Geography-independent mucosal microbiota alterations in primary sclerosing cholangitis persist after liver transplantation

TL;DR

This study finds that gut microbiota changes in primary sclerosing cholangitis persist after liver transplantation and are linked to liver disease severity, not intestinal inflammation.

Contribution

The study identifies geography-independent mucosal microbiota patterns in PSC that persist post-transplant and correlate with liver injury markers.

Findings

PSC is associated with a distinct mucosal microbiota profile dominated by Enterococcus, Pseudomonas, and others.

Microbial dysbiosis correlates with liver injury markers like ALP and GGT, but not with intestinal inflammation.

PSC recurrence shows similar microbial trends to pre-transplant PSC but lacks a unique microbiota profile.

Abstract

Primary sclerosing cholangitis (PSC)-associated alterations of fecal gut microbiota have already been described, but data on the mucosal microbiota are still limited. We aimed to further define disease-specific mucosal microbial patterns independent of geography and assess the relationship to liver transplantation (LTx), gut inflammation (inflammatory bowel disease), and PSC recurrence (rPSC).

We performed 16S ribosomal RNA gene (V3–V4) sequencing of ileocolonic biopsies from 115 patients with PSC (pre-LTx), 159 liver-transplanted patients (post_LTx, recurrence occurred in 38), and 96 healthy controls (HC) from Norway and the Czech Republic.

Alpha diversity was lower in all PSC groups compared with HC. Elastic net models discriminated pre_LTx (AUC ileum 0.97; colon 0.93; p <0.001) and post_LTx PSC patients (AUC ileum 0.97; colon 0.97; p <0.001) from HC, and distinguished pre_LTx from post_LTx (AUC ileum 0.83; colon 0.83; p <0.001). The shared, cohort-independent PSC microbiota was dominated by Enterococcus, Pseudomonas, Veillonella, Klebsiella, and Streptococcus, while several common commensals were underrepresented. A microbial dysbiosis index calculated from PSC-associated genera correlated negatively with alpha diversity and serum albumin, while a positive correlation was observed with markers of cholestatic disease (ALP, GGT) and liver fibrosis (APRI). There were no associations with the presence of inflammatory bowel disease or fecal calprotectin. Differences between post-LTx patients with and without recurrence were limited, but several genera deregulated in pre-LTx PSC (Klebsiella, Bilophila, Coprococcus, Odoribacter) showed similar trends in rPSC.

Our findings in two European countries revealed a distinct mucosal microbiota composition associated with PSC that persists after LTx. These microbial patterns correlate with the severity of liver injury in PSC but not with markers of intestinal inflammation.

This study provides an extensive evaluation of mucosa-associated microbiota in primary sclerosing cholangitis (PSC) before and after liver transplantation across two European cohorts. The persistence of PSC-related dysbiosis after transplantation highlights the importance of the gut–liver axis in PSC and supports further investigation into microbiota-driven mechanisms. Together with the strong association between microbiota composition and markers of cholestasis and fibrosis, this suggests potential clinical utility as an indicator of disease activity or even as a target for prevention or therapy.

Image 1

•PSC is associated with distinct, geography-independent mucosal microbiota alterations that persist after liver transplantation.•Microbiota alterations correlate with liver disease severity but not with intestinal inflammation.•PSC recurrence shows similar microbial trends to pre-transplant PSC but lacks a distinct microbiota profile.•Targeting the microbiota may help treat PSC, prevent recurrence, and reduce post-transplant relapse.

PSC is associated with distinct, geography-independent mucosal microbiota alterations that persist after liver transplantation.

Microbiota alterations correlate with liver disease severity but not with intestinal inflammation.

PSC recurrence shows similar microbial trends to pre-transplant PSC but lacks a distinct microbiota profile.

Targeting the microbiota may help treat PSC, prevent recurrence, and reduce post-transplant relapse.

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