The gut microbiota-derived butyrate improves gestational glucose homeostasis through HDAC3 inhibition and epigenetic activation of the SCGN/GLP-1 axis.
8 affiliations
- 1Department of Nutrition, Endocrinology, and Metabolism, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, 100026, China.
- 2Beijing Maternal and Child Health Care Hospital, Beijing, 100026, China.
- 3Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China.
- 4Department of Nutrition, Endocrinology, and Metabolism, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, 100026, China. [email protected].
- 5Beijing Maternal and Child Health Care Hospital, Beijing, 100026, China. [email protected].
- 6Department of Clinical Nutrition, Capital Medical University, Beijing, 100069, China. [email protected].
- 7Department of Nutrition, Endocrinology, and Metabolism, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, 100026, China. [email protected].
- 8Beijing Maternal and Child Health Care Hospital, Beijing, 100026, China. [email protected].
Abstract
Background
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.Methods
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.Results
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.Conclusions
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.
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BibTeX
@article{han2026microbiotaderived,
title = {{The gut microbiota-derived butyrate improves gestational glucose homeostasis through HDAC3 inhibition and epigenetic activation of the SCGN/GLP-1 axis.}},
author = {Weiling Han and Yujie Zhang and Junhua Huang and Yixuan Lu and Xin Yin and Yang Zhao and Xianxian Yuan and Ruihua Yang and Li Zhang and Wei Zheng and Guanghui Li},
journal = {Journal of translational medicine},
year = {2026},
month = sep,
doi = {10.1186/s12967-026-08720-y},
url = {https://europepmc.org/article/MED/42963805},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - The gut microbiota-derived butyrate improves gestational glucose homeostasis through HDAC3 inhibition and epigenetic activation of the SCGN/GLP-1 axis.
AU - Weiling Han
AU - Yujie Zhang
AU - Junhua Huang
AU - Yixuan Lu
AU - Xin Yin
AU - Yang Zhao
AU - Xianxian Yuan
AU - Ruihua Yang
AU - Li Zhang
AU - Wei Zheng
AU - Guanghui Li
PY - 2026
DA - 2026/09/14
JO - Journal of translational medicine
DO - 10.1186/s12967-026-08720-y
UR - https://europepmc.org/article/MED/42963805
AB - Background 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.Methods 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.Results 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.Conclusions 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.
SN - 1479-5876
ER -