Microbiome-derived metabolites alleviate chronic pain in a reserpine-induced model of fibromyalgia

Fibromyalgia is a chronic pain disorder driven by central sensitization and neuroinflammation, increasingly linked to gut-brain axis dysfunction. Here, we delineate a gut-to-CNS axis for pain modulation, demonstrating that an acetate-producing diet alleviates reserpine-induced-fibromyalgia in a rodent model. We show that diet rich in acetylated high-amylose maize starch shifts the gut microbiome to favor acetate-producing bacteria, increasing systemic acetate levels and reducing pain hypersensitivity. This is associated with reduced spinal microglia activation and anti-inflammatory cytokine gene expression, with elevated IL-10 mRNA in the DRG and IL-10, IL-2, and IL-6 in the spinal cord. Electrophysiologically, we observe reduced hyperexcitability in the dorsal horn and increased inhibitory activity. The mechanism driving this change involves reduced prostaglandin-E2 (PGE2)-mediated suppression of glycinergic inhibition, a direct consequence of maintaining microglia in quiescent state. These findings link dietary metabolites to reduced fibromyalgia-like pathology and identify targeted nutrition as a potential disease-modifying therapy for chronic pain.