Inflammatory Bowel Disease (Crohn's Disease and Ulcerative Colitis) Clinical Trial
Official title:
Study of Inflammatory Markers (VNN1) in Crohn Disease and Ulcerative Colitis
Inflammatory Bowel diseases (IBD) include Crohn's disease and ulcerative colitis. IBD's
precise origin is unknown until now. Today, the current hypothesis of the disease
pathogenesis is that IBD result from a dysregulated mucosal immune response to the gut
microbial flora in genetically susceptible hosts. The intestinal homeostasis depends on
interactions between immune and epithelial cells. Epithelial cells are the first line of
defense, are tightly connected to the underlying gut associated lymphoid tissue and their
alteration results in loss of tissue homeostasis.
Vanin-1 (Vnn1 in mice, VNN1 in humans) is an epithelial pantheinase which regulates the cell
response to stress.
This ectoenzyme hydrolyses the vitamin B5-derivative pantetheine to provide cysteamine to
tissues and regenerate pantothenate. Previous studies have shown that Vnn1 KO mice were more
resistant to experimental colitis and administration of cystamine (oxidized form of
cysteamine) restored their susceptibility to colitis. Furthermore, analysis of VNN1
expression in IBD patients show that high VNN1 expression is associated with severe clinical
features. Thus, analysis of VNN1 expression could represent a good prognostic marker.
In a recent published article, we characterized among a retrospective cohort of 500 IBD
patients and controls new SNPs (single nucleotide polymorphisms) in the VNN1 promoter and
showed their association with IBD incidence and high VNN1 expression. This suggested that
the VNN1gene might be a new predisposition marker of IBD.
In mouse, Vnn1 expression is tightly regulated by activation of PPARa and PPARg
transcription factors. Interestingly, one of the SNPs identified in patients participates to
a PPARg binding site. Interestingly, drugs related to the family of 5-ASA which are commonly
used in IBD, have PPARgamma agonist potential. Therefore, quantifying VNN1 levels in
patients under 5-ASA therapy might help predicting response to therapy and select patients
with the highest benefit for this therapy.
The purpose of this new project is to extend our initial analysis. The study will be
prospective, monocentric and controlled. Its primary objective is to evaluate the level of
VNN1 expression in the colonic mucosa between IBD patients and control subjects to confirm
the correlation between high VNN1 expression and IBD. In relation with its prospective
nature, we will also try to associate VNN1 expression level with specific endophenotypes
(severity and/or localization of the lesions, quality of the response to therapy). Finally,
we will screen patients for the previously identified SNPs to integrate this information in
the interpretation of the results of expression analysis.
This study is planned on 2 years. Two groups of patients will be constituted: one group will
include IBD patients followed in the " Service de Gastro-entérologie du Pr Grimaud à
l'Hôpital Nord " and the other group will constitute the control cohort including persons
who were proposed a screening colonoscopy for familial history of colon cancer or polyps, or
for Irritable Bowel Syndrome.
The investigator will have to fill a questionnaire for each included patient, collecting
information about age, sex, past medical history, taken medicine, digestive symptoms and
colonoscopy indication.
IBD patients will have a first set of biopsies (n = 10) and blood samples collected under
general anesthesia during a colonoscopy planned in their IBD usual follow-up; a second set
of similar samples will be collected within the next 12 months if an endoscopic control is
medically justified. The control subjects will have only one set of biopsy and blood samples
collected under general anesthesia during their colonoscopy. In the particular case of IBD
patients who require surgery, a small piece of the resection will be collected ex-vivo on
both healthy and pathologic areas.
The blood sample will serve for quantification of the VNN1 seric pantheteinase activity and
SNP's genetic study.
The colonic biopsies will be obtained in duplicates from 5 different ileocolonic areas, one
for histopathological analysis and the other for transcriptional analysis by qRT-PCR.
The surgical samples will be used for transcriptional activity, tissue pantheteinase
activity and constitution of TMA (Tissue MicroArrays) bank for immunohistochemistry.
Expected benefits are to validate a new IBD prognostic marker for disease severity or
potentially for evaluation of the therapeutic response.
n/a
Allocation: Non-Randomized, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Basic Science