Abstract
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.
Highlights
Humans are colonized by bacteria, archaea, eukaryotes and viruses, which are collectively called the microbiota
We showed that the TGFB1 induction by butyrate was independent of the short chain fatty acids (SCFAs) G-protein coupled receptors (GPR41, GPR43 and GPR109a), and of the SCFA transporter monocarboxylate transporter 1 (MCT1)
Metabolites derived from commensal bacteria modulate transforming growth factors β1 (TGFβ1) expression
Summary
Humans are colonized by bacteria, archaea, eukaryotes and viruses, which are collectively called the microbiota. We decided to investigate the impact of individual cultivable commensal bacteria on TGFB1 transcriptional expression in a human IEC model and to further characterise the underlying molecular mechanisms. We screened bacterial supernatants derived from over 120 commensal species on a TGFB1 reporter system and showed that butyrate was the main microbiota-derived metabolite inducing TGFB1 expression in the human intestinal epithelial cell-line HT-29. The TGFB1 up-regulation could be attributed to the HDAC inhibitory properties of SCFAs. by using specific inhibitors and point mutations of the promoter region of TGFB1, we excluded NFκB and AP1 as regulatory elements and showed that the SP1 transcription factor was involved in the butyrate-driven activation of TGFB1 expression
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