During pregnancy, the maternal gut microbiota experiences shifts that have been suggested to contribute to maternal metabolic and immune adaptations beneficial in pregnancy. Although these changes can be disrupted by maternal diet-induced obesity, little is known about the mechanisms behind the impact of diet-induced changes in the maternal gut microbiota on inflammatory and metabolic responses during pregnancy and their effect on the offspring.
A new study, led by Dr. Deborah M. Sloboda from McMaster University in Hamilton (Canada), has found that changes in the maternal gut microbiota contribute to an increased risk of obesity in the offspring through gut microbiota, gut barrier and placental adaptations.
The researchers fed female mice a control (17% kcal from fat) or high-fat diet (HFD, 60% kcal from fat) prior to and during pregnancy. They then explored the effect of the pregnant female’s diet on the maternal gut microbiota, gut barrier integrity and placental inflammation, as well as on fetal intestinal development.
Both pregnancy and maternal diet led to specific shifts in the maternal gut microbiota. Before pregnancy, the gut microbiota of HFD-fed females differed from control females. During pregnancy, the maternal HFD led to a higher abundance of Akkermansia and Clostridium, and decreased abundances of Bifidobacterium and 13 bacterial genera of the butyrate-producing families Ruminococcaceae and Lachnospiraceae. That is in agreement with previous findings from the same research group. These changes were in parallel with lower maternal cecal butyrate levels and decreased intestinal transcript levels of the short-chain fatty acid receptor GPR41.
The maternal HFD also altered intestinal transcript levels of immune cell markers involved in increased intestinal macrophage infiltration that correlated with increased transcripts of inflammatory markers, such as toll-like receptor (TLR) 2, TLR4 and interleukin-6.
At the intestinal functional level, both control mice and mice fed HFD showed impaired intestinal barrier integrity, reported through decreased levels of tight junction protein zonula occludens-1 and elevated occludin levels. These findings reveal that decreased intestinal barrier integrity may be a physiological adaptation during pregnancy, and maternal HFD may intensify that.
The impaired maternal gut barrier integrity secondary to the HFD increased maternal serum LPS and TNF levels, which are considered to be circulating inflammatory markers. Furthermore, maternal HFD led to placental hypoxia and subsequent stimulation of the formation of new blood vessels and altered endoplasmic reticulum stress markers in both male and female fetuses. Altogether, these hypoxia-driven changes that alter placental growth and development might predispose dams to pregnancy complications.
A decrease in carnitine levels due to the maternal HFD also influenced changes in placental carnitine and derived metabolites. As such, decreased uptake may affect mitochondrial function and have an impact on fetal development.
Strikingly, the maternal HFD also led to altered transcript levels of factors involved in regulating the fetal gut barrier in both the small and large intestines. In addition, fetuses that had been exposed to a HFD exhibited increased activation of the inflammatory nuclear factor-KB pathway and inhibition of the unfolded protein response in the developing intestine. The authors suggest these maternal HFD-induced alterations in fetal intestinal development could trigger later offspring dysbiosis and metabolic impairment.
In conclusion, these preclinical findings show that a maternal high-fat diet can lead to alterations in the maternal gut microbiota and gut barrier integrity which may ultimately contribute to prenatal changes involving both metabolic and immune response.
Gohir W, Kennedy KM, Wallace JG, et al. 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. J Physiol. 2019. doi: 10.1113/JP277353.
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