NUDT1 aggravates intestinal epithelial barrier injury through oxidative stress in ulcerative colitis.

Background: Nudix hydrolase 1 (NUDT1) plays a crucial role in tumours, where it helps limit cellular damage caused by reactive oxygen species. However, the exact function of NUDT1 in ulcerative colitis (UC) is not well understood.

Methods: NUDT1 expression in the intestinal mucosal tissues of patients with UC was analysed using quantitative reverse transcription polymerase chain reaction. A public database was used to analyse the expression of selected signature genes of interest in patients with UC with different NUDT1 expression levels. TH588, a potent NUDT1 inhibitor, was used to treat intestinal epithelial cells (IECs) in mice. The functions of the IECs were assessed using quantitative reverse transcription polymerase chain reaction, flow cytometry, western blotting, and fluorescence microscopy. A mouse model of dextran sodium sulphate-induced colitis was established.

Results: We examined NUDT1 expression and found that it was significantly elevated in the colon tissues of patients with UC. A colitis model was established in wild-type mice treated with TH588, which significantly reduced intestinal mucosal inflammation and induced notable alterations in faecal microbiota composition. Moreover, TH588 helped preserve intestinal mucosal barrier function. Inhibition of NUDT1 expression in IECs enhanced antioxidant activity by increasing Nrf2 expression and reducing ERK phosphorylation, which, in turn, stabilised tight junctions in IECs exposed to oxidative stress.

Conclusions: Our research emphasises the role of NUDT1 in modulating the intestinal microbiota and intestinal mucosal barrier in UC, indicating that targeting NUDT1 during intestinal mucosal inflammation could serve as a promising therapeutic strategy for UC.