Dietary advanced glycation products combined with chronic restraint stress induced anxiety-like and depression-like behaviors in male mice

Dietary advanced glycation end products (AGEs) and chronic stress might be involved in psychiatric disorders. It remains unclear whether dietary AGEs and chronic stress work together to trigger anxiety and depression. Firstly, mice were subjected to dietary AGEs (12 weeks) combined with chronic restraint stress (weeks 9-12, with daily restraint in a 50-mL cylindrical plastic tube for 3-4 h), defined as CRA group. Combined exposure aggravated anxiety-like and depression-like behaviors, disrupted gut microbiota homeostasis, induced inflammation, shifted tryptophan (TRP) metabolism towards kynurenine (KYN) pathway, mainly characterized by elevated KYN and 3-hydroxykynurenine (3-HK), and induced ferroptosis in the hippocampus. Secondly, IDO1 inhibitor, 1-methyltryptophan (1-MT), restored the TRP-KYN pathway disturbance post CRA, and inhibited neuronal ferroptosis post CRA. Thirdly, the ferroptosis inhibitor ferrostatin-1 restored CRA-induced neuronal ferroptosis, but had no effect on the TRP-KYN pathway. KYN and 3-HK induced ferroptosis in the mouse hippocampal neuron cell line (HT22), consistent with in vivo experimental results. In conclusion, combined exposure may first disturb gut microbiota homeostasis, followed by intestinal inflammatory responses, subsequently triggering tryptophan towards kynurenine metabolism via the gut-brain axis. These pathological processes led to the abnormal accumulation of neurotoxic metabolites, i.e., KYN and 3-HK, within neurons, which then induced neuronal ferroptosis.