Targeting of SUMOylation by the gut microbiota and dampening of intestinal inflammation – SUMONING

The gut microbiota produces a wide variety of metabolites, which modulate intestinal cell activities and participate to human physiology. The effect of gut bacteria on SUMOylation, an essential ubiquitin-like modification in intestinal physiology, has only been investigated in the case of bacterial pathogens. These pathogens inhibit intestinal SUMOylation to promote infection. We have recently demonstrated that gut commensal bacteria, in contrast to pathogens, increase intestinal protein SUMOylation via the production of specific metabolites. This “hyperSUMOylation” results in the dampening of inflammatory responses of enterocytes in vitro. These metabolites thus constitute interesting drug candidates to dampen intestinal inflammation in vivo. The project proposed here aims to (1) characterize which intestinal proteins are hyperSUMOylated in response to these metabolites; (2) characterize how these SUMOylated proteins modulate intestinal gene expression and (3) determine, using pre-clinical models, whether these metabolites dampen inflammation in two types of diseases: inflammatory bowel diseases (IBD) and irritable bowel syndrome (IBS). The ambitiousness of our project is to both accumulate basic knowledge on the mechanisms triggered by these gut microbiota metabolites to modulate intestinal cell activity, via the targeting of host SUMOylation, and to apply this knowledge to various pre-clinical models. We anticipate that this project will provide new insights on previously uncharacterized interactions between intestinal cells and gut bacteria, and will identify potential new therapeutic agents to treat prevalent inflammation-associated diseases in humans.