DIETARY FIBER REDUCES PAIN HYPERSENSITIVITY THROUGH IMMUNE SIGNALING IN WESTERN DIET–FED MICE​

Chronic pain is frequently associated with obesity and Western diet (WD) consumption, yet the mechanisms linking diet-induced metabolic dysfunction to nociceptive hypersensitivity remain unclear. Recent studies demonstrate that fecal microbiota transplantation from lean to obese mice alleviates WD-associated pain while restoring short-chain fatty acid (SCFA)–producing bacterial taxa. However, direct SCFA supplementation fails to fully reproduce these effects, suggesting that sustained, tissue-level SCFA signaling rather than acute exposure is required. We therefore tested whether a physiological strategy to restore endogenous SCFA signaling modulates nociception through immune pathways. Soluble dietary fiber such as inulin is a potent driver of microbial SCFA production and may engage gut–immune circuits regulating pain sensitivity. Mice were fed a WD with or without inulin supplementation, and nociceptive behavior, systemic inflammation, and adipose tissue immune profiles were assessed. WD feeding induced mechanical and thermal hypersensitivity accompanied by increased adiposity, elevated circulating inflammatory markers, and immune remodeling within adipose tissue. Inulin supplementation attenuated nociceptive hypersensitivity and disrupted the positive association between fat mass, inflammation, and pain sensitivity, indicating a peripheral, fat-associated mechanism. Molecular profiling of adipose-resident immune cells identified strong expression of the SCFA receptor FFAR2 under WD conditions. To directly test immune SCFA sensing in diet-associated pain, mice lacking FFAR2 selectively in immune cells were analyzed during WD feeding. Female immune-specific FFAR2-deficient mice exhibited exacerbated thermal hypersensitivity compared to control littermates. Together, these findings support a gut–immune–adipose axis in which dietary fiber modulates nociception through immune FFAR2-dependent signaling.