A Systems Biology Approach for Identification of Host and Microbial Mechanisms and Druggable Targets for the Treatment of PSC-IBD (PSC-Vanc)

Primary sclerosing cholangitis (PSC) is the classical hepatobiliary manifestation of inflammatory bowel disease (IBD). Although rare, PSC is associated with significant and disproportionate unmet needs; with heightened risks of colorectal cancer and colectomy, and greater all-cause mortality rates compared to matched IBD patients. Unfortunately, no medical therapy has been proven to slow disease progression in PSC-IBD, and liver transplantation is the only lifesaving intervention for patients.

The strong association between PSC and IBD has led to several pathogenic hypotheses, in which dysregulated mucosal immune responses are proposed to contribute. Of note, the investigators recently identified distinct mucosal transcriptomic profiles in PSC-IBD; with regards bile acid metabolism, bile acid signalling, and a central role of enteric dysbiosis. In parallel, pilot data from other groups have shown that treatment with oral vancomycin (a non-absorbable, gut-specific antibiotic) attenuates colonic inflammation and improves biochemical markers of cholestasis in PSC. However, there is no mechanistic data exploring the host-microbial alterations under vancomycin treatment in PSC-IBD, neither the impact of vancomycin on bile acid circulation. The investigators of this study hypothesize that oral vancomycin attenuates colonic mucosal inflammation in PSC-IBD, by restoring gut microbiota mediated bile acid homeostatic pathways. Through these means the study aims to identify druggable gut microbial and host molecular pathways associated with bile acid mediated colonic mucosal inflammation in PSC-IBD.

Study Overview

• Status: Recruiting
• Conditions: Inflammatory Bowel Diseases; Primary Sclerosing Cholangitis
• Intervention / Treatment: Drug: Oral Vancomycin

Detailed Description

Primary sclerosing cholangitis (PSC) is the classical hepatobiliary manifestation of inflammatory bowel disease (IBD). Although rare, PSC is associated with significant and disproportionate unmet needs; with heightened risks of colorectal cancer and colectomy, and greater all-cause mortality rates compared to age- and sex-matched IBD controls. Unfortunately, no medical therapy has been proven to slow disease progression in PSC-IBD, and liver transplantation is the only lifesaving intervention for patients. The strong association between PSC and IBD has led to several pathogenic hypotheses, in which dysregulated mucosal immune responses are proposed to contribute. Of note, the investigators of this study recently identified distinct mucosal transcriptomic profiles in PSC-IBD; with regards bile acid metabolism, bile acid signalling, and a central role of enteric dysbiosis. In parallel, pilot data from other groups have shown that treatment with oral vancomycin (a non-absorbable, gut-specific antibiotic) attenuates colonic inflammation and improves biochemical markers of cholestasis in PSC. However, there is no mechanistic data exploring the host-microbial alterations under vancomycin treatment in PSC-IBD, neither the impact of vancomycin on bile acid circulation.

In this study, fifteen PSC-IBD patients will be recruited through a large tertiary referral centre, who are undergoing lower gastrointestinal examination as per routine standard of care. Participants will be offered 4 weeks of treatment with oral vancomycin, and stool samples collected at different timepoints to evaluate changes in metagenomic, metatranscriptomic, and bile acid profiles. Colonic biopsies will be collected at baseline and at week 4 (flexible sigmoidoscopy) and subjected to FACS sorted RNA sequencing to identify changes in colonic epithelial cell pathways. Multi-omics data integration will be performed to uncover combinations of predictive profiles, model microbial networks, and host transcriptomic changes implicated in the response to oral vancomycin. This study will inform the downstream identification of specific host molecular and microbial pathways that has a potential for development of therapeutic targets for PSC-IBD in clinical practice.

• Study Type: Observational
• Enrollment (Anticipated): 15

Contacts and Locations

• Study Contact: Name: Nabil Quraishi, PhD, MRCP; Phone Number: 01213712000; Email: nabil.quraishi@nhs.net
• Study Contact Backup: Name: Palak Trivedi, PhD, MRCP; Phone Number: 01213712000; Email: p.j.trivedi@bham.ac.uk

Study Locations

• United Kingdom
  • Birmingham, United Kingdom, B15 2GW
    • Recruiting
    • University Hospitals Birmingham NHS Foundation Trust
    • Contact: Nabil Quraishi; Phone Number: 01213712000; Email: nabil.quraishi@nhs.net
    • Principal Investigator: Nabil Quraishi
    • Principal Investigator: Palak J Trivedi
    • Principal Investigator: Tariq Iqbal
    • Sub-Investigator: Naveen Sharma
    • Sub-Investigator: Andrew Beggs
    • Sub-Investigator: Christopher Quince
    • Sub-Investigator: Matthew Brookes
    • Sub-Investigator: Rachel Cooney

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

15 patients with active PSC-IBD will undergo 4 weeks of treatment with open label (standard of care) oral vancomycin.

Description

Inclusion Criteria:

• Patients with confirmed diagnosis of primary sclerosing cholangitis and concurrent colitis
• Mild to moderately active colitis based on partial Mayo score of ≥3 and ≤6
• Scheduled for a standard of care lower GI endoscopy as part of disease assessment / surveillance

Exclusion Criteria:

• History of previous colectomy
• Isolated small bowel disease
• Stricturing , fistulating or perianal phenotype
• Use of antibiotics and/or probiotics in the prior 3 months
• Use of steroids in last 2 weeks
• Commenced thiopurines / methotrexate in last 3 months
• History of intolerance to oral vancomycin
• Decompensated liver disease (Child C cirrhosis)
• Active infectious diarrhoea

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Identify stool metagenomic, metatranscriptomic and bile acid profiles following treatment with oral vancomycin in PSC-IBD	12 months
Investigate changes in colonic mucosal epithelial bile acid and immunological pathways through FACS sorted RNA-sequencing following oral vancomycin	12 months
Identification of druggable host molecular and microbial targets through multi-omic integration analysis	12 months

Collaborators and Investigators

• Sponsor: University Hospital Birmingham NHS Foundation Trust

Publications and helpful links

General Publications

• Quraishi MN, Acharjee A, Beggs AD, Horniblow R, Tselepis C, Gkoutos G, Ghosh S, Rossiter AE, Loman N, van Schaik W, Withers D, Walters JRF, Hirschfield GM, Iqbal TH. A Pilot Integrative Analysis of Colonic Gene Expression, Gut Microbiota, and Immune Infiltration in Primary Sclerosing Cholangitis-Inflammatory Bowel Disease: Association of Disease With Bile Acid Pathways. J Crohns Colitis. 2020 Jul 30;14(7):935-947. doi: 10.1093/ecco-jcc/jjaa021.

Helpful Links

• Related Info
• Related Info

Study record dates

Study Major Dates

• Study Start (ACTUAL): February 1, 2022
• Primary Completion (ANTICIPATED): February 1, 2023
• Study Completion (ANTICIPATED): April 1, 2023

Study Registration Dates

• First Submitted: May 11, 2022
• First Submitted That Met QC Criteria: May 11, 2022
• First Posted (ACTUAL): May 17, 2022

Study Record Updates

• Last Update Posted (ACTUAL): June 1, 2022
• Last Update Submitted That Met QC Criteria: May 27, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Keywords: microbiome; vancomycin; inflammatory bowel disease; primary sclerosing cholangitis
• Additional Relevant MeSH Terms: Digestive System Diseases; Gastrointestinal Diseases; Gastroenteritis; Biliary Tract Diseases; Bile Duct Diseases; Inflammatory Bowel Diseases; Intestinal Diseases; Cholangitis; Cholangitis, Sclerosing; Anti-Infective Agents; Anti-Bacterial Agents; Vancomycin
• Other Study ID Numbers: RRK7338

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No