Cesarean section-induced dysbiosis facilitates metabolic disease in high-fat diet-induced obese mice
The global rate of cesarean section CS births is rising. Growing evidence suggests that CS birth may alter the gut microbiota i.e. dysbiosis, and through this increase the risk of immune and metabolic disorders, though confounding factors make causality difficult to establish. This study aims to investigate the causal relationship between CS-induced gut dysbiosis and obesity in a high-fat diet HFD mouse model, and explore potential microbiota-targeted therapies.In the first study, male C57BL-6 mice were delivered via CS or vaginally VD and put on high- or low-fat diet for 12 weeks. In the next study, male germ-free BALB-c mice were transplanted with fecal microbiota from 1 month old children born by CS or VD and fed HFD or HFD + human milk oligosaccharides HMO for 16 weeks.CS in mice only induced minor difference in weight gain and had no effect on other metabolic endpoints, likely due to a lack of difference in the gut microbiota. In contrast, the human CS microbiota associated mice weighed significantly more and experienced enhanced insulin resistance compared to the mice receiving the VD microbiota. The phenotypic change was further supported by differences in serum cytokines, adipokines and metabolism-regulating hormones as well as differential gene expression in multiple metabolic tissues. Manifestations that were partially restored by feeding the mice HMOs. Furthermore, fecal metabolomics and short-chain fatty acids SCFAs were assessed in 4-week-old VD and CS microbiota associated mice prior to HFD feeding, revealing significant differences between the groups, consistent with findings from metagenomics analysis of the gut microbiome. Of interest, the CS microbiota altered key metabolic regulators PYY, FGF-21, BAFF, and reduced succinate impairing mitochondrial function and AMPK signaling, potentially driving metabolic dysfunction.