Consistent alterations in faecal microbiomes of patients with primary sclerosing cholangitis independent of associated colitis

Abstract

Summary Background Single‐centre studies reported alterations of faecal microbiota in patients with primary sclerosing cholangitis (PSC). As regional factors may affect microbial communities, it is unclear if a microbial signature of PSC exists across different geographical regions. Aim To identify a robust microbial signature of PSC independent of geography and environmental influences. Methods We included 388 individuals (median age, 47 years; range, 15‐78) from Germany and Norway in the study, 137 patients with PSC (n = 75 with colitis), 118 with ulcerative colitis (UC) and 133 healthy controls. Faecal microbiomes were analysed by 16S rRNA gene sequencing (V1‐V2). Differences in relative abundances of single taxa were subjected to a meta‐analysis. Results In both cohorts, microbiota composition (beta‐diversity) differed between PSC patients and controls (P < 0.001). Random forests classification discriminated PSC patients from controls in both geographical cohorts with an average area under the curve of 0.88. Compared to healthy controls, many new cohort‐spanning alterations were identified in PSC, such as an increase of Proteobacteria and the bile‐tolerant genus Parabacteroides, which were detected independent from geographical region. Associated colitis only had minor effects on microbiota composition, suggesting that PSC itself drives the faecal microbiota changes observed. Conclusion Compared to healthy controls, numerous microbiota alterations are reproducible in PSC patients across geographical regions, clearly pointing towards a microbiota composition that is shaped by the disease itself and not by environmental factors. These reproducibly altered microbial populations might provide future insights into the pathophysiology of PSC.

Emerging therapies in primary sclerosing cholangitis: pathophysiological basis and clinical opportunities

“…lipopolysaccharides, LPS) also contributes by involving innate immune responses [32][33][34][35]. Furthermore, a series of studies now strongly indicate that the gut microbiota may be involved in PSC pathogenesis [17,[36][37][38][39][40] giving rise to clinical trials involving fecal transplantation, non-absorbable antibiotics, and other means of manipulating the gut microbiome in patients [17,[41][42][43]. In the bile ducts, bacterial, and fungal colonization may follow cholestasis and endothelial damage, through the establishing of a pathogenic biliary microbiota further propagating inflammation and intercurrent infections [44].…”

“…Altogether, the multi-compound efficacy signals from activation of two distinct targets, FGF and FGF19, in the same biological pathway does hold promise for further trials in PSC, as they do for similar observations in PBC and NAFLD. The relationship between FXR/FGF19-signaling and changes observed in the gut microbiome in PSC also warrant clarification [17,38,108], and may even open for new treatment strategies in a disease in which inflammatory distribution overlaps almost perfectly with the enterohepatic circulation of bile acids [46,109].…”

The Role of the Intestine in the Pathogenesis of Primary Sclerosing Cholangitis: Evidence and Therapeutic Implications

“…(9) Compared to healthy controls (HC), patients with PSC have significant suppression of global diversity indices (intraindividual or α-diversity) as well as differences in population composition and species abundance between sampling units (β-diversity). (10)(11)(12)(13)(14)(15)(16)(17) In the largest study showing these differences, Rühlemann et al compared 127 patients with PSC from Norway and Germany to 118 patients with UC alone and 133 HC. (15) Interestingly, the majority of core microbiota was shared between German and Norwegian patients, although there were small differences in both α-diversity and β-diversity between the two.…”

Editorial: gut microbial profile associated with primary sclerosing cholangitis—what is new and how do we progress from here?

“…This makes it challenging to explore specific microbiota‐mediated disease mechanisms in PSC. Rühlemann et al presented the largest study to date in this field consisting of 388 individuals (137 with PSC) based in Norway and Germany . They confirmed that the gut (faecal) microbial profiles of patients with PSC were distinct to UC and healthy controls and this was independent of medication or presence of colitis, although there was a higher median faecal calprotectin level in the UC cohort.…”