Dietary Proanthocyanidins Ameliorate Age-Related Cognitive Decline and Neuroinflammation in Mice via the Gut Microbiota-SCFAs-5-HTP Axis

Age-related cognitive impairment represents a major global public health challenge closely linked to neuroinflammation and gut microbiota dysbiosis. Proanthocyanidins (PC), widely distributed dietary polyphenols, exhibit substantial potential for modulating gut-brain axis communication through their antioxidant and anti-inflammatory properties. This study elucidated the molecular mechanisms underlying PC-mediated amelioration of age-related cognitive impairment via the gut microbiota-SCFAs-5-HTP axis. Using an aging mouse model, we systematically evaluated PC's effects through behavioral tests, histopathology, molecular analyses, 16S rRNA gene sequencing, and targeted metabolomics. PC significantly improved spatial learning and memory in aging mice, as demonstrated by Morris water maze performance. Mechanistically, PC reshaped the disrupted gut microbiota by enriching SCFA-producing bacteria (e.g., Duncaniella and Ligilactobacillus ) and significantly increasing butyrate and propionate levels. Elevated SCFAs enhanced intestinal barrier integrity by upregulating tight junction proteins and promoting intestinal tryptophan hydroxylase 1 (TPH1) expression, thereby increasing 5-HTP biosynthesis. Circulating 5-HTP crossed the blood-brain barrier and was converted to serotonin (5-HT) in the hippocampus, where it activated 5-HT1A and 5-HT6 receptors, thereby inhibiting glial activation, reducing neuroinflammation, and improving cognitive function. This study systematically elucidated how proanthocyanidins exert neuroprotective effects via a microbiota-metabolite-neurotransmitter cascade, providing a mechanistic foundation for developing polyphenol-based precision nutrition strategies to prevent age-related cognitive decline.