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ABSTRACTThe commensal bacterium Faecalibacterium prausnitziiplays a key role in inflammatory bowel disease (IBD) pathogenesis and serves as a general health biomarker in humans. However, the host molecular mechanisms that underlie its anti-inflammatory effects remain unknown. In this study we performed a transcriptomic approach on human intestinal epithelial cells (HT-29) stimulated with TNF-α and exposed to F. prausnitziiculture supernatant (SN) in order to determine the impact of this commensal bacterium on intestinal epithelial cells. Moreover, modulation of the most upregulated gene after F. prausnitziiSN contact was validated both in vitroand in vivo. Our results showed that F. prausnitziiSN upregulates the expression of Dact3, a gene linked to the Wnt/JNK pathway. Interestingly, when we silenced Dact3expression, the effect of F. prausnitziiSN was lost. Butyrate was identified as the F. prausnitziieffector responsible for Dact3modulation. Dact3upregulation was also validated in vivoin both healthy and inflamed mice treated with either F. prausnitziiSN or the live bacteria, respectively. Finally, we demonstrated by colon transcriptomics that gut microbiota directly influences Dact3expression. This study provides new clues about the host molecular mechanisms involved in the anti-inflammatory effects of the beneficial commensal bacterium F. prausnitzii.