COmparison of Microbiota AccordIng to age in Crohn's Disease – COMeBACk

Inflammatory bowel disease (IBD) including Crohn’s Disease (CD) and Ulcerative Colitis (UC) are chronic diseases evolving in a relapsing-remitting pattern, characterised by an uncontrolled over-activation of the intestinal immune system. Its frequency is increasing over the world and the lifetime risk of developing IBD has been calculated to be 1%. It has been estimated that around 2.2 million persons are affected in Europe. All ages can be affected but generally CD begins in young adulthood. However, elderly-onset CD is more and more frequent. Although the exact aetiology of IBD remains unknown, it is accepted that it is a multifactorial disease resulting from the complex interplay between environmental factors, genetic susceptibility, and intestinal microbiota leading to an abnormal mucosal immune response. The intestinal microbiota appears to be the key factor triggering and maintaining inflammation. An imbalance in bacterial composition (dysbiosis) may be one of the main causes of mucosal inflammation, with individual bacterial species playing a specific role (i.e. Adherent Invasive E. coli). Genetic investigations (genome wide association studies) in CD have uncovered several mechanisms and pathways involved in the disease pathogenesis, including, innate (NOD2 and CARD9 genes) and adaptive immunity (IL23R gene), autophagy (ATG16L1 and IRGM genes) or endoplasmic reticulum stress (XBP1 gene). However, among the susceptibility genes identified (more than 160 in IBD to date) none is necessary or sufficient for disease onset. Both genes and serological markers associated with CD underscore the role of bacteria in disease etiology.
In 1988 the first French prospective registry on IBD was implemented and is now the largest in the world and has been scientifically proven by Inserm and InVS. Study area was Northern France with six million inhabitants. From 1988 to 2012, 22,976 incident patients were recorded and CD incidence rate significantly increased from 5.2 to 6.8 per 105 inhabitants. The most remarkable observation has been the striking increase in the incidence of CD in young patients less than 20 years old (from 6.5 to 12.9 per 105 inhabitants), as observed in other European countries. In the first time we performed a comparison of natural history and clinical course between paediatric- and elderly-onset CD patients in population-based cohorts. We published that the young-onset (n=530) and elderly-onset (n=374) CD patients were strikingly different at CD diagnosis as at maximal follow-up. Indeed disease extension and complicated behaviour (stricturing or penetrating) occurred in 40% of paediatric-onset IBD while location and behaviour were stable in time in more than 88% of the elderly. The main question is: “Is it the same disease”?
The cause of CD could be different according to age at onset of CD symptoms. Indeed we know that some very young patients at CD diagnosis have particular genetic variants as abnormalities of the IL10R that are regarded as quite monogenic disease. In the other way, the microbiota also undergoes substantial changes at the extremes of life, in infants and older people and the ramifications of which are very few being explored. The comparison of microbiota and genetic profile of patients with CD beginning at the extremes of life by Partial Least Square Discriminant Analysis (PLS-DA) could help us to better known physiopathology of CD according to age and provide arguments that CD beginning at the extremes of life could be different diseases.
The main objective is to to ascertain through population-based study the hypothesis that gut microbiota is different between paediatric-onset and elderly-onset CD patients in relation with genetic and environmental mechanisms.
The results issued from COMeBACk project will provide a better knowledge of the etiopathogenic ways in CD and will allow to purpose a personalized therapeutic care based on age at CD onset (i.e. according to the gut bacteria involved).