Tryptophan 2,3-dioxygenase deficiency attenuates dextran sodium sulphate -induced ulcerative colitis in mice by suppressing macrophage polarisation and reducing intestinal epithelial cell apoptosis

Background and purpose: Ulcerative colitis (UC) is a chronic, nonspecific inflammatory bowel disease. The kynurenine pathway (KP) of tryptophan metabolism has been implicated in several autoimmune diseases, including multiple sclerosis and rheumatoid arthritis. However, little is known about the role of KP in UC. This study investigated the role of tryptophan 2,3-dioxygenase (TDO2), a key rate-limiting enzyme of KP, in UC.

Experimental approach: Dextran sodium sulphate (DSS)- and 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis models were used to evaluate the effects of TDO2 deficiency in mice, and the therapeutic potential of pharmacological inhibition was further assessed in the DSS model. In vitro, TDO2 overexpression, small interfering RNA, and the TDO2 inhibitor 680C91 were applied to macrophages and intestinal epithelial cells (IECs) to elucidate underlying mechanisms.

Key results: TDO2 expression was significantly up-regulated in colonic tissues from UC patients and DSS-induced colitis mice, and was found to colocalise with macrophages and IECs. In macrophages, pharmacological inhibition or knockdown of TDO2 suppressed M1 polarisation and secretory function, whereas kynurenine supplementation restored these effects. In IECs, TDO2 inhibition restored tight junction protein expression and attenuated Apoptosis. TDO2 deficiency significantly alleviated disease severity in DSS- and TNBS-induced colitis models, as reflected by improvements in multiple clinical and histopathological parameters. In the DSS model, TDO2 deficiency or treatment with allopurinol reduced IEC Apoptosis and rebalanced macrophage M1/M2 polarisation.

Conclusions and implications: These findings identify TDO2 as a critical mediator of UC pathogenesis. Targeting TDO2 and KP may provide a promising therapeutic strategy for UC.