Trimethylamine N‐Oxide Mitigates Perioperative Neurocognitive Disorders via ANXA1 Nuclear Translocation and M2 Microglial Polarization in the Hippocampus

Aims This study investigates whether trimethylamine N‐oxide (TMAO) mitigates perioperative neurocognitive disorders (PND) by modulating Annexin A1 (ANXA1) and microglial polarization, thereby reducing neuroinflammation in the hippocampus. Methods A murine PND model was established via tibial fracture surgery under sevoflurane anesthesia. Mice were pretreated with TMAO (1.2, 12, or 120 mg/kg) for 21 days. Cognitive function was assessed using Y‐maze and fear conditioning tests. Hippocampal ANXA1 expression, microglial polarization (M1/M2 phenotypes), and cytokine levels (TNF‐α, IL‐1β, TGF‐β) were analyzed. Results TMAO administration (12 mg/kg) significantly improved cognitive performance. Mechanistically, TMAO upregulated ANXA1 expression, facilitating its nuclear translocation in microglia and shifting their polarization from pro‐inflammatory M1 phenotype to anti‐inflammatory M2 phenotype. This transition consequently suppressed pro‐inflammatory cytokines (TNF‐α and IL‐1β) while elevating TGF‐β. Additionally, TMAO attenuated microglial activation and associated neuroinflammatory morphological alterations. Conclusion Physiological concentrations of TMAO confer neuroprotection by augmenting ANXA1‐mediated resolution of neuroinflammation, supporting its therapeutic potential for preventing PND.