Free fatty acid receptor 2 (GPR43), Hydroxycarboxylic acid receptor 2 (GPR109A), and Histone deacetylases (HDACs) (SCFA targets)

The group comprising GPR43 (Free fatty acid receptor 2), GPR109A (Hydroxycarboxylic acid receptor 2), and Histone Deacetylases (HDACs) represents the primary molecular targets for short-chain fatty acids (SCFAs) like butyrate and propionate. GPR43 and GPR109A are G protein-coupled receptors that function as nutrient sensors on the surface of immune and epithelial cells, triggering signaling cascades that promote anti-inflammatory cytokine production and maintain intestinal barrier integrity. Simultaneously, SCFAs act as endogenous inhibitors of HDAC enzymes, particularly Class I HDACs, within the cell nucleus. This inhibition leads to increased histone acetylation, which relaxes chromatin structure and facilitates the transcription of genes involved in regulatory T-cell differentiation and cell cycle control. Together, these targets coordinate the host's response to microbial metabolites, playing a vital role in immune homeostasis and metabolic health. Dysregulation of this axis is associated with inflammatory bowel disease, colorectal cancer, and systemic inflammatory conditions like sepsis. Pharmacological modulation of these targets, either through direct agonists/inhibitors or dietary interventions that increase SCFA production, is a major area of therapeutic research.

Other names

GPR43FFAR2GPR109AHCAR2Histone deacetylasesHDAC familyShort-chain fatty acid receptors and epigenetic modifiers

Agonism of GPR43 and GPR109A receptors coupled with the inhibition of Histone Deacetylase (HDAC) enzymes.