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

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Crohn's Disease
• Intervention / Treatment: Biological: Blood samples; Biological: Stool simple; Biological: Ileocolonic biopsies

• Study Type: Interventional
• Enrollment (Estimated): 170
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: NANCEY Stéphane, Pr; Phone Number: +33 0478861289; Email: Stephane.nancey@chu-lyon.fr
• Study Contact Backup: Name: BOSCHETTI Gilles, Pr; Email: Gilles.boschetti@chu-lyon.fr

Study Locations

• France
  • Clermont-Ferrand, France, 63000
    • CHU Estaing
    • Contact: BUISSON Anthony, Pr; Phone Number: +33 04 73 75 05 23; Email: a-buisson@hotmail.fr
  • Pierre-Bénite, France, 69495
    • Centres Hospitalier Lyon Sud
    • Contact: NANCEY Stéphane, Pr; Phone Number: +33 04 78 86 12 89; Email: Stephane.nancey@chu-lyon.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

--- 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Patient with Crohn disease (n=150); 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)	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
Other: Patient without Crohn disease (n=20); 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).	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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Autophagy flux	Difference of the autophagy flux signature according to AIEC infection, autophagy related gene variants, and its relationship between CD activity and severity.	Baseline and the day of ileocolonoscopy

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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).	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.	Baseline and the day of ileocolonoscopy
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).	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.	Baseline and the day of ileocolonoscopy

Collaborators and Investigators

• Sponsor: Hospices Civils de Lyon
• Collaborators: Centre International de Recherche en Infectiologie (CIRI)

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2024
• Primary Completion (Estimated): January 1, 2026
• Study Completion (Estimated): January 1, 2026

Study Registration Dates

• First Submitted: December 14, 2023
• First Submitted That Met QC Criteria: January 29, 2024
• First Posted (Actual): February 6, 2024

Study Record Updates

• Last Update Posted (Actual): May 20, 2024
• Last Update Submitted That Met QC Criteria: May 16, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: Biomarker; Crohn disease; Intestinal microbiota; Autophagy flux; Non-inflammatory bowel diseases
• Additional Relevant MeSH Terms: Digestive System Diseases; Gastrointestinal Diseases; Gastroenteritis; Intestinal Diseases; Inflammatory Bowel Diseases; Crohn Disease
• Other Study ID Numbers: 69HCL22_1172

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No