Suppressing α-1,6-Fucosyltransferase With a Novel Small Molecule Inhibitor Ameliorates Inflammation in Murine T-Cell–Mediated Colitis Models

BACKGROUND & AIMS: Inflammatory bowel disease involves intractable intestinal inflammation often refractory to current pharmacotherapies. We investigated the therapeutic potential of a novel, orally available inhibitor targeting α-1,6-fucosyltransferase-the sole glycosyltransferase catalyzing core fucosylation of N-glycans in mammals-as an anti-inflammatory agent. METHODS: T cells from wild-type mice were treated with the α-1,6-fucosyltransferase inhibitor to evaluate its effects on cell signaling, cytokine production, and T helper 1, 2, and 17 differentiation. In vivo safety was assessed in wild-type mice. RESULTS: mice, demonstrating that the ameliorative effect of α-1,6-fucosyltransferase inhibition is directly mediated by T cells. In vitro, the inhibitor suppressed T-cell signal transduction and T helper 1, 2, and 17 cell differentiation. No apparent hepatorenal toxicity or intestinal mucus layer disruption was observed. CONCLUSIONS: α-1,6-Fucosyltransferase inhibition modulated T-cell core fucosylation and reduced inflammation in murine colitis models without apparent toxicity, indicating that targeting α-1,6-fucosyltransferase may offer a novel therapeutic approach for inflammatory bowel disease by disrupting proinflammatory T-cell responses.