The attenuation of gut microbiota-derived short-chain fatty acids elevates lipid transportation through suppression of the intestinal HDAC3-H3K27ac-PPAR-γ axis in gestational diabetes mellitus

Abstract

Gut flora is considered to modulate lipid transport from the intestine into the bloodstream, and thus may potentially participate in the development of GDM. Although previous studies have shown that the intestinal microbiota influences lipid transport and metabolism in GDM, the precise mechanisms remain elusive. To address this, we used a high-fat diet (HFD)-induced GDM mouse model and conducted 16s rRNA sequencing and fecal metabolomics to assess gut microbial community shifts and associated metabolite changes. Western blot, ELISA, and chromatin immunoprecipitation (ChIP) were utilized to elucidate how gut microbiota affect intestinal lipid transport and the insulin sensitivity of hepatic, adipose, and skeletal muscle tissues. We found that HFD impaired the oral glucose tolerance test (OGTT) and insulin tolerance test (ITT) in pregnant mice. 16s rRNA sequencing demonstrated profound compositional changes, especially in the relative abundances of Firmicutes and Bacteroidetes. Metabolomics analysis presented a decline in the concentration of short-chain fatty acids (SCFAs) in the GDM group. Western blot analyses showed an upregulation of HDAC3 and a concurrent reduction in H3K27 acetylation in the intestine. ChIP-qPCR showed that PPAR-γ was inhibited, which in turn activated lipid-transporter CD36. ELISA and insulin signaling pathway detection in insulin-target organs showed high concentrations of circulating fatty acids and triglycerides and insulin resistance in insulin-target organs. Our results suggest that gut microbiota is closely associated with the development of GDM, partly because decreased gut flora-associated SCFAs activate CD36 by suppressing the HDAC3-H3K27ac-PPAR-γ axis to transport excessive fatty acids and triglycerides into blood circulation, thereby dysregulating the insulin sensitivity of insulin target organs.