Resveratrol Attenuates Neuroinflammation and Gut–Brain Axis Dysfunction Induced by Lead and Cadmium Co‐Exposure by Modulating Gut Microbiota in Rats

ABSTRACT Resveratrol (RSV), a dietary polyphenol widely present in traditional medicinal plants and foods, exhibits antioxidant and anti‐inflammatory properties that are relevant to ethnopharmacological strategies for protecting against environmental neurotoxicants. Given increasing real‐world co‐exposure to lead (Pb) and cadmium (Cd), elucidating RSV's capacity to preserve gut–brain axis (GBA) homeostasis has direct translational relevance for populations relying on phytochemical interventions. Sprague–Dawley rats were randomized into control, Pb–Cd model, and RSV treatment groups (10, 20, or 40 mg/kg). For 4 weeks, rats received Pb (300 mg/L) and Cd (50 mg/L) in drinking water with daily RSV. Cognitive function was assessed by Morris water maze; barrier integrity by Evans blue assay, histology, and Western blot for ZO‐1/Occludin; synaptic ultrastructure by TEM; microbiota composition by 16S rRNA sequencing; and short‐chain fatty acids (SCFAs) by GC‐MS. Neurotransmitters (5‐HT, GABA, SP, VIP) and cytokines (IL‐6, IL‐1β, TNF‐α) were measured by ELISA. RSV improved spatial learning, reduced EB extravasation, preserved synaptic ultrastructure and proteins (BDNF, SYN, PSD‐95), and restored intestinal architecture with increased ZO‐1/Occludin. RSV attenuated cytokine release, normalized goblet cells, reversed dysbiosis by restoring Lactobacillaceae/Prevotellaceae, and increased acetate, propionate, and butyrate. It reinstated 5‐HT and GABA while reducing SP and restoring VIP across serum, colon, and hippocampus. RSV attenuated Pb–Cd–associated neurotoxicity and was accompanied by improved intestinal and BBB‐related readouts, partial normalization of gut microbiota features and SCFA levels, and preservation of synaptic and neurotransmitter‐related markers, consistent with a link to gut–brain axis function. This study is among the first to test RSV in a Pb–Cd co‐exposure model using a multi‐dose regimen with integrated behavioral, barrier, microbial, and neurochemical endpoints.