High‐fat diet intake modulates maternal intestinal adaptations to pregnancy and results in placental hypoxia, as well as altered fetal gut barrier proteins and immune markers

• Published in: The Journal of physiology 2019-06, Vol.597 (12), p.3029-3051
• Main Authors: Gohir, Wajiha, Kennedy, Katherine M., Wallace, Jessica G., Saoi, Michelle, Bellissimo, Christian J., Britz‐McKibbin, Philip, Petrik, Jim J., Surette, Michael G., Sloboda, Deborah M.
• Format: Article
• Language: English
• Subjects: Adaptation; Autophagy; Carnitine; Cecum; Cytokines; Digestive system; Embryogenesis; ER stres; Fetuses; Gastrointestinal tract; gut microbiota; gut permeability; High fat diet; Hypoxia; Inflammation; Intestinal microflora; Intestine; Lipopolysaccharides; Microbiota; mRNA; Phagocytosis; Placenta; placental hypoxia; Pregnancy; Protein folding; SCFA; Trimethylamine; Tumor necrosis factor; Tumors; Vascularization
• ISSN: 0022-3751; 1469-7793
• DOI: 10.1113/JP277353

Key points Maternal obesity has been associated with shifts in intestinal microbiota, which may contribute to impaired barrier function Impaired barrier function may expose the placenta and fetus to pro‐inflammatory mediators We investigated the impacts of diet‐induced obesity in mice on maternal and fetal intestinal structure and placental vascularization Diet‐induced obesity decreased maternal intestinal short chain fatty acids and their receptors, impaired gut barrier integrity and was associated with fetal intestinal inflammation. Placenta from obese mothers showed blood vessel immaturity, hypoxia, increased transcript levels of inflammation, autophagy and altered levels of endoplasmic reticulum stress markers. These data suggest that maternal intestinal changes probably contribute to adverse placental adaptations and also impart an increased risk of obesity in the offspring via alterations in fetal gut development. Shifts in maternal intestinal microbiota have been implicated in metabolic adaptations to pregnancy. In the present study, we generated cohorts of female C57BL/6J mice fed a control (17% kcal fat, n = 10–14) or a high‐fat diet (HFD 60% kcal from fat, n = 10–14; ad libitum) aiming to investigate the impact on the maternal gut microbiota, intestinal inflammation and gut barrier integrity, placental inflammation and fetal intestinal development at embryonic day 18.5. HFD was associated with decreased relative abundances of short‐chain fatty acid (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 in impaired gut barrier integrity, with corresponding increases in circulating maternal levels of lipopolysaccharide (LPS) and tumour necrosis factor. Placentas from HFD dams demonstrated blood vessel immaturity and hypoxia; decreased free carnitine, acylcarnitine derivatives and trimethylamine‐N‐oxide; and altered mRNA levels of inflammation, autophagy, and ER stress markers. HFD exposed fetuses had increased activation of nuclear factor‐kappa B and inhibition of the unfolded protein response in the developing intestine. Taken together, these data suggest that HFD intake prior to and during pregnancy shifts the composition of the maternal gut microbiota and impairs gut barrier integrity, resulting in inc