From Microbiota to Metabolomics: How Corylus heterophylla Fisch. Male Flower Extract Shields Mice from Cognitive Decline

<b>Background/Objectives:</b> Emerging evidence suggests that hippocampal neuroinflammation (HNF) drives cognitive decline via dysregulation of the microbiota-gut-brain axis. <i>Corylus heterophylla</i> Fisch. male flower extract (CFE), a flavonoid-rich by-product of hazelnut processing, presents a promising yet unexplored neuroprotective candidate. This study investigated the preventive effects and mechanisms of CFE against HNF-induced cognitive decline. <b>Methods:</b> In the present study, mice were pretreated with CFE (200 mg/kg) before the Lipopolysaccharide (LPS) administration. Cognitive function, inflammation, core pathology, neuroplasticity, gut microbiota and serum metabolites were assessed. The chemical composition of CFE was analyzed by UHPLC-MS and its direct immunomodulatory effects were investigated in BV2 cells. <b>Results:</b> Behavioral assessments demonstrated significant therapeutic efficacy. This was evidenced by the recovery from hippocampal damage, accompanied by reduced levels of core pathological markers (Aβ1-42, Tau, p-Tau (Ser404), GSK-3β), decreased expression of pro-inflammatory mediators including IL-33, elevated levels of neurotrophic factors (BDNF and MAP2), and attenuated abnormal activation of astrocytes and microglia. The 16S rRNA analysis confirmed that CFE ameliorated gut microbial dysbiosis. Notably, CFE significantly increased the relative abundance of <i>Muribaculaceae</i> and <i>Lachnospiraceae</i>, while significantly decreased <i>Staphylococcus</i> and <i>Helicobacter</i>. Metabolomics revealed enhanced levels of α-linolenic acid (ALA), serotonin (5-HT) and acetic acid, which correlated positively with <i>Muribaculaceae</i> and <i>Lachnospiraceae</i>. Phytochemical analysis identified luteolin and kaempferol as the predominant flavonoids in CFE. In BV2 cells, CFE, luteolin and kaempferol shifted microglial polarization from the M1 phenotype toward the M2 phenotype. <b>Conclusions:</b> CFE alleviated HNF-induced cognitive decline by regulating microbiota-gut-brain axis and microglial M1/M2 polarization.