Chronic restraint stress (CRS) in mice resulted in significant changes in tryptophan metabolism and behavior linked to depression and anxiety.
Mice subjected to CRS exhibited behaviors indicative of depression and anxiety.
Activation of the metabolic pathway was strongly observed in the brain of CRS mice.
Increased toxic signaling from kynurenine was particularly pronounced in the colon of CRS mice.
Indoleamine 2,3-dioxygenase (IDO) levels were significantly higher in both the brain and gut of CRS mice, indicating altered tryptophan metabolism.
Administration of an IDO inhibitor partially alleviated depression- and anxiety-like behaviors in CRS mice.
CRS increased intestinal permeability, allowing toxic metabolites to enter the bloodstream, which correlated with altered gut microbiome composition.
Simplified
Emerging evidence suggests that the gut microbiota may interact with the host brain and play pivotal roles in the pathogenesis of neuropsychiatric disorders. However, the mechanism underlying reciprocal interactions along the microbiota-gut-brain axis in depression remains unclear. In this study, a murine model of chronic restraint stress (CRS) was established to investigate the metabolic signaling of tryptophan (Trp) neurotransmission at the intestinal and central levels in depression. The results showed that CRS mice displayed depression- and anxiety-like behaviors. Additionally, (Kyn) and its metabolites, an important Trp metabolic pathway, were strongly activated in the brain. Intriguingly, the Kyn toxic signaling was exacerbated in the gut, especially in the colon. Indoleamine 2,3-dioxygenase (IDO), a rate-limiting enzyme responsible for Kyn metabolic pathway initiation, was significantly upregulated in the brain and gut in CRS mice compared with control mice, promoting transfer of Trp metabolic pathway to Kyn signaling. Additionally, administration of IDO inhibitor, 1-methyl-tryptophan (1-MT), partially rescued CRS-induced depression- and anxiety-like changes. Moreover, the enhanced intestinal permeability mediated by CRS allowed toxic metabolites to "leak" into the bloodstream. The microbiome profiles of CRS mice displayed obviously altered taxonomic composition and negative correlations were observed betweenand Kyn levels in the brain. Reciprocal crosstalk between the brain and gut was further validated by citalopram treatment, IDO inhibitor and microbiota intervention, which counteracted depression-like behavior, Kyn metabolic signaling and microbiota composition in CRS mice. Meanwhile,treatment affected Trp metabolism in mouse hippocampus, manifesting as elevated concentration of 5-HT as well as ratio of 5-HT to Trp. These results suggest that long-term stress disrupts Kyn metabolism and endocrine function along the gut-brain axis, accompanied by the disrupted homeostasis of certain microbiota, which collectively contribute to the development of depression-like behavior. Enterorhabdus, Parabacteroides Parabacteroides
Key numbers
3 of 10
Increase in levels
levels in the brain and gut compared to control mice.
50%
Decrease in sucrose consumption
Sucrose consumption ratio in CRS mice vs. control mice.
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