Cesarean section-induced changes in the gut microbiota facilitate metabolic disease in high-fat diet-induced obese mice

BACKGROUND: The global rate of cesarean section (CS) births is increasing. Growing evidence suggests that CS birth may alter the gut microbiota (i.e., dysbiosis) and increase the risk of immune and metabolic disorders, although confounding factors make causality difficult to establish. The studies presented here aimed to investigate the causal relationship between CS-induced gut dysbiosis and obesity in a diet-induced obese mouse model and explore potential microbiota-targeted therapies. RESULTS: In the first study, male C57BL/6 mice were delivered via CS or vaginally (VD) and fed a high- or low-fat diet (HFD, LFD) for 12 weeks. In the second study, male germ-free BALB/c mice were transplanted with fecal microbiota from 1-month-old infants born by CS or VD and fed a HFD or HFD + human milk oligosaccharides (HMOs) for 16 weeks. CS in mice induced only minor differences in weight gain and had no effect on other metabolic endpoints, likely because there was no difference in the gut microbiota between the CS and VD mice. In contrast, mice colonized with the human CS microbiota weighed significantly more and developed greater insulin resistance than mice colonized with the VD microbiota. These phenotypic changes were accompanied by alterations in serum cytokines, adipokines and metabolic hormones as well as differential gene expression across multiple metabolic tissues. Notably, these manifestations were partially ameliorated by HMO supplementation and by administration of Bacteroides fragilis, a taxon depleted in the CS donor microbiota, which directly reduced circulating FGF-21 levels, implicating this bacterium in host metabolic regulation. CONCLUSIONS: CS-induced gut dysbiosis can increase the risk of developing obesity and insulin resistance, but without dysbiosis, the metabolic effects of CS birth in isolation are minimal, suggesting that promising therapeutic targets may be identified in the gut microbiome. Video Abstract.