Dietary supplementation with resveratrol alleviates multiple stresses-induced neurobehavioral and intestinal impairments by regulating the microbial-gut-brain axis

Multiple stressors represent a major threat to animal welfare and productivity by triggering physiological and behavioral abnormalities. This study investigated whether dietary resveratrol (RES) mitigates the adverse effects of multiple stressors, on behavior, hypothalamic injury, intestinal barrier integrity, gut microbiota, and the microbial-gut-brain (MGB) axis in layer pullets, modeled by chronic unpredictable mild stress (CUMS). The experiment consisted of two phases. In Phase 1,300 one-day-old chicks were randomly assigned to control (CON) and CUMS groups. In Phase 2,480 chicks were allotted to five groups: CON, CUMS, and CUMS supplemented with 200, 400, or 800 mg kg −1 RES (L-RES, M-RES, H-RES). After a 1-wk acclimation period, all groups except CON were exposed to a 5-wk CUMS protocol, while RES treatments were simultaneously administered for the same duration. CUMS exposure induced depression-like behaviors, dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, and significant reductions in key neurotransmitters (serotonin and dopamine) and brain-derived neurotrophic factor (BDNF), collectively reflecting neuroinflammation and impaired neuroplasticity. Intestinal barrier integrity was also disrupted, as evidenced by the downregulation of tight junction proteins, while colonic inflammation was aggravated through activation of the TLR4-p38MAPK/NF-κB signaling cascade and elevated levels of IL-1β and TNF-α. Metagenomic sequencing revealed significant gut microbial dysbiosis, and metabolomics showed disruptions in phenylalanine, tryptophan, and tyrosine metabolism, with phenylalanine metabolism being the most affected, further supporting MGB axis dysfunction. Dietary RES supplementation alleviated behavioral abnormalities in a dose-dependent manner, normalized HPA axis activity, mitigated hypothalamic injury, restored neurotransmitters and cytokines, improved intestinal barrier integrity, and partially reversed gut microbial disruptions. In conclusion, dietary RES effectively ameliorates multiple stress-induced neurobehavioral and intestinal impairments by regulating the MGB axis, offering a promising feed approach to improve poultry resilience and welfare under intensive production conditions.