Disruption to tRNA Modification by Queuine Contributes to Inflammatory Bowel Disease

Area of Science:

• Molecular Biology
• Gastroenterology
• RNA Biology

Background:

• Transfer RNA (tRNA) is extensively modified, with queuosine (Q-tRNA) modification being vital for translation fidelity.
• In eukaryotes, Q-tRNA modification depends on the gut microbial product, queuine.
• The role of Q-tRNA modifications in inflammatory bowel disease (IBD) pathogenesis remains largely unknown.

Purpose of the Study:

• To investigate the role and mechanisms of Q-tRNA modifications in IBD.
• To examine QTRT1 (queuine tRNA-ribosyltransferase 1) expression and Q-tRNA modifications in IBD patients and models.

Main Methods:

• Analysis of human IBD biopsies and datasets.
• Utilized colitis models, QTRT1 knockout mice, organoids, and cell cultures.
• Investigated molecular mechanisms linking QTRT1 to intestinal inflammation.

Main Results:

• QTRT1 expression and key Q-tRNA synthetases were significantly downregulated in IBD patients and colitis models.
• Reduced QTRT1 correlated with impaired cell proliferation and altered intestinal barrier function (β-catenin, claudins).
• Queuine supplementation restored cell proliferation, junction activity, and reduced inflammation in vitro and in vivo.

Conclusions:

• tRNA modifications, particularly Q-tRNA via QTRT1, play a novel role in IBD pathogenesis.
• Altered Q-tRNA modification impacts epithelial proliferation and gut barrier integrity.
• Targeting tRNA modifications offers potential new therapeutic strategies for IBD.