<em>Bifidobacterium animalis subspecies lactic</em> derived-vesicles alleviate cognitive impairment in mice <em>via</em> modulating gut microbiota metabolism and 5-HT/BDNF pathway

Hippocampal neuroinflammation (<strong>HNF</strong>) causes gut microbial abnormalities to aggravate cognitive impairment. While&nbsp;<em>Bifidobacterium&nbsp;</em>has been shown to alleviate HNF and improve cognitive function, the role of&nbsp;<em>Bifidobacterium</em>-derived membrane vesicles (<strong>MV</strong>) in reshaping gut microbiota and their connection to cognitive impairment remains poorly understood. This study employed LPS-induced mice to determine the <em>Bifidobacterium animalis subsp. lactis </em>(<strong>BL</strong>) 99-MV on preventing cognitive impairment and the relevant mechanisms involved. Phenotypic results showed that BL99-MV supplementation inhibited IL-33, IL-1β and TNF-α level, increased brain-derived neurotrophic factor (<strong>BDNF</strong>) level, reduced Aβ, Tau, P-Tau (Ser404) and GSK-3β expression and improved cognitive impairment in mice. Metagenomic analysis revealed that BL99-MV supplementation restored gut microbiota dysbiosis, increased the relative abundance of <em>Clostridium </em>and <em>Oscillibacter</em>. Metagenomic analysis revealed that BL99-MV increased the hippocampal BDNF expression, which enhanced the conversion 5-hydroxytryptophan (<strong>5-HTP</strong>) to 5-hydroxytryptamine (<strong>5-HT</strong>) to improve learning. More importantly, the level of 5-HT exhibited a positive correlation with the abundances of <em>Clostridium </em>and <em>Oscillibacter</em>. Our findings illuminate that a novel and promising BL99-MV to improve LPS-induced HNF and accompanying gut disorder, and provide options for preventing gut-brain axis- related cognitive function.