Intestinal Fut2 deficiency exacerbated alcohol-related liver disease by disrupting nicotinamide metabolism

Abstract

Background: Fucosyltransferase 2 (FUT2)-dependent fucosylation of intestinal epithelial cells is vital for preserving gut barrier integrity and microbial balance. Nevertheless, its precise involvement in alcohol-associated liver disease has yet to be fully elucidated.

Methods: We generated mice with intestinal epithelial cell-specific Fut2 knockout (Fut2^△IEC) and established a chronic-binge alcohol model. 16S rRNA sequencing and metabolomics analysis were used to reveal differences in the composition and function of faecal bacteria.

Results: The loss of intestinal epithelial Fut2 exacerbates alcohol-related hepatic oxidative stress damage, and this effect is dependent on gut bacteria. A marked decrease in the abundance of bacteria carrying nicotinamidase (PncA) in the intestines of Fut2^△IEC mice was observed, leading to disrupted nicotinamide metabolism and decreased nicotinic acid production. This reduction in nicotinic acid synthesis results in decreased NAD⁺ production in the liver via the Preiss–Handler pathway. Administering pncA-overexpressing Escherichia coli promotes hepatic NAD⁺ synthesis and alleviates alcohol-related oxidative stress damage in Fut2^△IEC mice.

Conclusion: These findings reveal a gut microbiota–Fut2–pncA axis that modulates alcoholic liver injury in mice, which may offer insights into microbial contributions to alcoholic liver disease in people.

Keywords

alcohol-related liver disease / fucosyltransferase 2 / NAD / nicotinamidase

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2025 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.