Intestinal epithelial SETD2 maintains gut microbial homeostasis to attenuate colitis

Abstract

Background: Disruption of host–microbiota homeostasis is a fundamental hallmark of inflammatory bowel disease (IBD) pathogenesis. Host epigenetic modifications and corresponding alterations in gene expression levels can impact the composition of gut microbes. SET domain containing 2 (SETD2) is a critical epigenetic regulator with established tumor-suppressive roles, but its function in intestinal microbial ecology and colitis progression remains unexplored. We aimed to investigate the specific role of SETD2 in maintaining gut microbial homeostasis and modulating colitis progression.

Methods: RNA sequencing (RNA-seq), assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) and cleavage under targets and tagmentation sequencing (CUT&Tag-seq) were conducted on colonic epithelial cells from intestinal epithelial cell-specific SETD2 knockout (Setd2^vil-ko) mice to identify key mediators contributing to colitis development. Faecal samples underwent 16S rRNA sequencing and non-targeted metabolomics analysis to characterise microbial dysbiosis and metabolic perturbations. Molecular experiments and faecal microbiome transplantation experiment were conducted to explore and validate the role of SETD2 in colitis development.

Results: SETD2 deficiency induced overproduction of Reg3 lectins and disrupted gut microbiota composition. Beneficial commensal bacteria were depleted and dysregulated metabolites were accumulated in Setd2^vil-ko mice. Supplementation with healthy-like gut microbiota significantly ameliorated the exacerbated colitis induced by SETD2 deficiency.

Conclusions: Our findings uncover a previously unrecognised role for SETD2 in maintaining microbial homeostasis, offering new mechanistic insights into how epigenetic regulation preserves intestinal homeostasis and suggesting novel therapeutic avenues for IBD.

Keywords

AMPs / epigenetics / gut microbes / IBD / SETD2

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2026 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.