TOward a Better Understanding of the autoPhagy Machinery for the Identification of Potential Novel Biomarkers and Therapeutic Targets in Crohn's Disease - TOPIC Study
- Conditions
- Crohn's Disease
- Interventions
- Biological: Blood samplesBiological: Stool simpleBiological: Ileocolonic biopsies
- Registration Number
- NCT06244849
- Lead Sponsor
- Hospices Civils de Lyon
- Brief Summary
Crohn's disease (CD) belongs to chronic inflammatory bowel diseases (IBD) affecting over 2 million individuals in the North America and 3.2 million in Europe with an increasing incidence rate in newly industrialized countries experiencing a westernization of lifestyle (1). This highly disabling disease affects patients' life in several ways with severe complications requiring surgery for half of them and is responsible for considerable economic burdens (2,3). Decades of research displayed that CD pathogenesis is determined by inappropriate immune responses towards luminal microbiota in genetically susceptible hosts. Genome-wide association studies (GWAS) have identified autophagy as one of the main pathways associated with susceptibility to CD (4-6). Autophagy is a dynamic process of the lysosomal catabolism, called autophagy flux, which is crucial to degrade and recycle obsolete and deleterious cytosolic components of the cell (7). Autophagy is also the main cell-autonomous process to fight intracellular microorganisms by degrading them, and by contributing to antimicrobial host immune responses. However, the functional consequences of polymorphisms affecting autophagy-associated genes on the dynamic process of autophagy and its real impact on CD pathogenesis remain largely unknown. In addition, CD is associated with a gut microbiota dysbiosis, as exemplified by the higher prevalence of AIEC (a bacterium eliminated by autophagy) in ileal mucosa of CD patients (8-10). Hence, autophagy defect, linked to autophagy SNPs, could contribute to CD-related dysbiosis and to CD activity and severity.
Beyond, CD-associated abnormalities of the autophagy flux may affect the composition of the autophagic cargoes, as well as the one of other vesicular pathway, such as exosomes, known to influence autophagy. These impairments could affect at longer term both cell activities and immune responses, especially in antigen presenting cells, which drive host immune responses.
The TOPIC project concerns translational research, in which we plan to generate a prospective cohort of CD patients giving up the unique opportunity to collect clinical data, to analyse simultaneously the autophagy flux, genetic variants of interest (from blood samples) and intestinal microbiota (from intestinal samples) and allowing to perform more fundamental studies. The results of the fundamental part will allow a better understanding of the pathophysiology of CD, and ultimately better management of these patients.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- NOT_YET_RECRUITING
- Sex
- All
- Target Recruitment
- 170
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Patient with Crohn disease (n=150) Ileocolonic biopsies CD patients requiring to undergo an ileo-colonoscopy for routine investigations (assessment of disease activity or complications as stricture or screening of colorectal cancer for CD) Patient with Crohn disease (n=150) Blood samples CD patients requiring to undergo an ileo-colonoscopy for routine investigations (assessment of disease activity or complications as stricture or screening of colorectal cancer for CD) Patient with Crohn disease (n=150) Stool simple CD patients requiring to undergo an ileo-colonoscopy for routine investigations (assessment of disease activity or complications as stricture or screening of colorectal cancer for CD) Patient without Crohn disease (n=20) Stool simple Non-IBD patients (control) requiring to undergo an ileo-colonoscopy for routine investigations (screening for colorectal cancer or diagnosis of irritable bowel syndrome for controls). Patient without Crohn disease (n=20) Blood samples Non-IBD patients (control) requiring to undergo an ileo-colonoscopy for routine investigations (screening for colorectal cancer or diagnosis of irritable bowel syndrome for controls). Patient without Crohn disease (n=20) Ileocolonic biopsies Non-IBD patients (control) requiring to undergo an ileo-colonoscopy for routine investigations (screening for colorectal cancer or diagnosis of irritable bowel syndrome for controls).
- Primary Outcome Measures
Name Time Method Autophagy flux Baseline and the day of ileocolonoscopy Difference of the autophagy flux signature according to AIEC infection, autophagy related gene variants, and its relationship between CD activity and severity.
- Secondary Outcome Measures
Name Time Method Characterize and compare the autophagosomal proteome in CD genetic autophagicvariant expressing immune cells in ileum and in colon in CD patients from that in non IBD patients (controls). Baseline and the day of ileocolonoscopy Qualitative and/or quantitative comparative analysis of content of the autophagosomal cargos between CD patients expressing the CD-associated autophagy related variants and WT gene-expressing non-IBD controls.
Characterize and compare the exosomal proteome in CD genetic autophagic variant expressing immune cells in ileum and in colon in CD patients from that in non IBD patients (controls). Baseline and the day of ileocolonoscopy Qualitative and/or quantitative comparative analysis of content of the exosomal proteome cargos between CD patients expressing the CD-associated autophagy related variants and WT gene-expressing non-IBD controls.
Trial Locations
- Locations (2)
CHU Estaing
🇫🇷Clermont-Ferrand, France
Centres Hospitalier Lyon Sud
🇫🇷Pierre-Bénite, France