High-fat diet intake modulates maternal intestinal adaptations to pregnancy, and results in placental hypoxia and impaired fetal gut development

Shifts in maternal intestinal microbiota have been implicated in metabolic adaptations to pregnancy. We have previously shown a pregnancy-by-diet interaction effect on intestinal microbiota in mice. In this project we investigated how high-fat diet impacts the maternal gut microbiota, intestinal inflammation and gut barrier integrity, placental inflammation, and fetal intestinal development at E18.5. High-fat diet was associated with decreased relative abundances of SCFA producers during pregnancy. These diet-induced shifts paralleled decreased maternal intestinal mRNA levels of SCFA receptor Gpr41 , modestly decreased cecal butyrate, and altered mRNA levels of inflammatory cytokines and immune cell markers in the maternal intestine. Maternal high-fat diet resulted in impaired gut barrier integrity, with corresponding increases in circulating maternal levels of LPS and TNF. Placentas of high-fat dams demonstrated blood vessel immaturity and hypoxia, decreased free carnitine, acylcarnitine derivatives, trimethylamine-N-oxide, as well as altered mRNA levels of inflammation, autophagy and ER stress markers. High-fat diet exposed fetuses had increased activation of NF-κB and inhibition of the unfolded protein response in the developing intestine. Together, these data suggest that high-fat intake prior to and during pregnancy shifts the composition of the maternal gut microbiota and impairs gut barrier integrity, resulting in increased circulating LPS, which may ultimate contribute to changes in placental vascularization and fetal gut development.