1-methyl-tryptophan improves anxiety-like behavior in colitis mice by inhibiting neuroinflammation, promoting cell regeneration and decreasing apoptosis.

Abstract

Introduction: Mood disorders such as anxiety are important extra-intestinal manifestations of inflammatory bowel disease (IBD), and are more prevalent in active IBD. Studies have shown that pharmacologically-induced anxiety was correlated with changes in plasma Kynurenine (Kyn) concentrations. Our previous study also found that Kyn was abnormally increased in the serum and brain of mice with acute colitis. This study aimed to investigate the role and possible mechanism of Kyn in anxiety-like behavior induced by colitis.

Methods: Therefore, we established a 3% Dextran sulfate sodium (DSS)-induced mouse model of acute colitis. Kyn is produced by tryptophan metabolism in the presence of indoleamine 2,3-dioxygenase (IDO, rate-limiting enzyme). Furthermore, 1-methyl-tryptophan (1-MT), as an IDO inhibitor, was used to reduce Kyn synthesis in this study.

Results: We found that 1-MT significantly improved anxiety-like behaviors in mice with colitis, as assessed by the marbles burying test. Moreover, our study demonstrated that 1-MT reduced the level of pro-inflammatory cytokine IL-1β and the activation of glial cells in the mouse brain, indicating the anti-inflammatory effect of 1-MT. Similarly, 1-MT inhibited LPS-induced inflammatory responses in BV2 cells, which was consistent with the in vivo results. Furthermore, 1-MT reversed the low expression of DCX and PCNA in the hippocampus caused by colitis, suggesting a pro-neurogenesis and pro-proliferation effect. In addition, we found that Kyn promoted apoptosis by regulating the Bax/Bcl2 signaling cascade through in vitro and in vivo experiments.

Conclusion: Overall, these results suggest that 1-MT improved anxiety-like behaviors in mice with colitis by decreasing neuroinflammation, promoting neurogenesis and cell proliferation, and reducing apoptosis.