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

Autophagy flux

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.