Intermittent fasting alleviates hyperalgesia in ovariectomized mice via gut microbiota remodeling

Pain is a common symptom of menopause, yet effective therapeutic options are limited. Intermittent fasting (IF) has emerged as a promising dietary intervention; however, its effects on menopausal pain are still unclear. In this study, we established a hyperalgesia model in mice through ovariectomy (OVX) and subjected them to an alternate-day fasting regimen. IF significantly elevated the pain thresholds for mechanical, hot and cold stimuli in OVX mice and reduced the expression of pain-related molecules, including transient receptor potential vanilloid 1 (TRPV1) and calcitonin gene-related peptide (CGRP) in dorsal root ganglion (DRG). Moreover, IF remodeled the gut microbiota and metabolite profile, marked by a substantial increase in the abundance of Akkermansia muciniphila and its key metabolite, indole-3-propionic acid (IPA). Depletion of the gut microbiota via antibiotic treatment abolished the analgesic effects of IF on OVX-induced hyperalgesia. Conversely, fecal microbiota transplantation from IF-treated donors restored microbial composition and alleviated hyperalgesia in OVX recipients. Administration of A. muciniphila increased IPA levels and alleviated hyperalgesia in OVX mice. Importantly, exogenous IPA supplementation not only alleviated hyperalgesia but also reduced the excitability of DRG neurons. Together, these findings demonstrate that IF mitigates estrogen deficiency-related hyperalgesia through remodeling gut microbiota and metabolite profile, and identify IPA as a potential therapeutic target, offering new perspectives for the clinical management of menopausal pain.