Cydonia oblonga Mill. Fruit Extract Ameliorates Lipopolysaccharide-Induced Depression-like Behaviors in Mice by Modulating Inflammation, Metabolites and Gut Microbiota

Background: Cydonia oblonga Mill. is rich in flavonoid compounds and shows potential for application in functional foods. This study investigated the therapeutic potential of hydroethanolic extract of Cydonia oblonga Mill. fruit (HECO) in alleviating lipopolysaccharide (LPS)-induced depression-like behaviors in mice. Methods: Mice were treated with HECO (600 mg/kg, p.o.) for 21 consecutive days. From day 14 to day 21, depression-like behavior was induced by LPS (2.0 mg/kg injected i.p.). Behavioral parameters and biochemical markers were then assessed. Gut microbiota composition was analyzed by 16S rRNA gene sequencing, and serum metabolites were profiled through untargeted metabolomics. Results: HECO improved LPS-induced behavioral alterations, including increased locomotor activity in the open-field test and decreased immobility time in the forced swimming test and tail suspension test, and reduced serum IL-6 levels in LPS-treated mice. Furthermore, HECO markedly upregulated the expression of occludin and ZO-1 in the hippocampus and inhibited neuroinflammation by suppressing activation of the TLR4/MyD88/NF-κB signaling pathway. HECO significantly increased the relative abundance of Deferribacterota in LPS-induced mice. A total of 262 differential metabolites were identified between the LPS and HECO groups, with the top potential biomarkers predominantly categorized into lipids, flavonoid-containing phenylpropanoids, organic acids, and peptides. Conclusions: HECO improved depression-like behavior in LPS-induced mice, potentially through modulation of gut microbiota and serum metabolites, attenuation of systemic inflammation, and inhibition of the TLR4/MyD88/NF-κB signaling pathway in the hippocampus.