Dietary advanced glycation end products are associated with anxiety- and depression-like behavior in male mice via gut microbiota mediated disruption of tryptophan metabolism.

Dietary advanced glycation end products (AGEs) have been associated with neuropsychiatric disorders, yet the underlying mechanisms remain not fully understood. This study investigated whether the gut microbiota-tryptophan metabolism axis contributes to AGEs-induced anxiety- and depression-like behaviors in male mice. Male C57BL/6 mice were fed a heat-treated AGE-enriched diet for 12 weeks. This dietary intervention was associated with gut microbiota dysbiosis that disrupted hippocampal and colonic tryptophan metabolism by suppressing indole-AhR and serotonin pathways and overactivating kynurenine pathway. These metabolic alterations were accompanied by reduced expression of intestinal and hippocampal barrier-associated proteins, and exacerbated neuroinflammation and colonic inflammation, which collectively correlated with behavioral alterations compatible with anxiety- and depression-like phenotypes. A contributory role of microbiota dysbiosis was supported by fecal microbiota transplantation (FMT), which partially recapitulated behavioral deficits, tryptophan metabolic disorders, and inflammatory lesions in recipient mice. Supplementation with indole derivatives (IPA, IAA) or pharmacological inhibition of the kynurenine pathway with 1-MT attenuated AGEs-associated behavioral abnormalities and metabolic disruption. These results suggest that dietary AGEs may promote behavioral alterations compatible with anxiety- and depression-like phenotypes in male mice partly through gut microbiota-mediated tryptophan metabolism disruption, and targeting this axis may represent a promising therapeutic strategy.