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

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Brief Title

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

Official Title

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

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.
    

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


Primary Outcome

Identify stool metagenomic, metatranscriptomic and bile acid profiles following treatment with oral vancomycin in PSC-IBD


Condition

Inflammatory Bowel Diseases

Intervention

Oral Vancomycin


Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

15

Start Date

February 1, 2022

Completion Date

April 1, 2023

Primary Completion Date

February 1, 2023

Eligibility Criteria

        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
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

, 01213712000, [email protected]

Location Countries

United Kingdom

Location Countries

United Kingdom

Administrative Informations


NCT ID

NCT05376228

Organization ID

RRK7338


Responsible Party

Principal Investigator

Study Sponsor

University Hospital Birmingham NHS Foundation Trust


Study Sponsor

, , 


Verification Date

May 2022