Unveiling the Microbial Impact on Intestinal Fibrosis

NCT06073288 | Not Yet Recruiting

• 1 other identifier: RF-2021-12372637
• Study Type: observational
• Target: 20
• Locations: 1 country
• Sites: 1

Brief Summary

Crohn's disease (CD), belonging to the class of Inflammatory Bowel Diseases, is a chronic inflammatory disorder that may affect any location of the gastrointestinal tract. It is characterized by transmural inflammation and an overwhelming immune response of the gut mucosa, which leads to severe clinical symptoms. More than 50% of CD patients develop a penetrating or stricturing disease due to fibrostenosis, which most of the time requires surgical intervention since no therapies have been found as effective yet. Among the histological features of stricturing CD, the thickening of the muscularis mucosae and muscularis propria is the main hallmark, primarily due to the excessive proliferation of mesenchymal cells and the increased accumulation of a collagen-rich extracellular matrix in the submucosa, caused by multiple mechanisms, including i) the proliferation of existing local fibroblasts, the induction of both ii) epithelial-to-, and iii) endothelial-to-mesenchymal transition. Even if the alteration of these mucosal functions is mainly caused by the continuous tissue injury occurring during CD-associated chronic inflammation, recent reports suggested that CD associated fibrosis may be driven by inflammation-independent triggers, such as microbiota dysbiosis. Shedding the light on this aspect of CD fibrosis may lead to the development of innovative therapeutic strategies eventually blocking the gut thickening.

Conditions

Crohn Disease

Outcome Measures

Primary Outcomes (1)

• To perform flow cytometry, RNAseq, metatranscriptomics, transcriptomics and lipidomics on CD and non-IBD cells

  To evaluate how bacterial factors may impact the transcriptomic state of the different host cell compartments in terms of profibrotic pathway and gene activation. Cells will undergo FACS for CD31, EpCam, and CD90 markers for isolating endothelial cells, epithelial cells, and fibroblasts, respectively, as the well-known cellular players in the fibrotic process. Single-cell populations will undergo library preparation and will be analyzed by ribo-minus RNAseq at 30M reads of depth. Metatranscriptomics for profiling the microbial composition, as well as the transcriptomics to determine both the differential gene expression (DGE) and the Gene Set Enrichment Analysis (GSEA) will be performed. The relative abundances of Brevibacteriaceae, Caulobacteraceae, and Sphingomonadaceae-derived factors will be calculated using Kraken2 to identify which cell subtype(s) among CD-derived fibroblasts, endothelial cells, and epithelial organoids harbor(s) the fibrotic-specific microbial composition.

  1-36 months

Study Arms (2)

Crohn's Disease (CD)

15 CD patients (5 patients/stage: (B1 (more inflammatory, non-structuring), B2 (structuring, non-penetrating) and B3 (structuring and penetrating). Patient stratification is based on previous classifications done in accordance with the standard of care through TC, RMI or Ecography. For this reason, patients classification is known before surgery.

Other: Surgical specimens of CD and no-IBD patients

non-Intestinal Bowel Disease patients (no-IBD)

5 patients without IBD-related diseases (ex. diverticulitis)

Other: Surgical specimens of CD and no-IBD patients

Interventions

Surgical specimens of CD and no-IBD patients OTHER

Specimens of CD patients and patients without IBD-related disease (ex. diverticulitis) will be collected during the surgery, without other risks for the patients, since we will use only material left after pathologist analysis

Crohn's Disease (CD); non-Intestinal Bowel Disease patients (no-IBD)

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Probability Sample

Study Population

20 patients undergoing surgery: \- 15 CD patients (5 patients/stage: (B1 (more inflammatory, non-structuring), B2 (structuring, non-penetrating) and B3 (structuring and penetrating). Patient stratification is based on previous classifications done in accordance with the standard of care through TC, RMI or Ecography. For this reason, patients classification is known before surgery. \- 5 patients without IBD-related diseases (ex. diverticulitis)

You may qualify if:

• Adult patients ≥18 and \<70 years
• All patients will sign the informed consent
• Given that it is an observational study, also pregnant and breastfeed patients could be included
• Additionally, for CD patients:
• \- classification on different stages: (B1 (more inflammatory, non-structuring), B2 (structuring, non-penetrating) and B3 (structuring and penetrating). Patient stratification is based on previous classifications done in accordance with the standard of care through TC, RMI or Ecography.
• Additionally, for non-IBD patients:
• \- subjects undergoing surgery for non-IBD diseases (ex. diverticulitis) in accordance with the standard of care

You may not qualify if:

• For CD patients:
• CD subjects without previously classification in B1, B2, B3
• Patients \<18 years or \> 70 years
• Patients without the signed informed consent
• For non-IBD patients:
• Patients \<18 years or \> 70 years
• Patients without the signed informed consent

Sponsors & Collaborators

• IRCCS San Raffaele: lead

Study Sites (1)

IRCCS Ospedale San Raffaele

Milan, Italy

Location

MeSH Terms

Conditions

Crohn Disease

Condition Hierarchy (Ancestors)

Inflammatory Bowel Diseases; Gastroenteritis; Gastrointestinal Diseases; Digestive System Diseases; Intestinal Diseases

Central Study Contacts

Federica Ungaro

CONTACT

0226437864; ungaro-federica@hsr.it

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: CROSS SECTIONAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director of Gastroenterology and Endoscopy Unit

Study Record Dates

• First Submitted: September 25, 2023
• First Posted: October 10, 2023
• Study Start: November 1, 2023
• Primary Completion: October 1, 2024
• Study Completion (Estimated): November 1, 2026
• Last Updated: October 10, 2023

Record last verified: 2023-10

Locations

IT (1)