ABSTRACT Gut microbiota dysbiosis is closely linked to depression and can be modulated by dietary polysaccharides. This study aimed to characterize three polysaccharide fractions from Pericarpium Citri Reticulatae “Chachiensis” (PCRCP)—PCRCPI, PCRCPII, and PCRCPIII—and evaluate their antidepressant effects in a high‐fat diet–induced mouse model. Their average molecular weights were approximately 48.9 kDa (PCRCPI), 13.7 kDa (PCRCPII), and 34.8 kDa (PCRCPIII), with a composition primarily of galacturonic acid, arabinose, galactose, and rhamnose. PCRCPI most effectively mitigated depression‐like behaviors, as indicated by improved behavioral performance and neurotransmitter levels and reduced neuronal damage. The antidepressant effect of PCRCPI was contingent upon the gut microbiota, as demonstrated by the fact that fecal microbiota transplantation (FMT) from donors treated with PCRCPI conferred behavioral improvements. Mechanistically, PCRCPI treatment selectively increased the abundance of Lactobacillus species and elevated fecal levels of metabolites associated with retrograde endocannabinoid signaling, particularly 2‐arachidonoylglycerol (2‐AG). Subsequent colonization experiments with specific Lactobacillus strains, either alone or in combination with PCRCPI, activated hippocampal retrograde endocannabinoid signaling as revealed by transcriptomic analysis, and ameliorated depression‐like phenotypes. These findings demonstrate the potential of PCRCPI as a prebiotic for alleviating diet‐associated depression, through a novel microbiota–gut–brain axis mechanism targeting the endocannabinoid system.
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