IInflammatory Bowel diseases (IBD), such as Crohn’s disease (CD) and ulcerative colitis (UC) are characterized by chronic and relapsing inflammation of the intestine due to dysregulated immune responses to commensal bacteria. Their incidence and prevalence are high in western countries and are rising. Markers to predict relapse or complications and new treatments are needed and would have high socio-economic impacts. The pathogenesis of IBD is unclear. Genome Wide Association Studies and mouse models have emphasized the role of genetic factors. However, environmental factors or life habits are also involved, as supported by the growing incidence of IBD. Recent studies have shown the association of IBD with fecal microbiota dysbiosis, especially decreased abundance of Faecalibacterium prausnitzii, (F prau), a dominant bacteria of the Clostridium IV group. These data and the demonstration in mice that some gut microbiota can be colitogenic lead to suggest that dysbiotic microbiota contribute to IBD susceptibility. Importantly, a mechanism of this effect has been identified recently in mice as the induction by Clostridium IVa and XIV bacteria and their metabolite butyrate of IL-10 secreting Foxp3 Treg that prevent colitis in the colonic lamina propria. In humans, whereas IL-10 also plays a major role in IBD prevention, the contribution of Foxp3 colonic Treg to this process is unclear. In this context, we have identified in the human colonic LP a subset of Foxp3-negative IL-10-producing Treg that recognize F prau in a TCR-dependant manner. Interestingly, these cells shared most regulatory markers and functions of Foxp3 Treg and had a unique phenotype among LP lymphocytes (LPL) characterized by the stable expression of CD4 and CD8a allowing their quantification. These double positive (DP8a) Treg were relatively abundant in the healthy colonic mucosa (13% of CD4 LPL) and appeared to be decreased in the inflammed mucosa of CD patients. We also showed that around 2% of CD4 PBL exhibited the DP8a phenotype and were F prau-specific for about 10% of them. Moreover, DP8a PBL had Treg properties and were decreased in IBD patients compared with healthy donors (Sarrabayrouse et al 2014). Altogether, these data argue that F prau contributes to the induction of IL-10 producing DP8a Treg in a way similar to the induction of IL-10+ Foxp3 Treg by mouse Clostridia. Moreover, they suggest the existence of a connection between reduced level of F prau and decreased activity of F prau-specific DP8a Treg in CD patients, potentially resulting in disturbed colonic homeostasis. Consequently, this suggests that DP8a Treg play a role in the control of IBD. Our project aims to test this hypothesis towards the development of biologic markers and novel treatments to manage or cure IBD. To this end we will: 1/test the capacity of human DP8a Treg to prevent experimental colitis in a humanized mouse model; 2/characterize the transcriptome and activation signature of DP8a Treg to understand the basis of their regulatory function and identify markers that could permit to assess their prognostic value in colonic biopsies; 3/identify the mechanism of DP8a Treg induction from naive CD4 T cells by F prau towards the design of methods to regulate the number of these cells in patients; 4/ask if the level of DP8a PBL specific or not for F prau correlates with the amount of F prau and other bacteria in the fecal microbiota and may predict flare in IBD patients. To achieve these goals, a narrow collaboration will be pursued between the INSERM group who discovered the DP8a Treg, the INSERM team who demonstrated the anti-inflammatory properties and prognostic value of F prau in CD, and the Gastroenterology Department at Saint Antoine Hospital, who has a great recruitment of IBD patients. This collaboration is particularly suitable for the transfer of results from bench to bedside.
Monsieur Frédéric Altare (INSERM U892-CNRS 6299- Team 5)
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
APHP Service de Gastroenterologie, hopital Saint Antoine hospital, APHP
U1157 INSERM U1157-Equipe Avenir
CRCNA-T5 INSERM U892-CNRS 6299- Team 5
Help of the ANR 394,179 euros
Beginning and duration of the scientific project: September 2015 - 42 Months