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

NCT05376228 | Unknown

• 1 other identifier: RRK7338
• Study Type: observational
• Target: 15
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Inflammatory Bowel Diseases; Primary Sclerosing Cholangitis

Keywords

primary sclerosing cholangitis; inflammatory bowel disease; microbiome; vancomycin

Outcome Measures

Primary Outcomes (3)

• 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

Interventions

Oral Vancomycin DRUG

As part of standard of care

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• 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.

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University Hospital Birmingham NHS Foundation Trust: lead

Study Sites (1)

University Hospitals Birmingham NHS Foundation Trust

Birmingham, B15 2GW, United Kingdom

RECRUITING

Related Publications (2)

• 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.

  PMID: 32016358 BACKGROUND

• Quraishi MN, Cheesbrough J, Rimmer P, Mullish BH, Sharma N, Efstathiou E, Acharjee A, Gkoutus G, Patel A, Marchesi JR, Camuzeaux S, Chappell K, Valdivia-Garcia MA, Ferguson J, Brookes MJ, Walmsley M, Rossiter AE, van Schaik W, McInnes RS, Cooney R, Trauner M, Beggs AD, Iqbal TH, Trivedi PJ. Open Label Vancomycin in Primary Sclerosing Cholangitis-Inflammatory Bowel Disease: Improved Colonic Disease Activity and Associations With Changes in Host-Microbiome-Metabolomic Signatures. J Crohns Colitis. 2025 Feb 4;19(2):jjae189. doi: 10.1093/ecco-jcc/jjae189.

  PMID: 39673746 DERIVED

Related Links

• Related Info
• Related Info

MeSH Terms

Conditions

Inflammatory Bowel Diseases; Cholangitis, Sclerosing

Interventions

Vancomycin

Condition Hierarchy (Ancestors)

Gastroenteritis; Gastrointestinal Diseases; Digestive System Diseases; Intestinal Diseases; Cholangitis; Bile Duct Diseases; Biliary Tract Diseases

Intervention Hierarchy (Ancestors)

Glycopeptides; Glycoconjugates; Carbohydrates; Peptides; Amino Acids, Peptides, and Proteins

Central Study Contacts

Nabil Quraishi, PhD, MRCP

CONTACT

01213712000; nabil.quraishi@nhs.net

Palak Trivedi, PhD, MRCP

CONTACT

01213712000; p.j.trivedi@bham.ac.uk

Study Design

• Study Type: observational
• Observational Model: CASE ONLY
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Chief Investigator and Consultant Gastroenterologist

Study Record Dates

• First Submitted: May 11, 2022
• First Posted: May 17, 2022
• Study Start: February 1, 2022
• Primary Completion: February 1, 2023
• Study Completion: April 1, 2023
• Last Updated: June 1, 2022

Record last verified: 2022-05

Locations

GB (1)