Aerobic exercise improves chronic insomnia via increasing Akkermansia muciniphila-derived butyrate to activate GABAergic neurons

Chronic insomnia poses significant health risks, yet effective treatments are limited. While aerobic exercise (AE) is known to improve sleep, its underlying mechanisms remain unclear. Using a para-chlorophenylalanine (PCPA)-induced murine model, we demonstrate that moderate-intensity AE ameliorates chronic insomnia by shortening sleep latency and extending sleep duration. AE alleviates neuroinflammation and neuronal injury in the hypothalamic ventrolateral preoptic area (VLPO) and enhances intestinal barrier integrity. These benefits are linked to a restructuring of the gut microbiota, characterized by a marked increase in the abundance of Akkermansia muciniphila. Fecal microbiota transplantation from exercised donors recapitulated the improvements in sleep architecture and gut-brain pathology in recipient mice. Mono-colonization with Akkermansia muciniphila alone was sufficient to reduce sleep fragmentation, activate VLPO GABAergic neurons, and elevate butyrate levels in serum and hypothalamic tissue. Spatial metabolomic analysis revealed that butyrate localizes to GABAergic neurons, suggesting a direct mechanism for sleep modulation. Our findings delineate a concrete microbiota-gut-brain pathway through which exercise improves sleep, nominating Akkermansia muciniphila and butyrate as mechanistically defined, non-pharmacological targets for treating insomnia.