MArylAND · At the host-bacteria interface: Modulation of the intestinal microbiota and its metabolic activity by Card9 signalling in health and Inflammatory Bowel Diseases

At the host-bacteria interface: Modulation of the intestinal microbiota and its metabolic activity by Card9 signalling in health and Inflammatory Bowel Diseases

The microbial community living in the human intestine is crucial to the health and nutrition of the host. Loss of the fragile balance within this complex ecosystem is involved in numerous pathologies, including inflammatory bowel disease (IBD). IBD such as Crohn’s disease (CD) and ulcerative colitis (UC), are characterized by chronic and relapsing inflammation of the gastro-intestinal tract. Their incidence increased during the 20th century and continues to rise, affecting individuals in the most challenging and productive years of their lives 1 and thus representing major burdens of morbidity in western countries. Their incidence and prevalence are relatively high in industrialized countries (10-15 per 100 000 inhabitants/year and 100-150 per 100 000 respectively) and the lifelong risk to develop IBD is currently estimated to be over 1%. Unfortunately, no cure is currently possible for CD and UC. Most of the available treatments are immunosuppressants that are associated with potentially severe side effects such as infection and neoplasia. Moreover, despite recent progress, immunosuppressive treatments are not always effective and have, at best, suspensive effects. Finally, the course of these diseases remains poorly predictable leading to inappropriate treatment or delay in therapeutic adaptation. There is thus a great unmet medical need both of new therapeutic approaches and biomarkers to predict clinical events. Although the exact pathogenesis of IBD is not fully understood, it is currently admitted that it develops as a result of a combination of genetic predisposition, dysbiosis of the gut microbiota, and environmental influences. Deciphering the host-bacteria crosstalk will improve our understanding of IBD and enable new preventive and therapeutic strategies. Caspase recruitment domain 9 (Card9), one of the IBD susceptibility genes, codes for a protein involved in the response to fungi and bacteria. Sokol and colleagues showed that Card9-/- mice have an increased susceptibility to colitis, due to an altered gut microbiota that is not able to metabolise tryptophan into aryl hydrocarbon receptor (AhR) ligands. In humans, comparable mechanisms seem to be involved, as microbiota of IBD patients exhibit impaired production of AhR ligands, which mirrors the Card9-/- genotype. The aim of the present project was to better understand how Card9 signalling modulates the susceptibility to intestinal inflammation. For this purpose, we took advantage of a strong collaborative environment and cutting-edge techniques, including gnotobiotic animals, cre-lox technology, transcriptomics, metabolomics and systems biology. Specifically, we planed to identify (i) cell types involved in Card9-dependent susceptibilty to colitis and (ii) dysregulated host pathways and microbiota changes in the absence of Card9.

Data: CORDIS, © European Union