Early Inflammatory Bowel Disease Progression (PRO-IBD)

Composition and Metabolic Activity of Gut Microbiota to Predict Early Inflammatory Bowel Disease Progression

The purpose of this study is to assess the capacity of the gut microbial composition and function to predict the course of IBD during the first year after diagnosis.

Study Overview

• Status: Recruiting
• Conditions: Inflammatory Bowel Diseases; Crohn Disease (CD); Ulcerative Colitis (UC)

Detailed Description

Inflammatory bowel disease (IBD), comprising Crohn ́s disease (CD) and ulcerative colitis (UC), is an idiopathic inflammatory condition of the gastrointestinal tract which is characterized by alternating periods of active disease and remission. IBD is often progressive and associated with significant morbidity. A common endpoint for a progressive course of CD or UC is the need for treatment escalation; initially with immunomodulators and subsequently - if disease activity persists - with biologic therapy or surgery. Early use of biologic therapy improves clinical outcomes and can prevent complications such as strictures, fistulae or severe and progressive disease, obviating need for surgery. The success of early initiation of biologic therapy is most likely related to a therapeutic "window of opportunity" for the implementation of effective therapies in patients with rapidly progressive disease. However, indiscriminate use of biologic therapy would entail exposure of IBD patients with indolent disease to unnecessary expensive treatments and their associated side effects. Unfortunately, the need for biomarkers to reliably guide IBD treatment in a timely manner remains unmet. The literature supports a relevant role for host-gut microbiota interactions in IBD progression. This interaction is often mediated by microbial-derived metabolites. Fecal short chain fatty acids (SCFA) and secondary bile acids (BA) are remarkable examples of such metabolites. They are reduced in IBD patients, and in animal models are capable of mitigating exaggerated host immune response with consequent improvement in gut inflammation. Recently, researchers have started to explore the capacity of taxonomic and metabolomic signatures to predict meaningful clinical outcomes in IBD. Given the role of gut microbes and their metabolites in immune response, they are plausible biomarkers of IBD progression and therapy response. However, most of the studies exploring biomarkers for IBD include patients with longstanding IBD or previous failure to first-line therapies, rendering their results incompatible with early risk stratification. An inception cohort of newly diagnosed IBD patients integrating clinical, transcriptomics, microbial and metabolomic profiling can overcome these limitations, increasing the sensitivity to detect biomarkers of progressive disease before the therapeutic "window of opportunity" has passed. In the clinical setting, such biomarkers would enable clinicians to maximize therapeutic efficacy of biologic agents and implement as early as IBD diagnosis, a cost-effective therapeutic approach.

The objective of this project is to establish whether an impaired gut microbial capacity to synthesize SCFA and secondary BA at the time of IBD diagnosis can predict early need for treatment escalation (progression). To achieve this objective, our specific aims are:

1) To define the gut taxonomic and metabolomic profiles of newly diagnosed IBD patients and their associations with early clinical outcomes. The investigators will recruit an inception cohort of treatment-naïve IBD patients before undergoing their first diagnostic colonoscopy. The global metabolome, including SCFA and secondary BA abundance will be analyzed, as well as the taxonomic profile of fecal samples and mucosal-luminal interface (MLI) aspirates obtained at colonoscopy. The identified "omics" signatures will be correlated to the need for treatment escalation to derive predictive biomarkers of progressive IBD course. 2) To establish the impact of gut microbial dysbiosis and dysmetabolism of SCFA and BA of newly diagnosed IBD patients on mucosal inflammation and host gene expression. Analysis of taxonomic and metabolomics profiles obtained in MLI samples will be integrated to mucosal host gene expression analysis to identify host transcripts affected by differential SCFA and secondary BA abundance.

3) To quantify the in vitro capacity of gut microbiota of newly diagnosed IBD patients to synthesize SCFA and secondary BA. Gut microbiota from IBD patients will be inoculated into a batch bioreactor which closely mimics the gut luminal environment. The investigators will then perform serial measurements of SCFA, BA and bacterial abundance, estimating rates of metabolite synthesis. The metabolic activity will be correlated to in vivo metabolite abundance and clinical outcomes.

The investigators anticipate that IBD patients requiring early therapy escalation (progressors) will have decreased in vivo concentrations of SCFA and secondary BA, and an impaired in vitro microbial capacity to synthesize these compounds compared to patients not requiring therapy escalation. The investigators also expect to find that the taxonomic and metabolomic signatures of these patients have a distinct impact on host gene expression. Our comprehensive approach will allow us to identify reliable biomarkers which can be exploited in the clinical setting to guide early biologic treatment using a 'personalized medicine' approach and will provide novel insight into the biologic mechanisms underlying need for premature therapy escalation as a proxy of early progressive and aggressive course in IBD.

• Study Type: Observational
• Enrollment (Estimated): 140

Contacts and Locations

• Study Contact: Name: Cristian Hernández-Rocha, MD; Phone Number: 56-22-3543822; Email: caherna4@uc.cl
• Study Contact Backup: Name: Manuel Álvarez-Lobos, MD; Phone Number: 56-22-3543822; Email: manalvarezl@gmail.com

Study Locations

• Chile
  • Santiago, Chile
    • Recruiting
    • Pontificia Universidad Catolica of Chile
    • Contact: Maria E Balcells, MD; Phone Number: (+56)955048170; Email: proyectos.didemuc@uc.cl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Adult patients attending the gastroenterology clinic at Pontificia Universidad Católica of Chile with at least 3 weeks of GI symptoms including diarrhea, rectal bleeding, abdominal pain, tenesmus or urgency will be identified by members of the Gastroenterology Medical Group. As part of standard of care (SOC), these patients will undergo stool testing to rule out gastrointestinal infections followed by full colonoscopy

Description

Inclusion Criteria:

• Adult patients with with at least 3 weeks of gastrointestinal symptoms including diarrhea, rectal bleeding, abdominal pain, tenesmus or urgency

Exclusion Criteria:

• Confirmed infectious disease of the gastrointestinal tract

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
IBD; Patients with gastrointestinal symptoms for at least 3 weeks suggesting IBD in whom IBD is confirmed
Controls; Patients with gastrointestinal symptoms for at least 3 weeks suggesting IBD in whom IBD is ruled-out

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Compare gut microbiome composition and function from different sample types among participants with gastrointestinal symptoms with and without confirmed IBD by colonoscopy and biopsy	Researchers will obtain stool (before diagnostic colonoscopy), biopsy specimens (frozen and RNAlater stored samples), and intestinal washing (mucosal-luminal interface samples at colonoscopy)	36 months
In patients with confirmed IBD, researchers will identify whether there are differences in gut microbiome composition and function between patients who need therapy escalation (progressors) within the first 12 months after diagnosis	IBD patients who need therapy escalation (progressors) will be those who: Undergo surgery (colectomy or small bowel resection) within the first year after diagnosis; Start biologic therapy within the first year after diagnosis; Do not achieve clinical remission at week 24 (Average daily stool frequency (SF) ≤1.5 and abdominal pain (AP) score ≤1.0 for Crohn's disease (CD), and rectal bleeding (RB) = 0 and SF score <2 on the patient reported outcome measure (PROM) component of the Mayo score for ulcerative colitis (UC) and IBD-unclassified (IBD-U).; IBD patients with fecal calprotectine ≥250 mcg/g at week 24	12 months

Collaborators and Investigators

• Sponsor: Pontificia Universidad Catolica de Chile
• Collaborators: Fondo Nacional de Desarrollo CientÃ-fico y Tecnológico, FONDECYT (Chile).
• Investigators: Principal Investigator: Cristian Hernández-Rocha, MD, Pontificia Universidad Catolica of Chile

Study record dates

Study Major Dates

• Study Start (Actual): July 7, 2023
• Primary Completion (Estimated): April 1, 2027
• Study Completion (Estimated): April 1, 2027

Study Registration Dates

• First Submitted: September 30, 2024
• First Submitted That Met QC Criteria: December 24, 2024
• First Posted (Actual): March 25, 2025

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: December 24, 2024
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Keywords: Microbiome; Inflammatory bowel disease; Prediction
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Digestive System Diseases; Gastrointestinal Diseases; Gastroenteritis; Disease Progression; Crohn Disease; Intestinal Diseases; Inflammatory Bowel Diseases
• Other Study ID Numbers: 1230757

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
• product manufactured in and exported from the U.S.: No