Study of Tissue Repair in Inflammatory Bowel Disease Exploiting Organoid Technology

Overview

Inflammatory Bowel Diseases (IBD) are chronic inflammations of the gastrointestinal tract. Regardless of the etiology, a common trait of IBD pathogenesis is the inflammatory damage inflicted on the intestinal mucosa and the loss of intestinal epithelial barrier integrity. Therefore, understanding the mechanisms that govern IEC's capacity to maintain barrier function and to orchestrate mucosal healing is considered a major goal in translational research. The investigators are interested in understanding how the inflammatory environment present in the intestinal mucosa, of IBD patients influences epithelial cells capacity to govern repair. The complexities of the cytokine and metabolic milieu present in IBD patients render the study of the contribution of each cytokine, metabolite, and intracellular pathway extremely complicated. Therefore, most of the processes that govern tissue regeneration are studied with the use of mouse models that recapitulate one or multiple features of IBD and allow for genetical modifications of the gene and pathway of interest. While mouse models are uniquely suited to study the complex crosstalk between the immune system, the microbiota, and the intestinal epithelia, they introduce the important problem of species-specific differences, which can hamper the translational value of mouse studies. To overcome these shortcomings, the investigators propose to explore the influence of cytokines and metabolites in digestive organoids derived from patients and controls. Importantly, it was demonstrated that gene expression and innate immune responses are altered in primary organoids derived from patients with IBD, including altered ability to proliferate, respond to cytokines, metabolic capacity, and efficiently form organoids suggesting that major differences between patient's and control's epithelial cell biology can be faithfully replicated in this system. Given these premises, the investigators propose the following objectives: Primary objective: The main objective of this study is to establish that patient's epithelial cells from inflamed mucosae have decreased ability to repair the intestinal mucosa, as compared to epithelial cells from non-inflamed regions in the same patient, or to control subject with no inflammatory digestive diseases. The investigators will explore this question both deriving organoids from clinical samples and exposing them to pro inflammatory cytokines and metabolites in vitro, as well as by analyzing repair responses from the aforementioned clinical samples ex vivo. Secondary objective The secondary goals of this study are: \- To compare organoids derived from: epithelia in inflamed mucosa of IBD patients, epithelia in non-inflamed mucosa of IBD patients, and epithelia from the mucosa of non-IBD controls in their capacity to mount a repair response in response to inflammatory cytokines or luminal metabolites. Namely the investigators will evaluate the following parameters: * Their capacity to proliferate. * Their ability to survive treatment with pro-inflammatory cytokines * The activation of intracellular pathways associated with cell death. * Their overall metabolic activity. * The balance between stem and differentiated epithelial cell types. * The transcriptional activation of protective pathways such as those associated with proliferation, migration, differentiation and cell survival. * To evaluate hallmarks of tissue repair in biopsies derived from epithelia in inflamed mucosa of IBD patients, epithelia in non-inflamed mucosa of IBD patients, and epithelia from the mucosa of non-IBD controls, and to correlate them to the levels of inflammatory cytokines, luminal metabolites and overall disease severity. Namely the investigators will evaluate the following parameters: * The abundance of proliferating cells. * The activation of intracellular pathways associated with cell death and survival. * Their overall metabolic activity. * The balance between stem and differentiated epithelial cell types. * The transcriptional activation of protective pathways such as those associated with proliferation, migration, differentiation and cell survival.

Interventions

• Procedure Colonoscopy - IBD inflamed tissue
  Collection of 10 colonic biopsies in IBD inflamed tissue
• Procedure Surgical resection - IBD inflamed mucous membrane
  Collection of a portion of IBD inflamed mucous membrane
• Procedure Colonoscopy - biopsies in healthy tissue
  Collection of 10 colonic biopsies in healthy tissue
• Procedure Surgical resection - healthy mucous membrane
  Collection of a portion of healthy mucous membrane

Primary outcome measures

• Repair status of IBD patient's epithelial cells from inflamed mucosae [Time frame: From enrollmet to the end of following at 1 month]

Secondary outcome measures (3)

• Evaluate the molecular mechanism involved in the reduced capacity of epithelial cells of IBD patients to repair intestinal mucosa [Time frame: From enrollment to the end of following at 1 month]
• Genetically determine the involvement of cell death and protective pathways that reduce repair capacity in patients. [Time frame: From enrollment to the end of following at 1 month]
• 3. Explore the activation of molecular mechanisms identified in patient biopsies and correlate them with the inflammatory environment present in the patient's tissues [Time frame: From enrollment to the end of following at 1 month]

Eligibility criteria

For IBD group the inclusion criteria will be:

• Patients of either sex aged 18 years or older
• Patient that have read the information form and signed consent
• Patient covered with health insurance
• Patients with Crohn's Disease or ulcerative colitis in accordance with accepted clinical, endoscopic, histological and/or radiologic criteria, regardless of the level, severity of the disease or duration of disease progression.
• Patients with colonic involvement of Crohn's disease or ulcerative colitis
• Patients undergoing a screening colonoscopy in the context of IBD disease follow-up OR undergoing intestinal resection for IBD disease aggravation

For control group the inclusion criteria will be:

• Patients of either sex aged 18 years or older
• Patient that have read the information form and signed consent
• Patient covered with health insurance
• Patients undergoing a screening colonoscopy in the context of a family history of colonic neoplasia, follow-up of colonic polyps or functional intestinal disorders OR undergoing intestinal resection for intestinal neoplasia, occlusive syndrome or colostomy

The non-inclusion criteria for IBD group will be:

• Contraindication to the anaesthetic or colonoscopy procedure
• Patients without colonic involvement of Crohn's disease or ulcerative colitis
• Patients of Adults without legal capacity
• Patients in Health and Social Establishments
• Persons in emergency situations
• Persons deprived of their liberty
• Non-affiliated to a social security scheme
• Absence or refusal of the informed consent

The non-inclusion criteria for control group will be:

• IBD disease revealed during colonoscopy or gastrointestinal resection
• Patient suffering from Immune-Mediated Inflammatory Diseases (IMIDs)
• Contraindication to the anaesthetic or colonoscopy procedure
• Patients of Adults without legal capacity
• Patients in Health and Social Establishments
• Persons in emergency situations
• Persons deprived of their liberty
• Non-affiliated to a social security scheme
• Absence or refusal of the informed consent

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Basic science

Study locations

France · 1 center

• Nord Hospital — Marseille

Identifiers

NCT: NCT06805890 · RCAPHM24_0062 · 2024-A00510-47

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗