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The intestinal microbiota contributes to the global wellbeing of their host by their fundamental role in the induction and maintenance of a healthy immune system. Commensal bacteria shape the mucosal immune system by influencing the proportion and the activation state of anti-inflammatory regulatory T cells (Treg) by metabolites that are still only partially unravelled. Microbiota members such as  Clostridiales  provide a transforming growth factor β (TGFβ)-rich environment that promotes the accumulation of Treg cells in the gut. The intestinal epithelial cells (IECs) take a central part in this process, as they are a major source of TGFβ1 upon bacterial colonisation. In this study, we investigated which gut commensal bacteria were able to regulate the  TGFB1  human promoter in IECs using supernatants from cultured bacteria. We reported that Firmicutes and Fusobacteria supernatants were the most potent  TGFB1  modulators in HT-29 cells. Furthermore, we demonstrated that butyrate was the main metabolite in bacterial supernatants accounting for TGFβ1 increase. This butyrate-driven effect was independent of the G-protein coupled receptors GPR41, GPR43 and GPR109a, the transporter MCT1 as well as the transcription factors NF-κB and AP-1 present on  TGFB1  promoter. Interestingly, HDAC inhibitors were inducing a similar  TGFB1  increase suggesting that butyrate acted through its HDAC inhibitor properties. Finally, our results showed that SP1 was the main transcription factor mediating the HDAC inhibitor effect of butyrate on  TGFB1  expression. This is, to our knowledge, the first characterisation of the mechanisms underlying  TGFB1  regulation in IEC by commensal bacteria derived butyrate.

Butyrate produced by gut commensal bacteria activates TGF-beta1 expression through the transcription factor SP1 in human intestinal epithelial cells