The gut microbiota-derived butyrate improves gestational glucose homeostasis through HDAC3 inhibition and epigenetic activation of the SCGN/GLP-1 axis

A deficiency in the gut microbiota-derived metabolite butyrate is associated with gestational diabetes mellitus (GDM), yet the causative molecular pathways remain undefined. Given its established role as a histone deacetylase (HDAC) inhibitor, we hypothesised that butyrate exerts its beneficial effects on gestational glucose homeostasis through epigenetic reprogramming of intestinal hormone secretion. We integrated clinical observation with causal experimentation. First, a nested case-control study measured serum butyrate and active GLP-1 in pregnant women. Second, a GDM mouse model induced by high-fat diet and antibiotics was treated with the butyrate-producing probiotic Clostridium butyricum for metabolic and microbial profiling. Colon tissues were analysed for HDAC expression and histone acetylation. Third, the mechanism was dissected in enteroendocrine cells using sodium butyrate, HDAC3 modulation, and integrated RNA-sequencing/H3K27ac chromatin immunoprecipitation sequencing. Finally, HDAC3 heterozygous knockout mice were used for genetic validation. In the clinical cohort, serum butyrate and GLP-1 levels were consistently lower in women who developed GDM, evident both in early and mid-pregnancy (both p < 0.05). In mice, C. butyricum supplementation alleviated hyperglycaemia, insulin resistance, and circadian glucose rhythm disruption. This was paralleled by elevated systemic butyrate, enrichment of butyrate-producing gut bacteria, decreased colonic HDAC3 protein, and increased global histone H3K27 acetylation (H3K27ac). Multi-omics analysis in enteroendocrine cells identified secretagogin (SCGN) as a direct target gene, with butyrate enhancing both its transcription and promoter-associated H3K27ac. Consequently, butyrate and HDAC3 knockdown increased SCGN expression and GLP-1 secretion, whereas HDAC3 overexpression suppressed this axis—an effect reversible by co-treatment with butyrate. The metabolic improvements and SCGN upregulation driven by C. butyricum were abolished in HDAC3-haploinsufficient mice. We demonstrate that butyrate ameliorates GDM by specifically inhibiting intestinal HDAC3. This inhibition epigenetically activates the transcription of SCGN via enhanced H3K27ac, leading to potentiated GLP-1 secretion. Our work delineates a novel gut microbiota–epigenetic–hormonal axis, identifying HDAC3 and the downstream SCGN/GLP-1 pathway as potential targets for the prevention or treatment of GDM.