Intermittent Fasting Alleviates Anesthesia/Surgery-Induced Delirium-Like Behavior in Aged Mice by Remodeling Gut Microbiota.

BACKGROUND: Postoperative delirium (POD) is a serious complication in elderly patients, associated with prolonged recovery and adverse outcomes. Recent evidence links POD to mitochondrial dysfunction. While intermittent fasting (IF) has been shown to enhance mitochondrial function and exert neuroprotective effects, potentially through gut microbiota modulation, its ability to prevent POD and the underlying mechanisms remain unclear. METHODS: We examined the effects of preoperative IF on delirium-like behavior in aged mice following anesthesia/surgery. Assessments included neurobehavioral tests, gut microbiota composition, fecal shortchain fatty acids (SCFAs), hippocampal synaptic and mitochondrial ultrastructure via transmission electron microscopy, mitochondrial function, and related molecular markers. To establish causality, fecal microbiota transplantation and SCFA supplementation experiments were conducted. RESULTS: Preoperative IF significantly attenuated anesthesia/surgery-induced delirium-like behaviors. Mechanistically, IF reshaped the gut microbiota and preserved SCFA levels, which collectively maintained hippocampal mitochondrial homeostasis. Both fecal microbiota transplantation and SCFA supplementation replicated the protective effects of IF, confirming the causal role of gut microbiota and its metabolites. CONCLUSION: These findings demonstrate that preoperative intermittent fasting mitigates delirium-like behavior by modulating the gut microbiota-SCFA-mitochondrial axis, highlighting its potential as a non-pharmacological strategy to enhance neurocognitive resilience and prevent POD in elderly surgical patients.