Indole-3-acetic acid exerts protective effects on sleep deprivation-induced cognitive impairment

The gut microbiota and its metabolites have increasingly been recognized as crucial factors contributing to the cognitive deficits induced by sleep deprivation (SD), a condition characterized by diminished hippocampal neurogenesis. Nevertheless, the signaling pathways that integrate inputs from metabolites and gut endocrine hormones to influence neurobehavioral outcomes remain largely elusive. In the present study, the multiomics analysis demonstrated that SD led to a significant reduction in the levels of the microbial metabolite indole-3-acetic acid (IAA) in mice (male). Notably, oral administration of IAA effectively ameliorated cognitive impairments and restored intestinal integrity in SD mice. Mechanistically, IAA binds to the aryl hydrocarbon receptor (AhR) in enterochromaffin cells (ECs), thereby increasing the secretion of serotonin (5-hydroxytryptamine; 5-HT). 5-HT subsequently activates the vagus nerve via the 5-HT 3 receptor, which in turn stimulates hippocampal neuronal activity and promotes neurogenesis, ultimately alleviating cognitive impairments. These findings underscore the pivotal role of the gut-derived metabolite IAA in modulating hippocampal function through the gut–EC–vagus nerve–brain axis. Moreover, they provide perspectives on the mechanisms underlying SD-induced cognitive impairment, suggesting promising avenues for future therapeutic strategies.