Quercetin alleviates painful diabetic neuropathy in association with gut microbial remodeling and spinal betaine-related metabolic changes.

BACKGROUND: Painful diabetic neuropathy (PDN) involves metabolic, inflammatory, and neuroimmune disturbances. Quercetin may alleviate diabetic neuropathy, but the associated gut-spinal mechanisms remain unclear. PURPOSE: To investigate whether quercetin improves PDN in association with gut microbial remodeling, spinal betaine-related metabolism, and magnetic resonance imaging-derived spinal gadopentetate dimeglumine signal dynamics. STUDY DESIGN: A two-stage study combined quercetin intervention, antibiotic-associated gut perturbation, multi-omics analyses, and independent betaine validation in a diet/streptozotocin-induced rat model of PDN. METHODS: PDN rats received quercetin (30 or 60 mg/kg) or metformin. The 60 mg/kg dose was also evaluated during antibiotic co-treatment. Behavioral, metabolic, histological, inflammatory, oxidative-stress, immunofluorescence, western blot, fecal metagenomic, targeted spinal metabolomic, and magnetic resonance imaging assessments were performed. A separate cohort received intraperitoneal betaine. RESULTS: Quercetin improved pain hypersensitivity, metabolic dysfunction, intestinal barrier-associated readouts, inflammation, spinal oxidative stress, magnetic resonance imaging-derived gadopentetate dimeglumine signal dynamics, and the overlap between aquaporin-4 and glial fibrillary acidic protein, with stronger overall effects at 60 mg/kg. Antibiotic co-treatment attenuated several quercetin-associated effects. Multi-omics analyses highlighted betaine-related metabolic changes, while exploratory protein changes related to the spinal choline-betaine metabolic branch were attenuated by antibiotics. Betaine partially reproduced selected downstream effects and was accompanied by lower exploratory inflammatory-pathway protein readouts. CONCLUSION: Quercetin alleviated PDN and was associated with coordinated gut, systemic, and spinal changes. Betaine may represent one candidate functional contributor, although microbiota-specific causality and the directionality of the proposed gut-spinal connection remain unestablished.