A short-chain fatty acid triad in pain regulation

Short-chain fatty acids (SCFAs) are microbial-derived metabolites produced primarily through the fermentation of dietary fibre by the intestinal microbiota. Current evidence indicates that they play a key role in modulating nociception and pain processing across immune, metabolic, and neural pathways. The prevailing view that SCFAs suppress pain has been challenged by emerging evidence demonstrating that these same metabolites can also drive hyperalgesia. This apparent “SCFA paradox” persists because most studies have examined individual metabolites in isolation rather than considering them within their broader biological context. Here, we propose an integrative framework in which SCFAs function within a competitive receptor triad, and pain outcomes are dictated by the balance among three signalling axes: a pro-inflammatory immune axis driven by acetate acting through G protein-coupled receptor 43 (GPR43), a pro-resolutive metabolic axis mediated by butyrate via histone deacetylase (HDAC) inhibition and activation of GPR109A, and a direct neural sensing axis triggered by propionate through olfactory receptor 78 (OLFR78). Chronic pain, therefore, does not arise simply from the presence or absence of SCFAs, but from the pathological dominance of one of these axes shaped by specific dysbiosis profiles. This framework moves beyond correlation by providing a mechanistic basis for precision interventions designed to rebalance SCFA signalling, offering novel therapeutic opportunities for neuropathic and inflammatory pain conditions.