Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, 78350, Jouy-en-Josas, France.
Sorbonne Université, Collège Doctoral, F-75005, Paris, France.
Sci Rep. 2018 Jun 27;8(1):9742. doi: 10.1038/s41598-018-28048-y.
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.
肠道微生物群通过其在诱导和维持健康免疫系统方面的基本作用，为宿主的整体健康做出贡献。共生细菌通过影响抗炎调节性 T 细胞（Treg）的比例和激活状态，来塑造黏膜免疫系统，而这些影响仍然只是部分揭示出来的代谢物。微生物群成员，如梭状芽孢杆菌，通过提供富含转化生长因子 β（TGFβ）的环境，促进 Treg 细胞在肠道中的积累。肠道上皮细胞（IEC）在这个过程中起着核心作用，因为它们是细菌定植后 TGFβ1 的主要来源。在这项研究中，我们使用培养细菌的上清液，研究了哪些肠道共生细菌能够调节 IEC 中的 TGFB1 人类启动子。我们报告说，厚壁菌门和梭杆菌门的上清液是 HT-29 细胞中最有效的 TGFB1 调节剂。此外，我们证明了丁酸盐是细菌上清液中导致 TGFβ1 增加的主要代谢物。这种丁酸盐驱动的效应独立于 TGFB1 启动子上存在的 G 蛋白偶联受体 GPR41、GPR43 和 GPR109a、转运蛋白 MCT1 以及转录因子 NF-κB 和 AP-1。有趣的是，HDAC 抑制剂诱导了类似的 TGFB1 增加，表明丁酸盐通过其 HDAC 抑制剂特性发挥作用。最后，我们的结果表明，SP1 是介导丁酸盐对 TGFB1 表达的 HDAC 抑制剂作用的主要转录因子。这是我们所知的，共生细菌衍生的丁酸盐调节 IEC 中 TGFB1 的机制的首次特征描述。
