Characterization of the pro-inflammatory activity of short-chain fatty acids (SCFAs)

Abstract

Short-chain fatty acids (SCFAs), which are mainly derived from microbial fermentation of dietary fibres, have been considered to be beneficial to gut health for decades. Recently, a few of studies reported that some patients with inflammatory bowel disease (IBD) showed poor tolerance to diets rich in certain fibres, and that fibre fermentation-derived SCFAs could exacerbate gut inflammation in mouse colitis models. Therefore, intensive efforts are required to further define and characterize the roles of SCFAs under inflammatory state. <br /> Given the mobility (translocation) of microbiota-derived metabolites and recruitment of phagocytes, such as macrophages, in a leaky gut under inflammatory conditions in patients with IBD, I challenged primary human macrophages with the combinations of SCFAs and the TLR-4 agonist LPS. Transcriptomics and proteomics profiling, and measurement of cytokines secretion were performed, which, interestingly, showed that the SCFA butyrate displayed the strongest regulatory effect on the TLR-4-induced genes transcription and translation as well as cytokines production. Furthermore, I found that butyrate could aggravate inflammatory responses by enhancing the TLR-induced pro-inflammatory cytokine interleukin (IL) -1β and suppressing the anti-inflammatory cytokine IL-10. This was in contrast to the previously reported anti-inflammatory and protective roles of butyrate in intestinal epithelial cells (IECs). <br /> In further experiments, working on the mechanisms by which butyrate regulates TLR-mediated IL-1β and IL-10 production, I discovered that butyrate, together with LPS, induced IL-1β secretion in an NLRP3 inflammasome-dependent manner, with the engagement of multiple molecules including caspase-8, TBK-1, RIPK1, RIPK3, STAT3 and HDAC11. On the other hand, butyrate strongly inhibited TLR-induced IL-10 signaling with the involvement of STAT1, STAT3, p38 and the Akt-mTOR pathway. <br /> In my thesis, I characterized the effect of SCFAs on the TLR-mediated transcriptional and proteomic responses. Importantly, I showed that SCFAs might be detrimental to gut health in the patients with IBD through regulations of the cytokines IL-1β and IL-10 in primary human macrophages. I also identified a network of biomolecules engaged in these processes. These findings provide new evidences for a full understanding of how SCFAs impact on gut health and suggest potential novel targets for the treatment of patients with IBD.