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

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.


Eligibility Criteria:
--- Inclusion Criteria :

For CD patients :

* Aged over 18 years
* Men or non-pregnant women
* Patients with a diagnosis of terminal ileum or ileocolonic CD for at least three months who requires to perform an ileocolonoscopy for routine follow-up
* Inactive and moderately to severely active CD according to the Harvey-Bradshaw index
* Stable doses of oral prednisone (≤30 mg per day) or budesonide (≤9 mg per day), mesalamine, concomitant immunosuppressive agents, biologics including anti-TNF agents, vedolizumab or ustekinumab are allowed at stable dose for at least three months before inclusion.
* Informed written consent
* Beneficiary or beneficiary of a social security system

For non IBD controls :

* Aged over 18 years
* Men or non-pregnant women
* Patients without a diagnosis of Crohn's disease who requires to perform an ileocolonoscopy for routine follow-up
* Informed written consent
* Beneficiary or beneficiary of a social security system

  * Exclusion Criteria \* :

For patients and non-IBD controls :

* Existing pregnancy, lactation, or intended pregnancy within the next 15 months
* History of disease, including mental/emotional disorder that might interfere with their participation in the study
* Serious secondary illnesses of an acute or chronic nature, which in the opinion of the investigator renders the patient unsuitable for inclusion into the study
* Inability to comply with the protocol requirements
* Presence of an ileo-/colonic stoma
* Patients with known colonic stricture and exclusive or predominant anal or perineal Crohn's disease lesions
* Known previous or concurrent malignancy (other than that considered surgically cured, with no evidence for recurrence for 5 years)
* Short bowel syndrome
* Concomitant Clostridium difficile superinfection
* Indeterminate colitis
* Concomitant leukocyte apheresis
* Patients who will be exposed to antibiotics 4 weeks prior the inclusion, given the potential impact on the detection of AIEC colonization in ileal biopsies
* Patients who denied the protocol, not ability to accept or sign consent of the protocol
* Subject involved in another interventional research with an exclusion period still in progress at inclusion
* Pregnant women, women in labor or breastfeeding women\*.
* Persons deprived of their liberty by a judicial or administrative decision
* Persons under psychiatric care
* Persons admitted to a health or social institution for purposes other than research
* Adults subject to a legal protection measure (guardianship, curatorship)
* Subject involved in another clinical trial