Adaptation of the gut holobiont to malnutrition during mouse pregnancy depends on the type of nutritional adversity

Malnutrition can influence maternal physiology and programme offspring development. Yet, in pregnancy, little is known about how dietary challenges that influence maternal phenotype affect gut structure and function. Emerging evidence suggests that interactions between the environment, multidrug resistance (MDR) transporters and microbes may influence maternal adaptation to pregnancy and regulate fetoplacental development. We hypothesized that the gut holobiont (host and microbes) during pregnancy adapts differently to suboptimal maternal diets, evidenced by changes in the gut microenvironment, morphology, and expression of key protective MDR transporters during pregnancy. Mice were fed a control diet (CON) during pregnancy, or undernourished (UN) by 30% of control intake from gestational day (GD) 5.5-18.5, or fed 60% high fat diet (HF) for 8 weeks before and during pregnancy. At GD18.5, maternal small intestinal (SI) architecture (H&E), proliferation (Ki67), P-glycoprotein (P-gp - encoded by Abcb1a/b) and breast cancer resistance protein (BCRP/Abcg2) MDR transporter expression and levels of pro-inflammatory biomarkers were assessed. Circulating inflammatory biomarkers and maternal caecal microbiome composition (G3 PhyloChipTM) were measured. MDR transporter expression was also assessed in fetal gut. HF diet increased maternal SI crypt depth and proinflammatory load, and decreased SI expression of Abcb1a mRNA, whilst UN increased SI villi proliferation and Abcb1a, but decreased Abcg2, mRNA expression. There were significant associations between Abcb1a and Abcg2 mRNA levels with relative abundance of specific microbial taxa. Using a systems physiology approach we report that common nutritional adversities provoke adaptations in the pregnancy holobiont in mice, and reveal new mechanisms that could influence reproductive outcomes and fetal development.