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NCT Number: NCT06073288

Unveiling the Microbial Impact on Intestinal Fibrosis

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.

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Key information

Conditions

Crohn Disease Digestive System Diseases Gastroenteritis Gastrointestinal Diseases Inflammatory Bowel Diseases Intestinal Diseases

Age range

18 year–70 year

Sex eligibility

All sexes

Study type

Observational

Primary location

IRCCS Ospedale San Raffaele

Milan, Italy

About this study

This is a cross-sectional observational study involving patients with Crohn's Disease (CD) (n=15) and patients with non-Intestinal Bowel Disease (IBD) (n=5) undergoing surgery in the Gastroenterology and Digestive Endoscopy unit within Gastro Center (IRCCS Ospedale San Raffaele) according to the standard of care.

Specimens will be collected during the surgery, without other risks for the patients, since we will use only material left after pathologist analysis.

CD-derived surgical specimens will be processed to obtain a cell suspension, that will be frozen and stored for the following cell sorting. For non-IBD tissue processing, each surgical specimen will be cut into two pieces. One will be processed to obtain the cell suspension to be stored, whereas the remaining tissue will be processed to isolate lamina propria fibroblasts and endothelial cells, as well as to generate epithelial organoids.

Ospedale San Raffaele (OSR - Operative Unit (UO)1 (UO1)) is the promoter of this study. The other center participating in the study is University of Milan (UO2), which has in charge the development of 3D microfluidic devices for the in vitro experiments. Patients will be enrolled only in UO1.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

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

Exclusion criteria

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

Treatment and study plan

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

Primary outcomes

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

Time frame: 1-36 months

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.

Study contacts

Contact information is provided by the study sponsor or research team.

Federica Ungaro

CONTACT

[email protected]

0226437864

Sponsors and collaborators

Lead sponsor

IRCCS San Raffaele

Other

Registry information

Official study title

Unveiling the Microbial Impact on Intestinal Fibrosis: New Insights for the Pathogenesis and Treatment of Crohn's Disease-associated Complications

Important dates

Study start: 2023
Primary completion: 2024
Study completion: 2026
First posted: Oct 10, 2023
Registry last updated: Oct 10, 2023

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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