The SCFA receptor triad and its functional axes in pain regulation.
| Triad axis | SCFA receptor (gene) | Primary ligands & relative affinities | Key cell types expressing receptor in vivo | Output effect on pain (based on in vivo models) | Key supporting references |
|---|---|---|---|---|---|
| Immune axis (pro-algesic; primary driver of inflammatory pain) | GPR43 (FFAR2) | Acetate ≈ propionate > butyrate | Neutrophils, mast cells, colonic macrophages, colonic T-cells, enteroendocrine cells, adipocytes | Pro-nociceptive: Drives inflammatory and visceral pain. GPR43 activation promotes neutrophil recruitment, mast cell degranulation, and M1 macrophage polarisation, leading to the release of algogenic that sensitise nociceptors. | [5–8] |
| Neuronal axis (dual modulation; primary driver of direct neural sensing) | GPR41 (FFAR3) | Propionate ≈ butyrate > acetate | Neurons (DRG, sympathetic, enteric), adipocytes, endocrine cells, T-cells | Context-dependent (bidirectional): In visceral pain models, high propionate levels are pro-nociceptive, sensitising afferent neurons. Under homeostatic conditions, GPR41 signalling may exert an inhibitory tone. It is a central node for direct neural sensing of SCFAs. | [5, 9] |
| OLFR78 (OR51E2 in humans) | Acetate ≈ propionate | Enteroendocrine cells, vascular smooth muscle cells, vagal sensory neurons (evidence emerging) | Pro-nociceptive (proposed mechanism): As a Gαs-coupled receptor, its activation by high propionate levels in DRG neurons would increase cAMP/PKA signalling, leading to phosphorylation and sensitisation of ion channels (e.g., TRPV1, Nav). Direct in vivo pain studies are limited. | [10, 11] | |
| Metabolic axis (analgesic; primary driver of resolution) | GPR109A (HCAR2) | β-Hydroxybutyrate > butyrate | Macrophages, keratinocytes, Langerhans cells, T-cells, neutrophils, microglia, astrocytes, neurons, satellite cells, hepatocytes, colonic epithelial cells, adipocytes | Anti-nociceptive: Activation of microglial GPR109A attenuates chronic pain by suppressing p38 MAPK activity, NLRP3 activation, and pro-inflammatory cytokines. Its deficiency leads to chronic neuroinflammation. | [8, 12, 13] |
SCFA: short-chain fatty acid; GPR43: G protein-coupled receptor 43; DRG: dorsal root ganglia; OLFR78: olfactory receptor 78; cAMP: cyclic adenosine monophosphate; PKA: protein kinase A; TRPV1: transient receptor potential vanilloid 1; Nav: voltage-gated sodium channels; NLRP3: NOD-like receptor family pyrin domain-containing 3.