Propionate functions as a feeding-state-dependent regulatory metabolite to counter pro-inflammatory signaling linked to nutrient load and obesity.

Generally, fasting and refeeding confer anti- and pro-inflammatory effects, respectively. In humans, these caloric-load interventions function, in part, via regulation of CD4+ T cell biology. However, mechanisms orchestrating this regulation remain incomplete. We employed integrative bioinformatics of RNA-seq and HPLC-mass spectrometry data to measure serum metabolites and gene expression of peripheral blood mononuclear cells isolated from fasting and refeeding in volunteers to identify nutrient-load metabolite-driven immunoregulation. Propionate, a short chain fatty acid (SCFA), and the SCFA-sensing G-protein coupled receptor (GPCR) 43 (ffar2) were co-ordinately and inversely regulated by fasting and refeeding. Propionate and FFAR agonists decreased IFNγ and IL-17 and significantly blunted HDAC activity in CD4+ T cells. Furthermore, propionate blunted NFκB activity and diminished IL-6 release. In parallel, propionate reduced phosphorylation of canonical TH1 and TH17 regulators, STAT1 and STAT3, respectively. Conversely, knockdown of FFARs significantly attenuated the anti-inflammatory role of propionate. Interestingly, propionate recapitulated the blunting of CD4+ T helper cell activation in primary cells from obese individuals, extending the role of this metabolite to a disease associated with low-grade inflammation. Together, these data identify a nutrient-load responsive SCFA-GPCR linked pathway to regulate CD4+ helper T cell immune responsiveness.