Clinical trial NCT05376228: 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
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Inflammatory Bowel Diseases
Primary Sclerosing Cholangitis
Keywords: primary sclerosing cholangitis
inflammatory bowel disease
microbiome
vancomycin
Lead sponsor: University Hospital Birmingham NHS Foundation Trust
Sponsor class: OTHER
First posted: 2022-05-17
Enrollment: 15
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_ONLY
Time perspective: PROSPECTIVE
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.

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.

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

Primary outcomes:
measure: Identify stool metagenomic, metatranscriptomic and bile acid profiles following treatment with oral vancomycin in PSC-IBD
timeFrame: 12 months
measure: Investigate changes in colonic mucosal epithelial bile acid and immunological pathways through FACS sorted RNA-sequencing following oral vancomycin
timeFrame: 12 months
measure: Identification of druggable host molecular and microbial targets through multi-omic integration analysis
timeFrame: 12 months
Secondary outcomes:
Other outcomes:
Locations:
city: Birmingham
country: United Kingdom
facility: University Hospitals Birmingham NHS Foundation Trust
Study officials:
References:
citation: 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.