Disruption to tRNA Modification by Queuine Contributes to Inflammatory Bowel Disease

BACKGROUNDS AND AIMS: Transfer RNA (tRNA) is the most extensively modified RNA in cells. Queuosine modification is a fundamental process for ensuring the fidelity and efficiency of translation from RNA to protein. In eukaryotes, Queuosine tRNA (Q-tRNA) modification relies on the intestinal microbial product queuine. However, the roles and potential mechanisms of Q-containing tRNA (Q-tRNA) modifications in inflammatory bowel disease (IBD) are unknown.METHODS: We explored the Q-tRNA modifications and expression of QTRT1 (queuine tRNA-ribosyltransferase 1) in patients with IBD by investigating human biopsies and rean-alyzing datasets. We used colitis models, QTRT1 knockout mice, organoids, and cultured cells to investigate the molecular mechanisms of Q-tRNA modifications in intestinal inflammation.RESULTS: QTRT1 expression was significantly downregulated in ulcerative colitis and Crohn's disease patients. The 4 Q-tRNA-related tRNA synthetases (asparaginyl-, aspartyl-, his-tidyl-, and tyrosyl-tRNA synthetase) were decreased in IBD patients. This reduction was further confirmed in a dextran sulfate sodium-induced colitis model and interleukin-10-deficient mice. Reduced QTRT1 was significantly correlated with cell proliferation and intestinal junctions, including downregulation of b-catenin and claudin-5 and the upregula-tion of claudin-2. These alterations were confirmed in vitro by deleting the QTRT1 gene from cells and in vivo using QTRT1 knockout mice. Queuine treatment significantly enhanced cell proliferation and junction activity in cell lines and organoids. Queuine treatment also reduced inflammation in epithelial cells. Moreover, altered QTRT1-related metabolites were found in human IBD.CONCLUSIONS: tRNA modifications play an unexplored novel role in the pathogenesis of intestinal inflammation by altering epithelial proliferation and junction formation. Further inves-tigation of the role of tRNA modifications will uncover novel molecular mechanisms for the prevention and treatment of IBD.

Automated summary

This study found that the expression of QTRT1 was significantly downregulated in patients with inflammatory bowel disease (IBD). The 4 Q-tRNA-related tRNA synthetases were also decreased in IBD patients. These changes were associated with alterations in epithelial cell proliferation and junction formation. Further investigation revealed that queuine treatment enhanced cell proliferation and junction activity, and reduced inflammation in epithelial cells. These findings uncover a novel role for tRNA modifications in the pathogenesis of IBD.