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

Mar 7, 2026NPJ science of food

Dietary sugar-related compounds and long-term stress linked to anxiety and depression behaviors in male mice

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Abstract

Mice exposed to dietary advanced glycation end products and chronic restraint stress exhibited significant behavioral changes associated with anxiety and depression.

Combined exposure to dietary advanced glycation end products and chronic stress aggravated anxiety-like and depression-like behaviors.
This exposure disrupted gut microbiota balance and triggered inflammation.
Tryptophan metabolism shifted towards the kynurenine pathway, marked by elevated levels of kynurenine and 3-hydroxykynurenine.
Neuronal ferroptosis was induced in the hippocampus as a result of these changes.
The IDO1 inhibitor 1-methyltryptophan restored disturbances in tryptophan metabolism and inhibited neuronal ferroptosis.
Ferroptosis inhibitor ferrostatin-1 prevented neuronal ferroptosis but did not affect tryptophan metabolism.

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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.

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

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