Short-chain fatty acid signaling pathway (SCFA signaling)

The short-chain fatty acid (SCFA) signaling pathway is a critical mediator of the interaction between the gut microbiota and host physiology (Koh et al., 2016, Cell). SCFAs, primarily acetate, propionate, and butyrate, are produced by the bacterial fermentation of dietary fiber in the colon and serve as signaling molecules that regulate immune function and energy metabolism (Tan et al., 2014, Frontiers in Immunology). These metabolites exert their effects through two primary mechanisms: the activation of G protein-coupled receptors (GPCRs), such as Free Fatty Acid Receptor 2 (FFAR2/GPR43), Free Fatty Acid Receptor 3 (FFAR3/GPR41), and Hydroxycarboxylic Acid Receptor 2 (HCAR2/GPR109A), and the inhibition of histone deacetylases (HDACs) (Dalile et al., 2019, Nature Reviews Gastroenterology & Hepatology). Activation of these receptors on immune cells and enteroendocrine cells promotes anti-inflammatory responses and the secretion of metabolic hormones like GLP-1, while HDAC inhibition by butyrate regulates gene expression related to cell proliferation and apoptosis (Sivaprakasam et al., 2016, Pharmacology & Therapeutics). Dysregulation of SCFA signaling is associated with inflammatory bowel disease, obesity, type 2 diabetes, and colorectal cancer. Consequently, this pathway is a major focus for therapeutic development, including the use of prebiotics, probiotics, and targeted small-molecule agonists to treat metabolic and inflammatory disorders.

Other names

SCFA receptorsFree fatty acid receptor signalingButyrate-responsive pathwaysMicrobiota-derived metabolite signaling

Activation of G protein-coupled receptors (FFAR2, FFAR3, HCAR2) and inhibition of Class I and IIa histone deacetylases (HDACs).