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

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.

Diet and Mental Health: Review of the Recent Updates on Molecular Mechanisms

“…Interestingly, TGF-β1 plays a key role as a regulator of gut microbiota [85], and its deficit plays a central role in the pathophysiology of cognitive deficits both in depression and AD [84]. Gut dysbiosis-dependent fluctuations of butyrate can interfere with TGF-β1 synthesis and release from intestinal epithelial cells [86].…”

Gut microbiome and its role in obesity and insulin resistance

“…Second, metabolites from the gut microbiota were shown to modulate the host immune system. For example, butyrate, an SCFA, stimulated the expression of the transforming growth factor (TGFβ) from human intestinal epithelial cells, which, in turn, activated anti‐inflammatory regulatory T cells . Similarly, F. prausnitzii , a butyrate producer, is thought to alleviate inflammation through its metabolites that block nuclear factor‐kB activation and subsequent secretion of proinflammatory mediators …”

A regulatory variant in TBX2 promoter is related to the decreased susceptibility of congenital heart disease in the Han Chinese population

“…In our study, functional analyses using luciferase assays and EMSA indicated the rs4455026 C allele might decrease TBX2 promoter activity by altering the binding affinity of certain transcription factors. According to the online bioinformatic tools, Krox‐20 and Sp1 were predicted as potential stimulators with lower binding affinity with C allele, whereas another inhibitory factor called “represso” had higher binding affinity (Desmazieres, Charnay, & Gilardi‐Hebenstreit, ; Martin‐Gallausiaux et al, ). We inferred that the stimulators had more significant influence than the inhibitor, and as a result, G to C alteration gave rise to a lower TBX2 promoter activity and less gene expression.…”