LAUSR

The gut microbiota produces a wide variety of metabolites, which interact with intestinal cells and contribute to host physiology. These metabolites regulate intestinal cell activities by modulating either gene transcription or post-translational modifications of gut proteins. The effect of gut commensal bacteria on SUMOylation, an essential ubiquitin-like modification in intestinal physiology, remains however unknown. Here, we show that short chain fatty acids (SCFAs) and branched chain fatty acids (BCFAs) produced by the gut microbiota increase protein SUMOylation in different intestinal cell lines in a pH-dependent manner. We demonstrate that these metabolites induce an oxidative stress which inactivates intestinal deSUMOylases and promotes the hyperSUMOylation of chromatin-bound proteins. In order to determine the impact of these modifications on intestinal physiology, we focused on the NF-κB signaling pathway, a key player in inflammation known to be regulated by SUMOylation. We demonstrated that the hyperSUMOylation induced by SCFAs/BCFAs inhibits the activation of the NF-κB pathway in intestinal cells by blocking the degradation of the inhibitory factor IκBα in response to TNFα. This results in a decrease in pro-inflammatory cytokines expression, such as IL8 or CCL20, as well as a decrease in intestinal epithelial permeability in response to TNFα. Together, our results reveal that fatty acids produced by gut commensal bacteria regulate intestinal physiology by modulating SUMOylation and illustrate a new mechanism of dampening of host inflammatory responses by the gut microbiota.