AIM: To characterize the gut bacterial microbiota of patients with primary sclerosing cholangitis (PSC) and ulcerative colitis (UC). METHODS: Stool samples were collected and relevant clinical data obtained from 106 study participants, 43 PSC patients with (n = 32) or without (n = 11) concomitant inflammatory bowel disease, 32 UC patients, and 31 healthy controls. The V3 and V4 regions of the 16S ribosomal RNA gene were sequenced on Illumina MiSeq platform to cover low taxonomic levels. Data were further processed in QIIME employing MaAsLin and LEfSe tools for analysis of the output data. RESULTS: Microbial profiles in both PSC and UC were characterized by low bacterial diversity and significant change in global microbial composition. Rothia, Enterococcus, Streptococcus, Veillonella, and three other genera were markedly overrepresented in PSC regardless of concomitant inflammatory bowel disease (IBD). Rothia, Veillonella and Streptococcus were tracked to the species level to identify Rothia mucilaginosa, Streptococcus infantus, S. alactolyticus, and S. equi along with Veillonella parvula and V. dispar. PSC was further characterized by decreased abundance of Adlercreutzia equolifaciens and Prevotella copri. Decrease in genus Phascolarctobacterium was linked to presence of colonic inflammation regardless of IBD phenotype. Akkermansia muciniphila, Butyricicoccus pullicaecorum and Clostridium colinum were decreased in UC along with genus Roseburia. Low levels of serum albumin were significantly correlated with enrichment of order Actinomycetales. CONCLUSION: PSC is associated with specific gut microbes independently of concomitant IBD and several bacterial taxa clearly distinguish IBD phenotypes (PSC-IBD and UC).

Lukas Bajer Peter Macinga Jan Brezina Pavel Wohl Julius Spicak Pavel Drastich Department of Gastroenterology and Hepatology Institute for Clinical and Experimental Medicine 14021 Prague Czech Republic

Zobrazit více v PubMed

Gow PJ, Chapman RW. Liver transplantation for primary sclerosing cholangitis. Liver. 2000;20:97–103. PubMed

Chapman RW, Arborgh BA, Rhodes JM, Summerfield JA, Dick R, Scheuer PJ, Sherlock S. Primary sclerosing cholangitis: a review of its clinical features, cholangiography, and hepatic histology. Gut. 1980;21:870–877. PubMed PMC

Levy C, Lindor KD. Primary sclerosing cholangitis: epidemiology, natural history, and prognosis. Semin Liver Dis. 2006;26:22–30. PubMed

Karlsen TH, Schrumpf E, Boberg KM. Update on primary sclerosing cholangitis. Dig Liver Dis. 2010;42:390–400. PubMed

Chapman R, Fevery J, Kalloo A, Nagorney DM, Boberg KM, Shneider B, Gores GJ. Diagnosis and management of primary sclerosing cholangitis. Hepatology. 2010;51:660–678. PubMed

Hirschfield GM, Karlsen TH, Lindor KD, Adams DH. Primary sclerosing cholangitis. Lancet. 2013;382:1587–1599. PubMed

Loftus EV, Harewood GC, Loftus CG, Tremaine WJ, Harmsen WS, Zinsmeister AR, Jewell DA, Sandborn WJ. PSC-IBD: a unique form of inflammatory bowel disease associated with primary sclerosing cholangitis. Gut. 2005;54:91–96. PubMed PMC

Sartor RB. Microbial influences in inflammatory bowel diseases. Gastroenterology. 2008;134:577–594. PubMed

Bentley RW, Keenan JI, Gearry RB, Kennedy MA, Barclay ML, Roberts RL. Incidence of Mycobacterium avium subspecies paratuberculosis in a population-based cohort of patients with Crohn’s disease and control subjects. Am J Gastroenterol. 2008;103:1168–1172. PubMed

Tannock GW. Molecular analysis of the intestinal microflora in IBD. Mucosal Immunol. 2008;1 Suppl 1:S15–S18. PubMed

Lichtman SN, Keku J, Clark RL, Schwab JH, Sartor RB. Biliary tract disease in rats with experimental small bowel bacterial overgrowth. Hepatology. 1991;13:766–772. PubMed

Tabibian JH, Weeding E, Jorgensen RA, Petz JL, Keach JC, Talwalkar JA, Lindor KD. Randomised clinical trial: vancomycin or metronidazole in patients with primary sclerosing cholangitis - a pilot study. Aliment Pharmacol Ther. 2013;37:604–612. PubMed

Kummen M, Holm K, Anmarkrud JA, Nygård S, Vesterhus M, Høivik ML, Trøseid M, Marschall HU, Schrumpf E, Moum B, 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

Kummen M, Hov JR. Response to ‘Faecal microbiota profiles as diagnostic biomarkers in primary sclerosing cholangitis’ by Rühlemann et al. Gut. 2017;66:755–756. PubMed

Torres J, Bao X, Goel A, Colombel JF, Pekow J, Jabri B, Williams KM, Castillo A, Odin JA, Meckel K, et al. The features of mucosa-associated microbiota in primary sclerosing cholangitis. Aliment Pharmacol Ther. 2016;43:790–801. PubMed PMC

Sabino J, Vieira-Silva S, Machiels K, Joossens M, Falony G, Ballet V, Ferrante M, Van Assche G, Van der Merwe S, Vermeire S, et al. Primary sclerosing cholangitis is characterised by intestinal dysbiosis independent from IBD. Gut. 2016;65:1681–1689. PubMed PMC

Quraishi MN, Sergeant M, Kay G, Iqbal T, Chan J, Constantinidou C, Trivedi P, Ferguson J, Adams DH, Pallen M, et al. The gut-adherent microbiota of PSC-IBD is distinct to that of IBD. Gut. 2017;66:386–388. PubMed

Kevans D, Tyler AD, Holm K, Jørgensen KK, Vatn MH, Karlsen TH, Kaplan GG, Eksteen B, Gevers D, Hov JR, et al. Characterization of Intestinal Microbiota in Ulcerative Colitis Patients with and without Primary Sclerosing Cholangitis. J Crohns Colitis. 2016;10:330–337. PubMed PMC

Rossen NG, Fuentes S, Boonstra K, D’Haens GR, Heilig HG, Zoetendal EG, de Vos WM, Ponsioen CY. The mucosa-associated microbiota of PSC patients is characterized by low diversity and low abundance of uncultured Clostridiales II. J Crohns Colitis. 2015;9:342–348. PubMed

Rühlemann MC, Heinsen FA, Zenouzi R, Lieb W, Franke A, Schramm C. Faecal microbiota profiles as diagnostic biomarkers in primary sclerosing cholangitis. Gut. 2017;66:753–754. PubMed

Cardona S, Eck A, Cassellas M, Gallart M, Alastrue C, Dore J, Azpiroz F, Roca J, Guarner F, Manichanh C. Storage conditions of intestinal microbiota matter in metagenomic analysis. BMC Microbiol. 2012;12:158. PubMed PMC

Tedjo DI, Jonkers DM, Savelkoul PH, Masclee AA, van Best N, Pierik MJ, Penders J. The effect of sampling and storage on the fecal microbiota composition in healthy and diseased subjects. PLoS One. 2015;10:e0126685. PubMed PMC

Yu Y, Lee C, Kim J, Hwang S. Group-specific primer and probe sets to detect methanogenic communities using quantitative real-time polymerase chain reaction. Biotechnol Bioeng. 2005;89:670–679. PubMed

Caporaso JG, Kuczynski J, Stombaugh J, Bittinger K, Bushman FD, Costello EK, Fierer N, Peña AG, Goodrich JK, Gordon JI, et al. QIIME allows analysis of high-throughput community sequencing data. Nat Methods. 2010;7:335–336. PubMed PMC

Edgar RC, Flyvbjerg H. Error filtering, pair assembly and error correction for next-generation sequencing reads. Bioinformatics. 2015;31:3476–3482. PubMed

Lozupone C, Knight R. UniFrac: a new phylogenetic method for comparing microbial communities. Appl Environ Microbiol. 2005;71:8228–8235. PubMed PMC

Tickle T, Waldron L, Yiren Lu HC. Multivariate association of microbial communities with rich metadata in high-dimensional studies

Beuers U. Hepatic overlap syndromes. J Hepatol. 2005;42 Suppl:S93–S99. PubMed

Beuers U, Rust C. Overlap syndromes. Semin Liver Dis. 2005;25:311–320. PubMed

Lindor KD, Kowdley KV, Harrison ME. ACG Clinical Guideline: Primary Sclerosing Cholangitis. Am J Gastroenterol. 2015;110:646–659; quiz 660. PubMed

Langan RC, Gotsch PB, Krafczyk MA, Skillinge DD. Ulcerative colitis: diagnosis and treatment. Am Fam Physician. 2007;76:1323–1330. PubMed

Schroeder KW, Tremaine WJ, Ilstrup DM. Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis. A randomized study. N Engl J Med. 1987;317:1625–1629. PubMed

Kverka M, Tlaskalova-Hogenova H. Intestinal Microbiota: Facts and Fiction. Dig Dis. 2017;35:139–147. PubMed

Alipour M, Zaidi D, Valcheva R, Jovel J, Martínez I, Sergi C, Walter J, Mason AL, Wong GK, Dieleman LA, et al. Mucosal Barrier Depletion and Loss of Bacterial Diversity are Primary Abnormalities in Paediatric Ulcerative Colitis. J Crohns Colitis. 2016;10:462–471. PubMed PMC

Qin N, Yang F, Li A, Prifti E, Chen Y, Shao L, Guo J, Le Chatelier E, Yao J, Wu L, et al. Alterations of the human gut microbiome in liver cirrhosis. Nature. 2014;513:59–64. PubMed

Ramanan P, Barreto JN, Osmon DR, Tosh PK. Rothia bacteremia: a 10-year experience at Mayo Clinic, Rochester, Minnesota. J Clin Microbiol. 2014;52:3184–3189. PubMed PMC

Rosen R, Amirault J, Liu H, Mitchell P, Hu L, Khatwa U, Onderdonk A. Changes in gastric and lung microflora with acid suppression: acid suppression and bacterial growth. JAMA Pediatr. 2014;168:932–937. PubMed PMC

Davies YK, Tsay CJ, Caccamo DV, Cox KM, Castillo RO, Cox KL. Successful treatment of recurrent primary sclerosing cholangitis after orthotopic liver transplantation with oral vancomycin. Case Rep Transplant. 2013;2013:314292. PubMed PMC

McWhinney PH, Kibbler CC, Gillespie SH, Patel S, Morrison D, Hoffbrand AV, Prentice HG. Stomatococcus mucilaginosus: an emerging pathogen in neutropenic patients. Clin Infect Dis. 1992;14:641–646. PubMed

Bajaj JS, Hylemon PB, Ridlon JM, Heuman DM, Daita K, White MB, Monteith P, Noble NA, Sikaroodi M, Gillevet PM. 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–G685. PubMed PMC

Mjelle AB, Mulabecirovic A, Hausken T, Havre RF, Gilja OH, Vesterhus M. Ultrasound and Point Shear Wave Elastography in Livers of Patients with Primary Sclerosing Cholangitis. Ultrasound Med Biol. 2016;42:2146–2155. PubMed

Maruo T, Sakamoto M, Ito C, Toda T, Benno Y. Adlercreutzia equolifaciens gen. nov., sp. nov., an equol-producing bacterium isolated from human faeces, and emended description of the genus Eggerthella. Int J Syst Evol Microbiol. 2008;58:1221–1227. PubMed

Setchell KD, Zhao X, Jha P, Heubi JE, Brown NM. The pharmacokinetic behavior of the soy isoflavone metabolite S-(-)equol and its diastereoisomer R-(+)equol in healthy adults determined by using stable-isotope-labeled tracers. Am J Clin Nutr. 2009;90:1029–1037. PubMed PMC

Alvaro D, Invernizzi P, Onori P, Franchitto A, De Santis A, Crosignani A, Sferra R, Ginanni-Corradini S, Mancino MG, Maggioni M, et al. Estrogen receptors in cholangiocytes and the progression of primary biliary cirrhosis. J Hepatol. 2004;41:905–912. PubMed

Tamura S, Sugawara Y, Kokudo N. Primary sclerosing cholangitis as an intractable disease. Intractable Rare Dis Res. 2012;1:13–17. PubMed PMC

Png CW, Lindén SK, Gilshenan KS, Zoetendal EG, McSweeney CS, Sly LI, McGuckin MA, Florin TH. Mucolytic bacteria with increased prevalence in IBD mucosa augment in vitro utilization of mucin by other bacteria. Am J Gastroenterol. 2010;105:2420–2428. PubMed

Zoetendal EG, von Wright A, Vilpponen-Salmela T, Ben-Amor K, Akkermans AD, de Vos WM. Mucosa-associated bacteria in the human gastrointestinal tract are uniformly distributed along the colon and differ from the community recovered from feces. Appl Environ Microbiol. 2002;68:3401–3407. PubMed PMC

Eeckhaut V, Machiels K, Perrier C, Romero C, Maes S, Flahou B, Steppe M, Haesebrouck F, Sas B, Ducatelle R, et al. Butyricicoccus pullicaecorum in inflammatory bowel disease. Gut. 2013;62:1745–1752. PubMed

Duboc H, Rajca S, Rainteau D, Benarous D, Maubert MA, Quervain E, Thomas G, Barbu V, Humbert L, Despras G, et al. Connecting dysbiosis, bile-acid dysmetabolism and gut inflammation in inflammatory bowel diseases. Gut. 2013;62:531–539. PubMed

Fujimoto T, Imaeda H, Takahashi K, Kasumi E, Bamba S, Fujiyama Y, Andoh A. Decreased abundance of Faecalibacterium prausnitzii in the gut microbiota of Crohn’s disease. J Gastroenterol Hepatol. 2013;28:613–619. PubMed

Quévrain E, Maubert MA, Michon C, Chain F, Marquant R, Tailhades J, Miquel S, Carlier L, Bermúdez-Humarán LG, Pigneur B, et al. Identification of an anti-inflammatory protein from Faecalibacterium prausnitzii, a commensal bacterium deficient in Crohn’s disease. Gut. 2016;65:415–425. PubMed PMC

Begley M, Gahan CG, Hill C. The interaction between bacteria and bile. FEMS Microbiol Rev. 2005;29:625–651. PubMed

European Association for the Study of the Liver. EASL Clinical Practice Guidelines: management of cholestatic liver diseases. J Hepatol. 2009;51:237–267. PubMed

Van Assche G, Dignass A, Bokemeyer B, Danese S, Gionchetti P, Moser G, Beaugerie L, Gomollón F, Häuser W, Herrlinger K, et al. Second European evidence-based consensus on the diagnosis and management of ulcerative colitis part 3: special situations. J Crohns Colitis. 2013;7:1–33. PubMed

Halilbasic E, Fuchs C, Hofer H, Paumgartner G, Trauner M. Therapy of Primary Sclerosing Cholangitis--Today and Tomorrow. Dig Dis. 2015;33 Suppl 2:149–163. PubMed

Hommes DW, Erkelens W, Ponsioen C, Stokkers P, Rauws E, van der Spek M, ten Kate F, van Deventer SJ. A double-blind, placebo-controlled, randomized study of infliximab in primary sclerosing cholangitis. J Clin Gastroenterol. 2008;42:522–526. PubMed

Franceschet I, Cazzagon N, Del Ross T, D’Incà R, Buja A, Floreani A. Primary sclerosing cholangitis associated with inflammatory bowel disease: an observational study in a Southern Europe population focusing on new therapeutic options. Eur J Gastroenterol Hepatol. 2016;28:508–513. PubMed

Unique clinical, morphological, and molecular characteristics of tumors associated with PSC-IBD

Associations Among Estrogens, the Gut Microbiome and Osteoporosis

Microbiota as the unifying factor behind the hallmarks of cancer

Disease-associated dysbiosis and potential therapeutic role of Akkermansia muciniphila, a mucus degrading bacteria of gut microbiome

Skin microbiota signature distinguishes IBD patients and reflects skin adverse events during anti-TNF therapy

Plectin ensures intestinal epithelial integrity and protects colon against colitis

Diet Rich in Simple Sugars Promotes Pro-Inflammatory Response via Gut Microbiota Alteration and TLR4 Signaling

Oxidative Damage in Sporadic Colorectal Cancer: Molecular Mapping of Base Excision Repair Glycosylases in Colorectal Cancer Patients

Inflammatory Bowel Disease Types Differ in Markers of Inflammation, Gut Barrier and in Specific Anti-Bacterial Response

Diet Rich in Animal Protein Promotes Pro-inflammatory Macrophage Response and Exacerbates Colitis in Mice