Host short-chain fatty acid receptors and histone deacetylases (SCFA receptors and HDACs)

Host short-chain fatty acid (SCFA) receptors and histone deacetylases (HDACs) constitute a dual-pathway signaling system that mediates the effects of gut microbiota-derived metabolites on host physiology [MDPI, 2024]. SCFAs, such as acetate, propionate, and butyrate, are produced through the fermentation of dietary fiber and act as ligands for G protein-coupled receptors, specifically G protein-coupled receptor 41 (GPR41/FFAR3), G protein-coupled receptor 43 (GPR43/FFAR2), and G protein-coupled receptor 109A (GPR109A/HCAR2) [NIH, 2023]. These receptors are widely expressed in the gut epithelium, immune cells, and adipose tissue, where they regulate inflammatory responses, metabolic homeostasis, and the secretion of gut hormones like GLP-1 [Frontiers, 2024]. Simultaneously, SCFAs—most notably butyrate—act as endogenous inhibitors of Class I and IIa HDACs [NIH, 2016]. This inhibition leads to increased histone acetylation and chromatin remodeling, which promotes the differentiation of regulatory T cells (Tregs) and suppresses pro-inflammatory cytokine production [ResearchGate, 2025]. Dysregulation of these pathways is linked to inflammatory bowel disease, colorectal cancer, and metabolic disorders such as obesity and type 2 diabetes [NIH, 2022]. Consequently, this target complex is a major focus for therapeutic interventions involving prebiotics, probiotics, and small-molecule modulators of SCFA signaling [MDPI, 2021].

Other names

Short-chain fatty acid receptorsFree fatty acid receptorsFFARsHistone deacetylasesHDACsGPR41GPR43GPR109AFFAR2FFAR3HCAR2

Agonism of G protein-coupled receptors (GPR41, GPR43, GPR109A) and non-competitive inhibition of histone deacetylases (HDACs) to modulate gene expression and intracellular signaling pathways [NIH, 2023; MDPI, 2024].