Influence of the microbiota on neutrophil functions in intestinal homeostasis and inflammation – NeutroBiota

Inflammatory Bowel Disease (IBD) are chronic inflammatory conditions of the gastrointestinal tract with increasing prevalence. Current therapies are only partially efficient and associated with severe side effects. New therapeutic strategies with innovative targets are thus urgently needed. Neutrophils are key players of innate immunity in IBD, but their roles in disease development are neglected compared to those of other immune cells. Essential to host defense, their overactivation can cause chronic inflammation and tissue damage. Recently, converging evidence has highlighted interactions between neutrophils, gut inflammation and microbiota. Numerous IBD susceptibility genes are involved in neutrophil functions related to defense against microbes. Moreover, severe monogenic diseases with dysfunctional neutrophils, such as Chronic Granulomatous Disease (CGD), are characterized by recurrent infections but also intestinal inflammation mimicking IBD. In addition, both IBD and CGD are associated with alterations of the intestinal microbiota. However, the influence of microbiota on neutrophil functions, and the consequences in terms of disease development remain largely unknown. Our objectives are to (i) identify intestinal microorganisms and microbiota-derived factors that influence neutrophil functions, and (ii) decipher the effect of microbiota on neutrophil functions in the context of intestinal inflammation. Our project follows systematic approaches and takes advantage of up-to-date technologies (flow cytometry, Seahorse, high throughput microscopy, proteomics, scRNAseq), and to the access to unique mouse and human samples (blood, faeces and intestinal tissue from the Saint-Antoine Hospital). Based on both basic and translational research, this project is essential to better understand the roles played by neutrophils in host-microbiota interactions in homeostasis and intestinal inflammation, and to identify new therapeutic targets for IBD patients.