Microbial Players in Primary Sclerosing Cholangitis: Current Evidence and Concepts
2023; Elsevier BV; Volume: 17; Issue: 3 Linguagem: Inglês
10.1016/j.jcmgh.2023.12.005
ISSN2352-345X
AutoresBurcin Özdirik, Bernd Schnabl,
Tópico(s)Liver Disease Diagnosis and Treatment
ResumoPrimary sclerosing cholangitis (PSC) is a rare cholestatic liver disease with progressive biliary inflammation, destruction of the biliary tract, and fibrosis, resulting in liver cirrhosis and end-stage liver disease. To date, liver transplantation is the only definitive treatment option for PSC. The precise etiology of PSC remains elusive, but it is widely accepted to involve a complex interplay between genetic predisposition, immunologic dysfunction, and environmental influence. In recent years, the gut-liver axis has emerged as a crucial pathway contributing to the pathogenesis of PSC, with particular focus on the role of gut microbiota. However, the role of the fungal microbiome or mycobiome has been overlooked for years, resulting in a lack of comprehensive studies on its involvement in PSC. In this review, we clarify the present clinical and mechanistic data and concepts concerning the gut bacterial and fungal microbiota in the context of PSC. This review sheds light on the role of specific microbes and elucidates the dynamics of bacterial and fungal populations. Moreover, we discuss the latest insights into microbe-altering therapeutic approaches involving the gut-liver axis and bile acid metabolism. Primary sclerosing cholangitis (PSC) is a rare cholestatic liver disease with progressive biliary inflammation, destruction of the biliary tract, and fibrosis, resulting in liver cirrhosis and end-stage liver disease. To date, liver transplantation is the only definitive treatment option for PSC. The precise etiology of PSC remains elusive, but it is widely accepted to involve a complex interplay between genetic predisposition, immunologic dysfunction, and environmental influence. In recent years, the gut-liver axis has emerged as a crucial pathway contributing to the pathogenesis of PSC, with particular focus on the role of gut microbiota. However, the role of the fungal microbiome or mycobiome has been overlooked for years, resulting in a lack of comprehensive studies on its involvement in PSC. In this review, we clarify the present clinical and mechanistic data and concepts concerning the gut bacterial and fungal microbiota in the context of PSC. This review sheds light on the role of specific microbes and elucidates the dynamics of bacterial and fungal populations. Moreover, we discuss the latest insights into microbe-altering therapeutic approaches involving the gut-liver axis and bile acid metabolism. SummaryThis review provides an overview of the current knowledge on the gut bacterial and fungal microbiota in primary sclerosing cholangitis. It highlights the importance of certain microbes and explains the changes in bacterial and fungal populations. Additionally, it discusses recent advancements in microbe-altering therapeutic approaches involving the gut-liver axis and bile acid metabolism. This review provides an overview of the current knowledge on the gut bacterial and fungal microbiota in primary sclerosing cholangitis. It highlights the importance of certain microbes and explains the changes in bacterial and fungal populations. Additionally, it discusses recent advancements in microbe-altering therapeutic approaches involving the gut-liver axis and bile acid metabolism. Primary sclerosing cholangitis (PSC) is a rare cholestatic liver disease with progressive biliary inflammation, intrahepatic and extrahepatic strictures, and fibrosis, leading to liver cirrhosis and end-stage liver disease. It is associated with a high risk of biliary and colorectal carcinoma, and concomitant inflammatory bowel disease (IBD), most commonly ulcerative colitis (UC), has been reported in up to 80% of patients with PSC.1Hov J.R. Karlsen T.H. The microbiota and the gut-liver axis in primary sclerosing cholangitis.Nat Rev Gastroenterol Hepatol. 2023; 20: 135-154Crossref PubMed Scopus (16) Google Scholar,2Karlsen T.H. Folseraas T. Thorburn D. et al.Primary sclerosing cholangitis: a comprehensive review.J Hepatol. 2017; 67: 1298-1323Abstract Full Text Full Text PDF PubMed Scopus (468) Google Scholar It has even been proposed that PSC-associated colitis presents a distinct IBD entity alongside Crohn's disease (CD) and UC.3Loftus E.V. Harewood G.C. Loftus C.G. et al.PSC-IBD: a unique form of inflammatory bowel disease associated with primary sclerosing cholangitis.Gut. 2005; 54: 91-96Crossref PubMed Scopus (602) Google Scholar To date, no effective medical treatment has been proven to increase survival and the only definitive treatment option is liver transplantation. Even though outcome after liver transplantation is excellent, the risk of recurrent PSC in the new liver is considerably high (up to 30%).1Hov J.R. Karlsen T.H. The microbiota and the gut-liver axis in primary sclerosing cholangitis.Nat Rev Gastroenterol Hepatol. 2023; 20: 135-154Crossref PubMed Scopus (16) Google Scholar,4Lindström L. Jørgensen K.K. Boberg K.M. et al.Risk factors and prognosis for recurrent primary sclerosing cholangitis after liver transplantation: a Nordic Multicentre Study.Scand J Gastroenterol. 2018; 53: 297-304Crossref PubMed Scopus (58) Google Scholar The development of prognostic markers and more effective treatment modalities have been limited partly by a lack of studies aiming to understand the disease pathogenesis of this rare but serious disease. In addition to small patient numbers, the absence of in vitro and in vivo models that accurately represent the disease constitutes a limitation in this field.2Karlsen T.H. Folseraas T. Thorburn D. et al.Primary sclerosing cholangitis: a comprehensive review.J Hepatol. 2017; 67: 1298-1323Abstract Full Text Full Text PDF PubMed Scopus (468) Google Scholar Within this framework, the gut microbiota, encompassing bacteria, viruses, fungi, and archaea, play an emerging role. Understanding the composition and dynamics of the gut microbiota in PSC holds great promise for improving the comprehension of disease pathogenesis and identifying potential therapeutic targets. In this review, we clarify the present clinical and mechanistic data and concepts concerning the gut bacterial and fungal microbiota in the context of PSC. Moreover, we elucidate the latest insights into microbe-altering therapeutic approaches involving the gut-liver axis and bile acid metabolism. The precise etiology of PSC remains elusive, but it is widely accepted to involve a complex interplay between genetic predisposition, immunologic dysfunction, and environmental factors.2Karlsen T.H. Folseraas T. Thorburn D. et al.Primary sclerosing cholangitis: a comprehensive review.J Hepatol. 2017; 67: 1298-1323Abstract Full Text Full Text PDF PubMed Scopus (468) Google Scholar In recent years, the gut-liver axis has emerged as a crucial pathway contributing to the pathogenesis of PSC, with particular focus on the role of the gut microbiota.1Hov J.R. Karlsen T.H. The microbiota and the gut-liver axis in primary sclerosing cholangitis.Nat Rev Gastroenterol Hepatol. 2023; 20: 135-154Crossref PubMed Scopus (16) Google Scholar The high prevalence of IBD in patients with PSC suggests a significant involvement of the gut-liver axis. The concept of the gut-liver axis revolves around the bidirectional interaction between the gut and the liver, facilitated by the portal blood circulation to the liver and the flow of bile to the intestine.5Tripathi A. Debelius J. Brenner D.A. et al.The gut-liver axis and the intersection with the microbiome.Nat Rev Gastroenterol Hepatol. 2018; 15: 397-411Crossref PubMed Scopus (814) Google Scholar,6Albillos A. de Gottardi A. Rescigno M. The gut-liver axis in liver disease: pathophysiological basis for therapy.J Hepatol. 2020; 72: 558-577Abstract Full Text Full Text PDF PubMed Scopus (827) Google Scholar In addition, liver metabolites from dietary or xenobiotic substances (eg, free fatty acids, ethanol metabolites, choline metabolites) pass from the liver to the intestine through the systemic circulation (Figure 1A).5Tripathi A. Debelius J. Brenner D.A. et al.The gut-liver axis and the intersection with the microbiome.Nat Rev Gastroenterol Hepatol. 2018; 15: 397-411Crossref PubMed Scopus (814) Google Scholar,7Seo Y.S. Shah V.H. The role of gut-liver axis in the pathogenesis of liver cirrhosis and portal hypertension.Clin Mol Hepatol. 2012; 18: 337-346Crossref PubMed Scopus (0) Google Scholar The gut barrier has the delicate function to allow nutrient absorption, while it must contain microbes and microbial products within the gut lumen. Gut barrier function can be influenced in both directions, positively (eg, butyrate) and negatively (eg, acetaldehyde).5Tripathi A. Debelius J. Brenner D.A. et al.The gut-liver axis and the intersection with the microbiome.Nat Rev Gastroenterol Hepatol. 2018; 15: 397-411Crossref PubMed Scopus (814) Google Scholar Gut barrier dysfunction with an impaired intestinal epithelial barrier (eg, injured by infection, inflammation, or chemical injury) enables portal influx of microbes and their products, also referred to as microbe-associated molecular patterns (MAMPs), to the liver, triggering an inflammatory cascade.6Albillos A. de Gottardi A. Rescigno M. The gut-liver axis in liver disease: pathophysiological basis for therapy.J Hepatol. 2020; 72: 558-577Abstract Full Text Full Text PDF PubMed Scopus (827) Google Scholar This activates Kupffer cells and hepatic stellate cells and results in production of inflammatory cytokines and chemokines, and fibrosis. Gut barrier dysfunction leads to the development of chronic biliary tract infection and inflammation, causing progression of disease.7Seo Y.S. Shah V.H. The role of gut-liver axis in the pathogenesis of liver cirrhosis and portal hypertension.Clin Mol Hepatol. 2012; 18: 337-346Crossref PubMed Scopus (0) Google Scholar, 8Lichtman S.N. Keku J. Clark R.L. et al.Biliary tract disease in rats with experimental small bowel bacterial overgrowth.Hepatology. 1991; 13: 766-772Crossref PubMed Google Scholar, 9Lichtman S.N. Okoruwa E.E. Keku J. et al.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: 1313-1322Crossref PubMed Google Scholar, 10Guicciardi M.E. Trussoni C.E. Krishnan A. et al.Macrophages contribute to the pathogenesis of sclerosing cholangitis in mice.J Hepatol. 2018; 69: 676-686Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar The liver connects with the intestine through secretion of antimicrobial molecules (angiogenin 1, IgA) and bile acids through the biliary tract, which drains into the small intestine. Bile acid metabolism is a fundamental component in the progression of cholestatic liver disorders, such as PSC. As end products of cholesterol metabolism, bile acids, the major constituents of human bile, are synthesized in hepatocytes and enter the small intestine via the bile ducts. Most bile acids (95%) are reabsorbed in the terminal ileum by the apical sodium-dependent bile acid transporter and transported back to the liver. This well-organized process, also referred to as enterohepatic circulation, aims to maintain systemic bile acid homeostasis.11Krautkramer K.A. Fan J. Bäckhed F. Gut microbial metabolites as multi-kingdom intermediates.Nat Rev Microbiol. 2021; 19: 77-94Crossref PubMed Scopus (472) Google Scholar, 12Jia W. Xie G. Bile acid-microbiota crosstalk in gastrointestinal inflammation and carcinogenesis.Nat Rev Gastroenterol Hepatol. 2018; 15: 111-128Crossref PubMed Scopus (1016) Google Scholar, 13Sayin S.I. Wahlström 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: 225-235Abstract Full Text Full Text PDF PubMed Scopus (1562) Google Scholar Bile acids are crucial signaling molecules and regulators of metabolism and immunity, triggering immune reactions that may cause liver injury (Figure 1A).12Jia W. Xie G. Bile acid-microbiota crosstalk in gastrointestinal inflammation and carcinogenesis.Nat Rev Gastroenterol Hepatol. 2018; 15: 111-128Crossref PubMed Scopus (1016) Google Scholar,14Li T. Chiang J.Y. Bile acid signaling in metabolic disease and drug therapy.Pharmacol Rev. 2014; 66: 948-983Crossref PubMed Scopus (636) Google Scholar The signaling of bile acids involves the nuclear farnesoid X receptor (FXR) and TGR5, a membrane-bound G protein–coupled receptor located in the apical membrane of cholangiocytes, among other pathways.15Reich M. Deutschmann K. Sommerfeld A. et al.TGR5 is essential for bile acid-dependent cholangiocyte proliferation in vivo and in vitro.Gut. 2016; 65: 487-501Crossref PubMed Scopus (139) Google Scholar, 16Reich M. Spomer L. Klindt C. et al.Downregulation of TGR5 (GPBAR1) in biliary epithelial cells contributes to the pathogenesis of sclerosing cholangitis.J Hepatol. 2021; 75: 634-646Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar, 17Vavassori P. Mencarelli A. Renga B. et al.The bile acid receptor FXR is a modulator of intestinal innate immunity.J Immunol. 2009; 183: 6251-6261Crossref PubMed Scopus (457) Google Scholar TGR5 modulates the "bicarbonate umbrella," which is produced by cholangiocytes to prevent bile acid toxicity caused by their constant exposure to high bile acid concentrations.18Hohenester S. Wenniger L.M. Paulusma C.C. et al.A biliary HCO3- umbrella constitutes a protective mechanism against bile acid-induced injury in human cholangiocytes.Hepatology. 2012; 55: 173-183Crossref PubMed Scopus (237) Google Scholar,19Beuers U. Hohenester S. de Buy Wenniger L.J. et al.The biliary HCO(3)(-) umbrella: a unifying hypothesis on pathogenetic and therapeutic aspects of fibrosing cholangiopathies.Hepatology. 2010; 52: 1489-1496Crossref PubMed Scopus (287) Google Scholar The bicarbonate/chloride anion exchanger AE2 is a crucial contributor to this protective mechanism and not only located on cholangiocytes but also on apical hepatocyte membranes.18Hohenester S. Wenniger L.M. Paulusma C.C. et al.A biliary HCO3- umbrella constitutes a protective mechanism against bile acid-induced injury in human cholangiocytes.Hepatology. 2012; 55: 173-183Crossref PubMed Scopus (237) Google Scholar Bicarbonate may keep potentially toxic bile acids, such as glycochenodeoxycholic acid, a glycine-conjugated form of the primary bile acid chenodeoxycholic acid, in their negatively loaded form, preventing them from protonation, which results in diffusional penetration and apoptotic cell death in human cholangiocyte cell lines.18Hohenester S. Wenniger L.M. Paulusma C.C. et al.A biliary HCO3- umbrella constitutes a protective mechanism against bile acid-induced injury in human cholangiocytes.Hepatology. 2012; 55: 173-183Crossref PubMed Scopus (237) Google Scholar FXR is an important signaling pathway in bile acid metabolism that directly regulates bile acid synthesis, and is involved in immunomodulation and maintenance of intestinal epithelial barrier function. Activation of FXR, which is also located in the small intestine, leads to the transcription and release of FGF19 into the portal vein, which binds to fibroblast growth factor (FGF) receptor 4 on hepatocytes and results in suppression of hepatic bile acid synthesis.12Jia W. Xie G. Bile acid-microbiota crosstalk in gastrointestinal inflammation and carcinogenesis.Nat Rev Gastroenterol Hepatol. 2018; 15: 111-128Crossref PubMed Scopus (1016) Google Scholar,20Gadaleta R.M. Moschetta A. Dark and bright side of targeting fibroblast growth factor receptor 4 in the liver.J Hepatol. 2021; 75: 1440-1451Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Furthermore, bile acids have bacteriostatic properties, whereas gut bacteria can metabolize primary into secondary bile acids by deconjugation and dehydroxylation.12Jia W. Xie G. Bile acid-microbiota crosstalk in gastrointestinal inflammation and carcinogenesis.Nat Rev Gastroenterol Hepatol. 2018; 15: 111-128Crossref PubMed Scopus (1016) Google Scholar,21Li Y. Tang R. Leung P.S.C. et al.Bile acids and intestinal microbiota in autoimmune cholestatic liver diseases.Autoimmun Rev. 2017; 16: 885-896Crossref PubMed Scopus (158) Google Scholar In recent years, a variety of publications described the gut microbiota in PSC with or without IBD compared with IBD and healthy cohorts (Table 1). Most microbiome studies sequenced the 16S ribosomal RNA (rRNA) gene for microbiota composition analysis.22Kummen M. Holm K. Anmarkrud J.A. 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: 611-619Crossref PubMed Scopus (277) Google Scholar, 23Sabino J. Vieira-Silva S. Machiels K. et al.Primary sclerosing cholangitis is characterised by intestinal dysbiosis independent from IBD.Gut. 2016; 65: 1681-1689Crossref PubMed Scopus (279) Google Scholar, 24Rühlemann 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: 580-589Crossref PubMed Scopus (60) Google Scholar, 25Bajer L. Kverka M. Kostovcik M. et al.Distinct gut microbiota profiles in patients with primary sclerosing cholangitis and ulcerative colitis.World J Gastroenterol. 2017; 23: 4548-4558Crossref PubMed Scopus (228) Google Scholar, 26Kummen M. Thingholm L.B. Rühlemann M.C. et al.Altered gut microbial metabolism of essential nutrients in primary sclerosing cholangitis.Gastroenterology. 2021; 160: 1784-1798Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar, 27Awoniyi M. Wang J. Ngo B. et al.Protective and aggressive bacterial subsets and metabolites modify hepatobiliary inflammation and fibrosis in a murine model of PSC.Gut. 2023; 72: 671-685Crossref PubMed Scopus (16) Google Scholar, 28Iwasawa K. Suda W. Tsunoda T. et al.Characterisation of the faecal microbiota in Japanese patients with paediatric-onset primary sclerosing cholangitis.Gut. 2017; 66: 1344-1346Crossref PubMed Scopus (45) Google Scholar, 29Lemoinne S. Kemgang A. Ben Belkacem K. et al.Fungi participate in the dysbiosis of gut microbiota in patients with primary sclerosing cholangitis.Gut. 2020; 69: 92-102Crossref PubMed Scopus (130) Google Scholar Previous research on the fecal microbiome in PSC has shown that alterations of specific microbes vary, but they consistently demonstrate a notable decrease in microbial diversity and a distinct shift toward a dysbiotic state compared with healthy subjects and IBD populations. Patients with PSC showed a higher abundance of Enterococcus spp (especially Enterococcus faecalis), Fusobacterium, Veillonella spp, and Enterobacteriaceae (Escherichia coli, Klebsiella pneumonia), suggesting a potential translocation of those microbes, which may contribute to PSC pathogenesis.22Kummen M. Holm K. Anmarkrud J.A. 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: 611-619Crossref PubMed Scopus (277) Google Scholar, 23Sabino J. Vieira-Silva S. Machiels K. et al.Primary sclerosing cholangitis is characterised by intestinal dysbiosis independent from IBD.Gut. 2016; 65: 1681-1689Crossref PubMed Scopus (279) Google Scholar, 24Rühlemann 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: 580-589Crossref PubMed Scopus (60) Google Scholar, 25Bajer L. Kverka M. Kostovcik M. et al.Distinct gut microbiota profiles in patients with primary sclerosing cholangitis and ulcerative colitis.World J Gastroenterol. 2017; 23: 4548-4558Crossref PubMed Scopus (228) Google Scholar, 26Kummen M. Thingholm L.B. Rühlemann M.C. et al.Altered gut microbial metabolism of essential nutrients in primary sclerosing cholangitis.Gastroenterology. 2021; 160: 1784-1798Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar, 27Awoniyi M. Wang J. Ngo B. et al.Protective and aggressive bacterial subsets and metabolites modify hepatobiliary inflammation and fibrosis in a murine model of PSC.Gut. 2023; 72: 671-685Crossref PubMed Scopus (16) Google Scholar,30Liu Q. Li B. Li Y. et al.Altered faecal microbiome and metabolome in IgG4-related sclerosing cholangitis and primary sclerosing cholangitis.Gut. 2022; 71: 899-909Crossref PubMed Scopus (0) Google Scholar Additionally, bacterial species, such as Lactobacillus spp and Streptococcus spp, were increased, whereas there was a decrease in Coprococcus spp and Blautia spp in the studied samples.22Kummen M. Holm K. Anmarkrud J.A. 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: 611-619Crossref PubMed Scopus (277) Google Scholar,24Rühlemann 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: 580-589Crossref PubMed Scopus (60) Google Scholar, 25Bajer L. Kverka M. Kostovcik M. et al.Distinct gut microbiota profiles in patients with primary sclerosing cholangitis and ulcerative colitis.World J Gastroenterol. 2017; 23: 4548-4558Crossref PubMed Scopus (228) Google Scholar, 26Kummen M. Thingholm L.B. Rühlemann M.C. et al.Altered gut microbial metabolism of essential nutrients in primary sclerosing cholangitis.Gastroenterology. 2021; 160: 1784-1798Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar, 27Awoniyi M. Wang J. Ngo B. et al.Protective and aggressive bacterial subsets and metabolites modify hepatobiliary inflammation and fibrosis in a murine model of PSC.Gut. 2023; 72: 671-685Crossref PubMed Scopus (16) Google Scholar,29Lemoinne S. Kemgang A. Ben Belkacem K. et al.Fungi participate in the dysbiosis of gut microbiota in patients with primary sclerosing cholangitis.Gut. 2020; 69: 92-102Crossref PubMed Scopus (130) Google Scholar,31Rühlemann M.C. Solovjeva M.E.L. Zenouzi R. et al.Gut mycobiome of primary sclerosing cholangitis patients is characterised by an increase of Trichocladium griseum and Candida species.Gut. 2020; 69: 1890-1892Crossref PubMed Scopus (19) Google Scholar,32Nakamoto 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: 492-503Crossref PubMed Scopus (245) Google Scholar So far, the high abundance of Veillonella spp in PSC (eg, Veillonella atypica and Veillonella parvula) has been validated by several published studies.23Sabino J. Vieira-Silva S. Machiels K. et al.Primary sclerosing cholangitis is characterised by intestinal dysbiosis independent from IBD.Gut. 2016; 65: 1681-1689Crossref PubMed Scopus (279) Google Scholar,25Bajer L. Kverka M. Kostovcik M. et al.Distinct gut microbiota profiles in patients with primary sclerosing cholangitis and ulcerative colitis.World J Gastroenterol. 2017; 23: 4548-4558Crossref PubMed Scopus (228) Google Scholar,26Kummen M. Thingholm L.B. Rühlemann M.C. et al.Altered gut microbial metabolism of essential nutrients in primary sclerosing cholangitis.Gastroenterology. 2021; 160: 1784-1798Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar,28Iwasawa K. Suda W. Tsunoda T. et al.Characterisation of the faecal microbiota in Japanese patients with paediatric-onset primary sclerosing cholangitis.Gut. 2017; 66: 1344-1346Crossref PubMed Scopus (45) Google Scholar,29Lemoinne S. Kemgang A. Ben Belkacem K. et al.Fungi participate in the dysbiosis of gut microbiota in patients with primary sclerosing cholangitis.Gut. 2020; 69: 92-102Crossref PubMed Scopus (130) Google Scholar,33Liwinski T. Zenouzi R. John C. et al.Alterations of the bile microbiome in primary sclerosing cholangitis.Gut. 2020; 69: 665-672Crossref PubMed Scopus (77) Google Scholar Veillonella seems to be more prevalent in advanced PSC and in patients with PSC and cirrhosis.23Sabino J. Vieira-Silva S. Machiels K. et al.Primary sclerosing cholangitis is characterised by intestinal dysbiosis independent from IBD.Gut. 2016; 65: 1681-1689Crossref PubMed Scopus (279) Google Scholar,26Kummen M. Thingholm L.B. Rühlemann M.C. et al.Altered gut microbial metabolism of essential nutrients in primary sclerosing cholangitis.Gastroenterology. 2021; 160: 1784-1798Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar On conducting a more detailed analysis that excluded patients with cirrhosis, no substantial correlation between Veillonella spp and PSC remained.23Sabino J. Vieira-Silva S. Machiels K. et al.Primary sclerosing cholangitis is characterised by intestinal dysbiosis independent from IBD.Gut. 2016; 65: 1681-1689Crossref PubMed Scopus (279) Google Scholar Because high abundance of Veillonella spp has also been associated with metabolic dysfunction-associated steatotic liver disease, autoimmune hepatitis, and primary biliary cholangitis, its presence might also be more a sign of progressive chronic liver disease than a PSC-specific association.34Tang 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: 534-541Crossref PubMed Scopus (292) Google Scholar, 35Wei Y. Li Y. Yan L. et al.Alterations of gut microbiome in autoimmune hepatitis.Gut. 2020; 69: 569-577Crossref PubMed Scopus (187) Google Scholar, 36Liwinski T. Casar C. 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Walters T.D. et al.Prediction of complicated disease course for children newly diagnosed with Crohn's disease: a multicentre inception cohort study.Lancet. 2017; 389: 1710-1718Abstract Full Text Full Text PDF PubMed Scopus (411) Google Scholar Thus, additional studies with larger patient cohorts including patients with cirrhosis supported by experimental studies, is crucial for further characterization of the role of Veillonella spp in PSC.40Özdirik B. Müller T. Wree A. et al.The role of microbiota in primary sclerosing cholangitis and related biliary malignancies.Int J Mol Sci. 2021; 22: 6975Crossref PubMed Scopus (17) Google Scholar A Japanese study found high abundance of K pneumoniae and Proteus mirabilis in patients with PSC.32Nakamoto 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: 492-503Crossref PubMed Scopus (245) Google Scholar To support their clinical findings mechanistically, they colonized gnotobiotic mice with fecal samples from a PSC-IBD patient with high K pneumoniae abundance in stool. Colonization with K pneumoniae in vivo was linked to bacterial translocation and predisposition to T helper cell type 17 (Th17)-driven hepatobiliary injuries in mice. Bacteriophage treatment successfully suppressed intestinal K pneumoniae levels and reduced liver inflammation and disease severity in germ-free mice colonized with K pneumoniae and specific-pathogen free mice.41Ichikawa M. Nakamoto N. Kredo-Russo S. et al.Bacteriophage therapy against pathological Klebsiella pneumoniae ameliorates the course of primary sclerosing cholangitis.Nat Commun. 2023; 14: 3261Crossref PubMed Scopus (0) Google Scholar Enterococcus and Fusobacterium are other microbes enriched in the fecal microbiome of patients with PSC.23Sabino J. Vieira-Silva S. Machiels K. et al.Primary sclerosing cholangitis is characterised by intestinal dysbiosis independent from IBD.Gut. 2016; 65: 1681-1689Crossref PubMed Scopus (279) Google Scholar,24Rühlemann 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: 580-589Crossref PubMed Scopus (60) Google Scholar Fecal Enterococcus spp abundance was associated with high serum alkaline phosphatase (ALP) levels, indicating a connection between the presence of this bacterium and the degree of cholestasis.23Sabino J. Vieira-Silva S. Machiels K. et al.Primary sclerosing cholangitis is characterised by intestinal dysbiosis independent from IBD.Gut. 2016; 65: 1681-1689Crossref PubMed Scopus (279) Google Scholar,42Vieira-Silva S. Sabino J. Valles-Colomer M. et al.Quantitative microbiome profiling disentangles inflammation- and bile duct obstruction-associated microbiota alterations across PSC/IBD diagnoses.Nat Microbiol. 2019; 4: 1826-1831Crossref PubMed Scopus (117) Google Scholar Additionally, measuring levels of fecal calprotectin revealed an association between Enterococcus spp and Veillonella with intestinal inflammation, indicating a potential link between cholestasis and intestinal
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