ramakrishna BS. Role of the gut microbiota in human nutrition and metabolism. J Gastroenterol Hepatol 2013; 28 (Suppl. 04) 9-17
  • 20 Cha HR, Chang SY, Chang JH , et al. Downregulation of Th17 cells in the small intestine by disruption of gut flora in the absence of retinoic acid. J Immunol 2010; 184 (12) 6799-6806
  • 21 Ivanov II, Atarashi K, Manel N , et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 2009; 139 (3) 485-498
  • 22 Gaboriau-Routhiau V, Rakotobe S, Lécuyer E , et al. The key role of segmented filamentous bacteria in the coordinated maturation of gut helper T cell responses. Immunity 2009; 31 (4) 677-689
  • 23 Kau AL, Ahern PP, Griffin NW, Goodman AL, Gordon JI. Human nutrition, the gut microbiome and the immune system. Nature 2011; 474 (7351) 327-336
  • 24 Reddy BS, Pleasants JR, Wostmann BS. Effect of intestinal microflora on iron and zinc metabolism, and on activities of metalloenzymes in rats. J Nutr 1972; 102 (1) 101-107
  • 25 Qin J, Li R, Raes J , et al; MetaHIT Consortium. A human gut microbial gene catalogue established by metagenomic sequencing. Nature 2010; 464 (7285) 59-65
  • 26 Byrne CS, Chambers ES, Morrison DJ, Frost G. The role of short chain fatty acids in appetite regulation and energy homeostasis. Int J Obes 2015; 39 (9) 1331-1338
  • 27 Ríos-Covián D, Ruas-Madiedo P, Margolles A, Gueimonde M, de Los Reyes-Gavilán CG, Salazar N. Intestinal short chain fatty acids and their link with diet and human health. Front Microbiol 2016; 7: 185
  • 28 Bird JJ, Brown DR, Mullen AC , et al. Helper T cell differentiation is controlled by the cell cycle. Immunity 1998; 9 (2) 229-237
  • 29 Peng L, He Z, Chen W, Holzman IR, Lin J. Effects of butyrate on intestinal barrier function in a Caco-2 cell monolayer model of intestinal barrier. Pediatr Res 2007; 61 (1) 37-41
  • 30 Jung TH, Park JH, Jeon WM, Han KS. Butyrate modulates bacterial adherence on LS174T human colorectal cells by stimulating mucin secretion and MAPK signaling pathway. Nutr Res Pract 2015; 9 (4) 343-349
  • 31 Fukuda S, Toh H, Hase K , et al. Bifidobacteria can protect from enteropathogenic infection through production of acetate. Nature 2011; 469 (7331) 543-547
  • 32 Fox CJ, Hammerman PS, Thompson CB. Fuel feeds function: energy metabolism and the T-cell response. Nat Rev Immunol 2005; 5 (11) 844-852
  • 33 Michalek RD, Rathmell JC. The metabolic life and times of a T-cell. Immunol Rev 2010; 236: 190-202
  • 34 Hofmann AF. The enterohepatic circulation of bile acids in mammals: form and functions. Front Biosci (Landmark Ed) 2009; 14: 2584-2598
  • 35 Patel AK, Singhania RR, Pandey A, Chincholkar SB. Probiotic bile salt hydrolase: current developments and perspectives. Appl Biochem Biotechnol 2010; 162 (1) 166-180
  • 36 Ridlon JM, Kang DJ, Hylemon PB. Bile salt biotransformations by human intestinal bacteria. J Lipid Res 2006; 47 (2) 241-259
  • 37 Degirolamo C, Rainaldi S, Bovenga F, Murzilli S, Moschetta A. Microbiota modification with probiotics induces hepatic bile acid synthesis via downregulation of the Fxr-Fgf15 axis in mice. Cell Reports 2014; 7 (1) 12-18
  • 38 Ridlon JM, Kang DJ, Hylemon PB, Bajaj JS. Bile acids and the gut microbiome. Curr Opin Gastroenterol 2014; 30 (3) 332-338
  • 39 Islam KB, Fukiya S, Hagio M , et al. Bile acid is a host factor that regulates the composition of the cecal microbiota in rats. Gastroenterology 2011; 141 (5) 1773-1781
  • 40 Kakiyama G, Pandak WM, Gillevet PM , et al. Modulation of the fecal bile acid profile by gut microbiota in cirrhosis. J Hepatol 2013; 58 (5) 949-955
  • 41 Bajaj JS, Ridlon JM, Hylemon PB , et al. Linkage of gut microbiome with cognition in hepatic encephalopathy. Am J Physiol Gastrointest Liver Physiol 2012; 302 (1) G168-G175
  • 42 Bajaj JS, Hylemon PB, Ridlon JM , 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 (6) G675-G685
  • 43 Bajaj JS, Heuman DM, Hylemon PB , et al. Altered profile of human gut microbiome is associated with cirrhosis and its complications. J Hepatol 2014; 60 (5) 940-947
  • 44 Tyler AD, Smith MI, Silverberg MS. Analyzing the human microbiome: a “how to” guide for physicians. Am J Gastroenterol 2014; 109 (7) 983-993
  • 45 Rastogi G, Sani R. Molecular techniques to assess microbial community structure, function, and dynamics in the environment. In: Ahmad I, Ahmad F, Pichtel J, , eds. Microbes and Microbial Technology. New York: Springer; 2011: 29-57
  • 46 Fraher MH, O'Toole PW, Quigley EM. Techniques used to characterize the gut microbiota: a guide for the clinician. Nat Rev Gastroenterol Hepatol 2012; 9 (6) 312-322
  • 47 Song SJ, Amir A, Metcalf J , et al. Preservation methods differ in fecal microbiome stability, affecting suitability for field studies. MSystem 2016; 1: 1-12
  • 48 Nechvatal JM, Ram JL, Basson MD , et al. Fecal collection, ambient preservation, and DNA extraction for PCR amplification of bacterial and human markers from human feces. J Microbiol Methods 2008; 72 (2) 124-132
  • 49 Stearns JC, Lynch MD, Senadheera DB , et al. Bacterial biogeography of the human digestive tract. Sci Rep 2011; 1: 170
  • 50 Clarridge III JE. Impact of 16S rRNA gene sequence analysis for identification of bacteria on clinical microbiology and infectious diseases. Clin Microbiol Rev 2004; 17 (4) 840-862
  • 51 Schloss PD, Westcott SL. Assessing and improving methods used in operational taxonomic unit-based approaches for 16S rRNA gene sequence analysis. Appl Environ Microbiol 2011; 77 (10) 3219-3226
  • 52 Hehemann JH, Correc G, Barbeyron T, Helbert W, Czjzek M, Michel G. Transfer of carbohydrate-active enzymes from marine bacteria to Japanese gut microbiota. Nature 2010; 464 (7290) 908-912
  • 53 Leffler DA, Lamont JT. Clostridium difficile infection. N Engl J Med 2015; 372 (16) 1539-1548
  • 54 Surawicz CM, Brandt LJ, Binion DG , et al. Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections. Am J Gastroenterol 2013; 108 (4) 478-498 , quiz 499
  • 55 van Nood E, Vrieze A, Nieuwdorp M , et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med 2013; 368 (5) 407-415
  • 56 Cruchet S, Furnes R, Maruy A , et al. The use of probiotics in pediatric gastroenterology: a review of the literature and recommendations by Latin-American experts. Paediatr Drugs 2015; 17 (3) 199-216
  • 57 Tursi A, Brandimarte G, Papa A , et al. Treatment of relapsing mild-to-moderate ulcerative colitis with the probiotic VSL#3 as adjunctive to a standard pharmaceutical treatment: a double-blind, randomized, placebo-controlled study. Am J Gastroenterol 2010; 105 (10) 2218-2227
  • 58 Turnbaugh PJ, Hamady M, Yatsunenko T , et al. A core gut microbiome in obese and lean twins. Nature 2009; 457 (7228) 480-484
  • 59 Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 2006; 444 (7122) 1027-1031
  • 60 Ley RE, Bäckhed F, Turnbaugh P, Lozupone CA, Knight RD, Gordon JI. Obesity alters gut microbial ecology. Proc Natl Acad Sci U S A 2005; 102 (31) 11070-11075
  • 61 Ley RE, Turnbaugh PJ, Klein S, Gordon JI. Microbial ecology: human gut microbes associated with obesity. Nature 2006; 444 (7122) 1022-1023
  • 62 Raman M, Ahmed I, Gillevet PM , et al. Fecal microbiome and volatile organic compound metabolome in obese humans with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 2013; 11 (7) 868-75 .e1, 3
  • 63 Olsson R, Danielsson A, Järnerot G , et al. Prevalence of primary sclerosing cholangitis in patients with ulcerative colitis. Gastroenterology 1991; 100 (5 Pt 1) 1319-1323
  • 64 Schrumpf E, Elgjo K, Fausa O, Gjone E, Kolmannskog F, Ritland S. Sclerosing cholangitis in ulcerative colitis. Scand J Gastroenterol 1980; 15 (6) 689-697
  • 65 Lichtman SN, Keku J, Clark RL, Schwab JH, Sartor RB. Biliary tract disease in rats with experimental small bowel bacterial overgrowth. Hepatology 1991; 13 (4) 766-772
  • 66 Lichtman SN, Wang J, Clark RL. A microcholangiographic study of liver disease models in rats. Acad Radiol 1995; 2 (6) 515-521
  • 67 Lichtman SN, Keku J, Schwab JH, Sartor RB. Evidence for peptidoglycan absorption in rats with experimental small bowel bacterial overgrowth. Infect Immun 1991; 59 (2) 555-562
  • 68 Bharucha AE, Jorgensen R, Lichtman SN, LaRusso NF, Lindor KD. A pilot study of pentoxifylline for the treatment of primary sclerosing cholangitis. Am J Gastroenterol 2000; 95 (9) 2338-2342
  • 69 Lichtman SN, Okoruwa EE, Keku J, Schwab JH, Sartor RB. Degradation of endogenous bacterial cell wall polymers by the muralytic enzyme mutanolysin prevents hepatobiliary injury in genetically susceptible rats with experimental intestinal bacterial overgrowth. J Clin Invest 1992; 90 (4) 1313-1322
  • 70 Lichtman SN, Keku J, Schwab JH, Sartor RB. Hepatic injury associated with small bowel bacterial overgrowth in rats is prevented by metronidazole and tetracycline. Gastroenterology 1991; 100 (2) 513-519
  • 71 Yamada S, Ishii M, Liang LS, Yamamoto T, Toyota T. Small duct cholangitis induced by N-formyl L-methionine L-leucine L-tyrosine in rats. J Gastroenterol 1994; 29 (5) 631-636
  • 72 Sasatomi K, Noguchi K, Sakisaka S, Sata M, Tanikawa K. Abnormal accumulation of endotoxin in biliary epithelial cells in primary biliary cirrhosis and primary sclerosing cholangitis. J Hepatol 1998; 29 (3) 409-416
  • 73 Tabibian JH, O'Hara SP, Trussoni CE , et al. Absence of the intestinal microbiota exacerbates hepatobiliary disease in a murine model of primary sclerosing cholangitis. Hepatology 2016; 63 (1) 185-196
  • 74 Sabino J, Vieira-Silva S, Machiels K , et al. Primary sclerosing cholangitis is characterised by intestinal dysbiosis independent from IBD. Gut 2016; 65 (10) 1681-1689
  • 75 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 2016; gutjnl-2015-310500
  • 76 Quraishi MN, Sergeant M, Kay G , et al. The gut-adherent microbiota of PSC-IBD is distinct to that of IBD. Gut 2016; DOI: ;gutjnl-2016-311915.
  • 77 Rühlemann MC, Heinsen FA, Zenouzi R, Lieb W, Franke A, Schramm C. Faecal microbiota profiles as diagnostic biomarkers in primary sclerosing cholangitis. Gut 2016; gutjnl-2016-312180
  • 78 Torres J, Bao X, Goel A , et al. The features of mucosa-associated microbiota in primary sclerosing cholangitis. Aliment Pharmacol Ther 2016; 43 (7) 790-801
  • 79 Rossen NG, Fuentes S, Boonstra K , et al. The mucosa-associated microbiota of PSC patients is characterized by low diversity and low abundance of uncultured Clostridiales II. J Crohn's Colitis 2015; 9 (4) 342-348
  • 80 Canani RB, Costanzo MD, Leone L, Pedata M, Meli R, Calignano A. Potential beneficial effects of butyrate in intestinal and extraintestinal diseases. World J Gastroenterol 2011; 17 (12) 1519-1528
  • 81 Bowlus CL. Cutting edge issues in primary sclerosing cholangitis. Clin Rev Allergy Immunol 2011; 41 (2) 139-150
  • 82 Rankin JG, Boden RW, Goulston SJ, Morrow W. The liver in ulcerative colitis; treatment of pericholangitis with tetracycline. Lancet 1959; 2 (7112) 1110-1112
  • 83 Mistilis SP, Skyring AP, Goulston SJ. Effect of long-term tetracycline therapy, steroid therapy and colectomy in pericholangitis associated with ulcerative colitis. Australas Ann Med 1965; 14 (4) 286-294
  • 84 Tada S, Ebinuma H, Saito H, Hibi T. Therapeutic benefit of sulfasalazine for patients with primary sclerosing cholangitis. J Gastroenterol 2006; 41 (4) 388-389
  • 85 Kozaiwa K, Tajiri H, Sawada A , et al. Three paediatric cases of primary sclerosing cholangitis treated with ursodeoxycholic acid and sulphasalazine. J Gastroenterol Hepatol 1998; 13 (8) 825-829
  • 86 Vleggaar FP, Monkelbaan JF, van Erpecum KJ. Probiotics in primary sclerosing cholangitis: a randomized placebo-controlled crossover pilot study. Eur J Gastroenterol Hepatol 2008; 20 (7) 688-692
  • 87 Cox KL, Cox KM. Oral vancomycin: treatment of primary sclerosing cholangitis in children with inflammatory bowel disease. J Pediatr Gastroenterol Nutr 1998; 27 (5) 580-583
  • 88 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 (6) 604-612
  • 89 Boner AL, Peroni D, Bodini A, Delaini G, Piacentini G. Azithromycin may reduce cholestasis in primary sclerosing cholangitis: a case report and serendipitous observation. Int J Immunopathol Pharmacol 2007; 20 (4) 847-849
  • 90 Färkkilä M, Karvonen AL, Nurmi H , et al. Metronidazole and ursodeoxycholic acid for primary sclerosing cholangitis: a randomized placebo-controlled trial. Hepatology 2004; 40 (6) 1379-1386
  • 91 Silveira MG, Torok NJ, Gossard AA , et al. Minocycline in the treatment of patients with primary sclerosing cholangitis: results of a pilot study. Am J Gastroenterol 2009; 104 (1) 83-88
  • 92 Tabibian JH, Gossard A, El-Youssef M , et al. Prospective clinical trial of rifaximin therapy for patients with primary sclerosing cholangitis. Am J Ther 2014; DOI: 10.1097/MJT.0000000000000102.
  • 93 Davies YK, Cox KM, Abdullah BA, Safta A, Terry AB, Cox KL. Long-term treatment of primary sclerosing cholangitis in children with oral vancomycin: an immunomodulating antibiotic. J Pediatr Gastroenterol Nutr 2008; 47 (1) 61-67
  • 94 Dudley MN, Quintiliani R, Nightingale CH, Gontarz N. Absorption of vancomycin. Ann Intern Med 1984; 101 (1) 144
  • 95 Matzke GR, Halstenson CE, Olson PL, Collins AJ, Abraham PA. Systemic absorption of oral vancomycin in patients with renal insufficiency and antibiotic-associated colitis. Am J Kidney Dis 1987; 9 (5) 422-425
  • 96 Matzke GR, Zhanel GG, Guay DR. Clinical pharmacokinetics of vancomycin. Clin Pharmacokinet 1986; 11 (4) 257-282
  • 97 Abarbanel DN, Seki SM, Davies Y , et al. Immunomodulatory effect of vancomycin on Treg in pediatric inflammatory bowel disease and primary sclerosing cholangitis. J Clin Immunol 2013; 33 (2) 397-406
  • 98 Shimizu M, Iwasaki H, Mase S, Yachie A. Successful treatment of primary sclerosing cholangitis with a steroid and a probiotic. Case Rep Gastroenterol 2012; 6 (2) 249-253