Intermittent fasting alleviates neuropathic pain and cognitive deficits via an Alistipes finegoldii-Hippuric...

Chronic pain is frequently accompanied by cognitive and affective impairments, yet effective non-pharmacological interventions remain limited. Here, we show that intermittent fasting (IF) alleviates mechanical allodynia, thermal hyperalgesia, and cognitive deficits across multiple chronic pain models, and reduces anxiety-like behavior in the chronic constriction injury (CCI) model. IF strengthened intestinal barrier integrity, reduced neuroinflammation, and reshaped the gut microbiota, with Alistipes finegoldii (A. finegoldii) emerging as the most consistently enriched species. Supplementation with live A. finegoldii recapitulated the analgesic and pro-cognitive effects of IF. Integrated metabolomics identified hippuric acid as the key IF-responsive metabolite, and systemic hippuric acid administration restored pain, cognitive, and anxiety-like behaviors in CCI mice. Mechanistically, both IF and hippuric acid downregulated the STING (Stimulator of Interferon Genes) neuroimmune pathway, and pharmacological STING activation abolished the therapeutic effects of hippuric acid, establishing STING inhibition as a mechanistic requirement. Genomic annotation predicted that A. finegoldii contains homologs of enzymes consistent with the potential to generate benzoate, which could enable host co-metabolism to hippuric acid. Together, these findings identify an IF-A. finegoldii-hippuric acid-STING axis that links microbial metabolism to neuroimmune modulation and behavioral improvement, highlighting microbiota-derived metabolites as promising targets for treating chronic pain and its cognitive comorbidities.