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. In this study we investigated how high-fat diet intake impacts the maternal gut microbiota, intestinal inflammation and gut barrier integrity, placental inflammation, and fetal intestinal development at E18.5. High-fat diet (HFD) was associated with decreased relative abundancesof SCFA producing genera 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 HFD resulted inimpaired gut barrier integrity, with corresponding increases in circulating maternal levels of LPS and TNF.Placentafromhigh-fat fed damsdemonstrated blood vessel immatu-rityand hypoxia, decreased freecarnitine, acylcarnitine derivatives, TMAO, as well as altered mRNA levels of inflammation, autophagy and ER stress markers. HFD 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 diet intake prior to and during pregnancy shifts the composition of the maternal gut microbiota and impairs gut barrier integrity, resulting in increased maternal circulating LPS, which may ultimate contribute to changes in placental vasculariza-tion and fetal gut development. Funding information Farncombe Family Digestive Health Research Institute (KMK); Canadian Institute of Health Research (CJB); Canada Research Chairs Program (MGS, DMS); Natural Sciences and Engineering Research Council of Canada, Genome Canada (PBM).