Tryptophan-kynurenine metabolic characterization in the gut and brain of depressive-like rats induced by chronic restraint stress

Feb 6, 2023Journal of affective disorders

Changes in tryptophan metabolism in the gut and brain of rats showing depression-like behavior from chronic stress

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Abstract

Chronic restraint stress in rats induced significant increases in kynurenine and 3-hydroxykynurenine along the gut-brain axis.

Kynurenine and 3-hydroxykynurenine levels were notably elevated in multiple regions of the gut-brain axis, particularly in the hippocampus and colon.
The expression of indoleamine 2,3-dioxygenase 1 (IDO1), a key enzyme in tryptophan metabolism, showed region-specific activation along the gut-brain axis.
A general inflammatory response was indicated by increased mRNA expression of IL-1β, IFN-γ, and IL-10 in the analyzed segments.
Correlation analysis revealed significant associations between kynurenine, 3-hydroxykynurenine, serotonin, and depressive behaviors in the rats.
Activation of the NLRP3 inflammasome signaling pathway was observed in the hippocampus and colon, suggesting its role in the inflammatory responses induced by chronic restraint stress.

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Accumulating evidence revealed the role of tryptophan (TRP) metabolism, especially its kynurenine pathway (KP), in the communication along the gut-brain axis. However, the underlying characterization of such interaction was not precise. In the present study, the rat depression model was induced by chronic restraint stress (CRS). After depression behavior tests, seven segments (cortex, hippocampus, striatum, hypothalamus, serum, cecum, and colon) along the gut-brain axis were collected to characterize their KP metabolism. mRNA expression of IL-1β, IFN-γ, IL-10 and indoleamine 2,3-dioxygenase 1 (IDO1) enzyme revealed a general inflammatory response and region-specific activated IDO1 along the gut-brain axis. Determination of KP metabolites and enzymes displayed a general KP activation with region-specificity, especially in the hippocampus and colon, where the changes were more pronounced. KYN and 3-HK were increased dramatically along the gut-brain axis; hippocampal KA revealed a significant decrease while colonic KA showed a notable increase, evidenced by the same alternation trends of the corresponding enzymes. The expression of quinolinic acid phosphoribosyltransferase (QPRT), the crucial enzyme to produce NADfrom QA, was significantly upregulated in the gut but not changed in the brain. Pearson's correlation analysis suggested that kynurenine (KYN), 3-hydroxycaninuric acid (3-HK), serotonin (5-HT), TRP and kynurenic acid (KA) significantly correlated with depressive behaviors in rats. Furthermore, western blot analysis on nod-like receptor protein 3/2 (NLRP3/NLRP2) inflammasome signaling displayed that NLRP3 and cleaved IL-1β/caspase-1 were significantly activated in the hippocampus and colon of CRS rats. However, NLRP2 was only activated in the hippocampus. These results revealed CRS induced inflammatory responses along the brain-gut axis of rats might be controlled through the NLRP3/NLRP2 inflammasome signaling pathway, which may be the underlying regulator for CRS-induced TRP-KYN metabolic changes. This study provides a new experimental background for developing stress-related health products. +

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Tryptophan-kynurenine metabolic characterization in the gut and brain of depressive-like rats induced by chronic restraint stress

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