Modulation of the Mucosa-Associated Microbiome Linked to the PTPN2 Risk Gene in Patients with Primary Sclerosing Cholangitis and Ulcerative Colitis.

Luisa Denoth,Andreas E Kremer,Michael Scharl,Pascal Juillerat,Bahtiyar Yilmaz,On Behalf Of The Swiss Ibd Cohort Study ,Gerhard Rogler,Sena Bluemel

doi:10.3390/microorganisms9081752

Abstract

Gut microbiota appears to be involved in the pathogenesis of primary sclerosing cholangitis (PSC). The protein tyrosine phosphatase nonreceptor 2 (PTPN2) gene risk variant rs1893217 is associated with gut dysbiosis in inflammatory bowel disease (IBD), and PTPN2 was mentioned as a possible risk gene for PSC. This study assessed the microbial profile of ulcerative colitis (UC) patients with PSC and without PSC (non-PSC). Additionally, effects of the PTPN2 risk variant were assessed. In total, 216 mucosal samples from ileum, colon, and rectum were collected from 7 PSC and 42 non-PSC patients, as well as 28 control subjects (non-IBD). The microbial composition was derived from 16S rRNA sequencing data. Overall, bacterial richness was highest in PSC patients, who also had a higher relative abundance of the genus Roseburia compared to non-PSC, as well as Haemophilus, Fusobacterium, Bifidobacterium, and Actinobacillus compared to non-IBD, as well as a lower relative abundance of Bacteroides compared to non-PSC and non-IBD, respectively. After exclusion of patients with the PTPN2 risk variant, Brachyspira was higher in PSC compared to non-PSC, while, solely in colon samples, Eubacterium and Tepidimonas were higher in PSC vs. non-IBD. In conclusion, this study underlines the presence of gut mucosa-associated microbiome changes in PSC patients and rather weakens the role of PTPN2 as a PSC risk gene.

Highlights

Patients and the control ure 1. α-diversity was higher in primary sclerosing cholangitis (PSC) patients compared to non-PSC patients and the congroup
protein tyrosine phosphatase nonreceptor 2 (PTPN2) has been discussed as risk gene for PSC [25]
When analyzing the data in patients without the PTPN2 C-allele according to the origin of the biopsy, in the right colon the genus Eubacterium and Tepidimonas were increased in PSC compared to non-inflammatory bowel disease (IBD), and Dialister was increased in non-PSC compared to non-IBD

Summary

Introduction

Primary sclerosing cholangitis (PSC) is a rare cholestatic liver disease causing intraand extrahepatic bile duct strictures and fibrosis, which leads to liver cirrhosis [1,2]. PSC is often associated with ulcerative colitis (UC), affecting roughly 4% of all UC patients [3,4,5]. Changes in the microbiome, metabolome, and intestinal barrier function were extensively studied to unravel the pathogenesis of PSC [9]. This system is often referred to as “gut–liver axis”, which symbolizes the interaction of gut microbiota and the liver: Intestinal dysbiosis, i.e., the change in the microbiota linked to disease, may weaken

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Conclusion