TOward a Better Understanding of the autoPhagy Machinery for the Identification of Potential Novel Biomarkers and Therapeutic Targets in Crohn's Disease - TOPIC Study

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.

Conditions

• Crohn's Disease

Interventions

BIOLOGICAL

Blood samples

A 28 mL (5 EDTA tubes of 4 mL and 2 dry tubes) venous blood will be collected added to the standard blood analysis performed in routine

BIOLOGICAL

Stool simple

A fresh stool sample will be collected and conserved at room temperature until shipment

BIOLOGICAL

Ileocolonic biopsies

An ileo-colonoscopy with 10 ileal biopsies scheduled in their regular medical follow-up will be performed

Sponsors & Collaborators

• Centre International de Recherche en Infectiologie (CIRI)

  collaborator UNKNOWN

• Hospices Civils de Lyon

  lead OTHER

Study Design

Allocation

NON_RANDOMIZED

Purpose

OTHER

Masking

NONE

Model

PARALLEL

Eligibility

Min Age

18 Years

Max Age

99 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2024-06-01

Primary Completion

2026-01-01

Completion

2026-01-01

Countries

• France

Study Locations