Role of Dact3 in the intestinal homeostasis: Elucidating the mechanism of Action of the anti-inflammatory Commensal bacTerium Faecalibacterium prausnitzii (REACT) – REACT

Inflammatory bowel diseases (IBD) are chronic inflammatory disorders of the gut with a substantial socioeconomic and health impact worldwide. Unfortunately, there is no cure for IBD and present therapies are only attenuating the inflammatory response. A promising approach to prevent and treat IBD includes the oral administration of both probiotic and commensal bacteria. For instance, the commensal bacterium Faecalibacterium prausnitzii (one of the most abundant gut bacterial species in healthy individuals) has been shown to play a key role in intestinal diseases and serves as a general health biomarker in humans. Indeed, this bacterium efficiently lowers intestinal inflammation and improves gut barrier function through secreted metabolites able to block NF-kb activation and IL-8 production. In addition, F. prausnitzii produces high quantities of butyrate, a short-chain fatty acid (SCFA), which is important in intestinal homeostasis and contributes to F. prausnitzii anti-inflammatory effects. To identify the host receptor and signaling pathways involved, we performed a transcriptomic analysis using human intestinal epithelial cells (IECs, i.e. HT-29 cells) and the supernatant (SN) of a F. prausnitzii. We found that F. prausnitzii SN upregulates the expression of Dact3, a gene linked to the Wnt/JNK pathway, which is part of the inflammatory process. Dact3 upregulation is associated with reduced IL-8 expression. Strikingly, silencing of Dact3 expression results in a loss of the anti-inflammatory effects of F. prausnitzii SN, suggesting an important role on Dact3 modulation. Interestingly, butyrate was identified as one of the F. prausnitzii effectors responsible for Dact3 modulation and IL-8 inhibition. These results provide new clues about the host molecular mechanisms involved in the anti-inflammatory effects of F. prausnitzii. Despite important progress, most of the host molecular mechanisms that underlie F. prausnitzii anti-inflammatory effects remain to be discovered. The aim of this project is to determine the role of Dact3 in intestinal homeostasis (in particular in inflammatory conditions) and most important, to elucidate the impact of F. prausnitzii and gut microbiota on Dact3 expression. Our hypothesis is that Dact3 could be a master regulator of intestinal homeostasis. We expect to provide robust data on the mechanisms involved in the beneficial effects of F. prausnitzii with the perspective to confirm the key role of Dact3 in intestinal homeostasis and to propose a new innovative biomedical alternative for the prevention and treatment of IBD either by using this commensal bacterium or Dact3 as a pharmacologic drug.