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.