Bifidobacterium pseudolongum alleviates chronic intermittent hypoxia-induced cognitive impairment by restoring acetate metabolism and suppressing hippocampal neuroinflammation and neuronal PANoptosis.

Obstructive sleep apnea, characterized by chronic intermittent hypoxia (CIH), is a common sleep disorder frequently accompanied by cognitive impairment. Emerging evidence suggests that gut microbiota and their metabolites modulate neuroinflammation and neuronal survival, playing critical roles in neurological disorders. However, their contributions to CIH-related cognitive dysfunction remain incompletely understood. Here, we show that CIH caused gut dysbiosis, marked by reduced Bifidobacterium pseudolongum (B.p). FMT and 16S rRNA sequencing revealed protective associations of B.p in CIH-induced cognitive impairment. B.p supplementation mitigated the activation of microglia, reduced pro-inflammatory cytokine expression (TNF-α, IL-6, IL-1β), and attenuated hippocampal neuronal PANoptosis, thereby alleviating cognitive dysfunction. SCFAs targeting metabolomics demonstrated that B.p supplementation restored acetate levels in serum. Consistently, oral acetate supplementation replenished acetate levels and reproduced the neuroprotective and anti-neuroinflammatory effects of B.p. In vitro, acetate reduced mitochondrial DNA release, inhibited cGAS-STING (cyclic GMP-AMP synthase-stimulator of interferon genes) activation, and attenuated PANoptosis in HT22 cells. Collectively, our findings demonstrated that B.p supplementation was associated with restoration of acetate metabolism and attenuation of hippocampal neuroinflammation and neuronal PANoptosis, thereby alleviating CIH-induced cognitive dysfunction. Targeting B.p and acetate may offer a promising therapeutic strategy for neuroprotection in OSA.