The gut microbiota plays a central role in regulating host metabolism. While substantial progress has been made in discerning how the microbiota influences host functions post birth and beyond, little is known about how key members of the maternal gut microbiota can influence feto-placental growth. Notably, in pregnant women, Bifidobacterium represents a key beneficial microbiota genus, with levels observed to increase across pregnancy. Here, using germ-free and specific-pathogen-free mice, we demonstrate that the bacterium Bifidobacterium breve UCC2003 modulates maternal body adaptations, placental structure and nutrient transporter capacity, with implications for fetal metabolism and growth. Maternal and placental metabolome were affected by maternal gut microbiota (i.e. acetate, formate and carnitine). Histological analysis of the placenta confirmed that Bifidobacterium modifies placental structure via changes in Igf2P0, Dlk1, Mapk1 and Mapk14 expression. Additionally, B. breve UCC2003, acting through Slc2a1 and Fatp1-4 transporters, was shown to restore fetal glycaemia and fetal growth in association with changes in the fetal hepatic transcriptome. Our work emphasizes the importance of the maternal gut microbiota on feto-placental development and sets a foundation for future research towards the use of probiotics during pregnancy.

Maternal-offspring interactions in mammals involve both cooperation and conflict. The fetus has evolved ways to manipulate maternal physiology to enhance placental nutrient transfer, but the mechanisms involved remain unclear. The imprinted Igf2 gene is highly expressed in murine placental endocrine cells. Here, we show that Igf2 deletion in these cells impairs placental endocrine signaling to the mother, without affecting placental morphology. Igf2 controls placental hormone production, including prolactins, and is crucial to establish pregnancy-related insulin resistance and to partition nutrients to the fetus. Consequently, fetuses lacking placental endocrine Igf2 are growth restricted and hypoglycemic. Mechanistically, Igf2 controls protein synthesis and cellular energy homeostasis, actions dependent on the placental endocrine cell type. Igf2 loss also has additional long-lasting effects on offspring metabolism in adulthood. Our study provides compelling evidence for an intrinsic fetal manipulation system operating in placenta that modifies maternal metabolism and fetal resource allocation, with long-term consequences for offspring metabolic health.

Intrauterine growth restriction (IUGR) affects approximately 10% of human pregnancies globally and has immediate and life‐long consequences for offspring health. However, the mechanisms underlying the pathogenesis of IUGR and its association with later health and disease outcomes are poorly understood. To address these knowledge gaps, the use of experimental animals is critically important. Since the 50's different environmental, pharmacological, and surgical manipulations have been performed in the rabbit to improve our knowledge of the control of fetal growth, fetal responses to IUGR, and mechanisms by which offspring may be programmed by an adverse gestational environment. The purpose of this review is therefore to summarize the utility of the rabbit as a model for IUGR research. It first summarizes the knowledge of prenatal and postnatal development in the rabbit and how these events relate to developmental milestones in humans. It then describes the methods used to induce IUGR in rabbits and the knowledge gained about the mechanisms determining prenatal and postnatal outcomes of the offspring. Finally, it discusses the application of state of the art approaches in the rabbit, including high‐resolution ultrasound, magnetic resonance imaging, and gene targeting, to gain a deeper integrative understanding of the physiological and molecular events governing the development of IUGR. Overall, we hope to engage and inspire investigators to employ the rabbit as a model organism when studying pregnancy physiology so that we may advance our understanding of mechanisms underlying IUGR and its consequences in humans and other mammalian species.

Studies suggest that placental nutrient supply adapts according to fetal demands. However, signaling events underlying placental adaptations remain unknown. Here we demonstrate that phosphoinositide 3-kinase p110α in the fetus and the trophoblast interplay to regulate placental nutrient supply and fetal growth. Complete loss of fetal p110α caused embryonic death, whilst heterozygous loss resulted in fetal growth restriction and impaired placental formation and nutrient transport. Loss of trophoblast p110α resulted in viable fetuses, abnormal placental development and a failure of the placenta to transport sufficient nutrients to match fetal demands for growth. Using RNA-seq we identified genes downstream of p110α in the trophoblast that are important in adapting placental phenotype. Using CRISPR/Cas9 we showed loss of p110α differentially affects gene expression in trophoblast and embryonic stem cells. Our findings reveal important, but distinct roles for p110α in the different compartments of the conceptus, which control fetal resource acquisition and growth.

Fetal growth depends on placental function, which requires energy from mitochondria. Here we investigated whether mitochondrial function in the placenta relates to the growth of the lightest and heaviest fetuses of each sex within the litter of mice. Placentas from the lightest and heaviest fetuses were taken to evaluate placenta morphology (stereology), mitochondrial energetics (high-resolution respirometry), mitochondrial regulators, nutrient transporters, hormone handling, and signaling pathways (qPCR and Western blotting). We found that mitochondrial complex I and II oxygen consumption rate was greater for placentas supporting the lightest female fetuses, although placental complex I abundance of the lightest females and complexes III and V of the lightest males were decreased compared to their heaviest counterparts. Expression of mitochondrial biogenesis (Nrf1) and fission (Drp1 and Fis1) genes was lower in the placenta from the lightest females, whilst biogenesis-related gene Tfam was greater in the placenta of the lightest male fetuses. In addition, placental morphology and steroidogenic gene (Cyp17a1 and Cyp11a1) expression were aberrant for the lightest females, but glucose transporter (Slc2a1) expression was lower in only the lightest males versus their heaviest counterparts. Differences in intra-litter placental phenotype were related to changes in the expression of hormone-responsive (androgen receptor) and metabolic signaling (AMPK, AKT, and PPARγ) pathways. Thus, in normal mouse pregnancy, placental structure, function, and mitochondrial phenotype are differentially responsive to the growth of the female and male fetus. This study may inform the design of sex-specific therapies for placental insufficiency and fetal growth abnormalities with life-long benefits for the offspring. Here, we showed that in normal mouse pregnancy, placenta function varies between the lightest and the heaviest female and male fetuses within the litter. In particular, there are differences in mitochondria function, structure, nutrient transporters, metabolic pathways, and steroid signaling in the placental transport zone (labyrinth zone) that relate to fetal growth in the litter.

Conditions such as small for gestational age (SGA), which is defined as birthweight less than 10^th percentile for gestational age can predispose to neurodevelopmental abnormalities compared to babies with normal birthweight. Fetal growth and birthweight depend on placental function, as this organ transports substrates to the developing fetus and it acts as a source of endocrine factors, including steroids and prolactins that are required for fetal development and pregnancy maintenance. To advance our knowledge on the aetiology of fetal growth disorders, the vast majority of the research has been focused on studying the transport function of the placenta, leaving practically unexplored the contribution of placental hormones in the regulation of fetal growth. Here, using mice and natural variability in fetal growth within the litter, we compared fetuses that fell on or below the 10^th percentile (classified as SGA) with those that had adequate weight for their gestational age (AGA). In particular, we compared placental endocrine metabolism and hormone production, as well as fetal brain weight and expression of developmental, growth and metabolic genes between SGA and AGA fetuses. We found that compared to AGA fetuses, SGA fetuses had lower placental efficiency and reduced capacity for placental production of hormones (e.g. steroidogenic gene Cyp17a1, prolactin Prl3a1, and pregnancy-specific glycoproteins Psg21). Brain weight was reduced in SGA fetuses, although this was proportional to the reduction in overall fetal size. The expression of glucose transporter 3 (Slc2a3) was reduced despite the abundance of AKT, FOXO and ERK proteins were similar. Developmental (Sv2b and Gabrg1) and microglia genes (Ier3), as well as the pregnancy-specific glycoprotein receptor (Cd9) were lower in the brain of SGA versus AGA fetuses. In this mouse model of SGA, our results therefore demonstrate that placental endocrine dysfunction is associated with changes in fetal growth and fetal brain development.