Proanthocyanidins Inhibit Neuroinflammation in High-Fat-Induced Obese Mice by Modulating Intestinal Flora and Their Metabolites

Background/Objectives: The effect of proanthocyanidins (PAs) on neuroinflammation through the modulation of colonic microflora and their metabolites was investigated in obese mice fed a high-fat diet (HFD). Methods: Thirty healthy male C57BL/6J mice of similar body weight were randomly divided into control (CON), high-fat diet (HFD), and proanthocyanidin (PA_HFD) groups. HFD and PA_HFD groups were fed an HFD, whereas the CON group was fed a basic diet for 8 weeks. Subsequently, the CON and HFD groups were administered equal doses of saline, and the PA_HFD group was administered PA (100 mg/kg/day) daily. We evaluated microbial changes through gut microbiota richness and probiotic relative abundance, analyzed metabolite variations via non-targeted metabolomics and pathway enrichment, assessed neuroinflammation via related gene expression, and measured cognitive function using platform crossing frequency and target quadrant time in the Morris water maze, where longer duration and more crossings indicate better cognition. Results: Body weight was significantly lower in the PA_HFD group than in the HFD group. In the PA_HFD group, fewer inflammatory and hepatic fat cells were observed, and hepatocellular edema was alleviated. PA significantly decreased total cholesterol, low-density lipoprotein, IL-1β, TNF-α, lipopolysaccharide, and Lc3 expression and increased Sirt1 and FGF21 expression in hippocampal tissue (p < 0.01). PA significantly altered the abundance of colonic microbiota (p < 0.01), including phyla Patescibacteria and Bacteroidota and genera Lactobacillus and Akkermansia. KEGG analysis revealed that differences in metabolite profiles between CON and HFD groups were reflected in glycerophospholipid metabolism, while those between HFD and PA_HFD groups were in steroid hormone biosynthesis and tryptophan metabolism. Metabolomic analysis demonstrated that changes in metabolites and microbiota were significantly correlated with neuroinflammation. Conclusions: In conclusion, PAs play a role in modulating neuroinflammation, colonic microflora, and colonic metabolites in mice and have a mitigating effect on cognitive decline in HFD-induced obese mice.