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

• Published in: Journal of leukocyte biology 2024-03, Vol.115 (4), p.738-749
• Main Authors: Han, Kim, Meadows, Allison M, Rodman, Matthew J, Russo, Anna Chiara, Sharma, Rahul, Singh, Komudi, Hassanzadeh, Shahin, Dagur, Pradeep K, Huffstutler, Rebecca D, Krause, Fynn N, Griffin, Julian L, Baumer, Yvonne, Powell-Wiley, Tiffany M, Sack, Michael N
• Format: Article
• Language: English
• Subjects: Fatty Acids, Nonesterified; Humans; Leukocytes, Mononuclear; Obesity; Propionates - pharmacology; Receptors, G-Protein-Coupled - genetics
• ISSN: 1938-3673; 1938-3673
• DOI: 10.1093/jleuko/qiae006

Generally, fasting and refeeding confer anti- and proinflammatory 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 sequencing and high-performance liquid chromatography-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 43 (ffar2) were coordinately and inversely regulated by fasting and refeeding. Propionate and free fatty acid receptor agonists decreased interferon-γ and interleukin-17 and significantly blunted histone deacetylase activity in CD4+ T cells. Furthermore, propionate blunted nuclear factor κB activity and diminished interleukin-6 release. In parallel, propionate reduced phosphorylation of canonical T helper 1 (TH1) and TH17 regulators, STAT1 and STAT3, respectively. Conversely, knockdown of free fatty acid receptors significantly attenuated the anti-inflammatory role of propionate. Interestingly, propionate recapitulated the blunting of CD4+ TH 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-G protein-coupled receptor linked pathway to regulate CD4+ TH cell immune responsiveness.