Amanda N. Sferruzzi-Perri’s research while affiliated with University of Cambridge and other places

Purpose Homoarginine (hArg) is an arginine metabolite that has been known for years, but its physiological role in the body remains poorly understood. For instance, it is well known that high hArg concentrations in the blood are protective against several disease states, yet the mechanisms behind these health benefits are unclear. This review compiles what is known about hArg, namely its synthetic pathways, its role in different diseases and conditions, and its proposed mechanisms of action in humans and experimental animals. Findings Previous work has identified multiple pathways that control hArg synthesis and degradation in the body. Furthermore, endogenous hArg can modulate the cardiovascular system, with decreased hArg being associated with cardiovascular complications and increased mortality. Studies also suggest that hArg could serve as a diagnostic biomarker for a variety of immune, pancreatic, renal, and hepatic dysfunctions. Finally, in women, hArg concentrations rapidly increase throughout pregnancy and there are suggestions that alterations in hArg could indicate pregnancy complications like pre‐eclampsia. Summary Homoarginine is an under‐appreciated amino acid with potential wide‐ranging roles in systemic health, pregnancy, and pathophysiology. Although recent research has focused on its health or disease associations, there is a need for more investigations into understanding the mechanistic pathways by which hArg may operate. This could be aided using metabolomics, which provides a comprehensive approach to correlating multiple metabolites and metabolic pathways with physiological effects. Increasing our knowledge of hArg's roles in the body could pave the way for its routine use as both a diagnostic and therapeutic molecule.

Climate change has resulted in an increase in heat exposure globally. There is strong evidence that this increased heat stress is associated with poor maternal and fetal outcomes, especially in vulnerable populations. However, there remains poor understanding of the biological pathways and mechanisms involved in the impact of heat in pregnancy. This observational cohort study of 764 pregnant participants based in sub-Saharan Africa, a geographical region at risk of extreme heat events, aims to evaluate the physiological and biochemical changes that occur in pregnancy due to heat stress. The key objectives of the study are to 1) map exposure to heat stress in the cohort and understand what environmental, social and community factors increase the risk of extreme heat exposure; 2) assess the impact of heat stress on maternal health, e.g. heat strain, subjective psychological well-being, sleep and activity level; 3) evaluate how heat stress impacts placenta structure and function; 4) determine how chronic heat exposure impacts birth outcomes; and 5) explore the epigenetic changes in the placenta and infant by heat stress exposure per trimester. Pregnant women will be recruited from two distinct regions in The Gambia to exploit the naturally occurring heat gradient across the country. Microclimate mapping of the area of recruitment will give detailed exposure measurements. Participants will be asked to wear a watch-style device at 28- and 35-weeks gestational age to evaluate maternal heart rate, activity and sleep. At the end of the week, an ultrasound scan will be performed to evaluate fetal size and placental blood flow. At delivery, birth outcomes will be recorded and maternal, placental and cord samples taken for epigenetic, biochemical and histological evaluation. Evaluation of neuro-behaviour and final infant samples will be taken at 1 month following birth.

The placenta is a gatekeeper between the mother and fetus, adapting its structure and functions to support optimal fetal growth. Studies exploring adaptations of placentae that support the development of genetically small fetuses are lacking. Here, using a mouse model of impaired fetal growth, achieved by deleting insulin-like growth factor 2 (Igf2) in the epiblast, we assessed placental nutrient transfer and umbilical artery (UA) blood flow during late gestation. At embryonic day (E) 15.5, we observed a decline in the trans-placental flux of glucose and system A amino acids (by using 3H-MeG and 14C-MeAIB), proportionate to the diminished fetal size, whereas UA blood flow was normal. However, at E18.5, the trans-placental flux of both tracers was disproportionately decreased and accompanied by blunted UA blood flow. Feto-placental growth and nutrient transfer were more impaired in female conceptuses. Thus, reducing the fetal genetic demand for growth impairs the adaptations in placental blood flow and nutrient transport that normally support the fast fetal growth during late gestation. These findings have important implications for our understanding of the pathophysiology of pregnancies afflicted by fetal growth restriction.

Background Recent advances have significantly expanded our understanding of the gut microbiome's influence on host physiology and metabolism. However, the specific role of certain microorganisms in gestational health and fetal development remains underexplored. Objective This study investigates the impact of Bifidobacterium breve UCC2003 on fetal brain metabolism when colonized in the maternal gut during pregnancy. Methods Germ-free pregnant mice were colonized with or without B. breve UCC2003 during pregnancy. The metabolic profiles of fetal brains were analyzed, focusing on the presence of key metabolites and the expression of critical metabolic and cellular pathways. Results Maternal colonization with B. breve resulted in significant metabolic changes in the fetal brain. Specifically, ten metabolites, including citrate, 3-hydroxyisobutyrate, and carnitine, were reduced in the fetal brain. These alterations were accompanied by increased abundance of transporters involved in glucose and branched-chain amino acid uptake. Furthermore, supplementation with this bacterium was associated with elevated expression of critical metabolic pathways such as PI3K-AKT, AMPK, STAT5, and Wnt-β-catenin signaling, including its receptor Frizzled-7. Additionally, there was stabilization of HIF-2 protein and modifications in genes and proteins related to cellular growth, axogenesis, and mitochondrial function. Conclusions The presence of maternal B. breve during pregnancy plays a crucial role in modulating fetal brain metabolism and growth. These findings suggest that Bifidobacterium could modify fetal brain development, potentially offering new avenues for enhancing gestational health and fetal development through microbiota-targeted interventions.

TRPV2 is a calcium-permeable ion channel with a broad expression pattern that contributes to neuronal outgrowth, immune response, and cardiac function. Mice lacking Trpv2 are more susceptible to perinatal lethality, a phenotype that cannot be explained by its previously allocated functions. We recently reported functional TRPV2 expression in mouse trophoblast cells and described temporal expression changes during placental development in mice. Here, we provide compelling evidence that TRPV2 plays a vital role in normal placental development, determining fetal size and survival. Specifically, Trpv2 is abundantly present in a subset of murine placental syncytiotrophoblast cells II (SynTII) during early development. Its absence results in region-specific loss of SynTII cells and fetal vascular invasion, severely affecting placental morphology. Consequently, global Trpv2 knockout mice suffer from fetal growth restriction and embryonic lethality, a phenotype found to be allocated to a non-redundant role in the trophoblast, but not in the embryo. CRISPR/Cas9-mediated Trpv2 deletion in mouse trophoblast stem cells identified a critical role of Trpv2 in the differentiation process towards SynTII cells, which was confirmed by the growth restriction phenotype in SynTII-specific Trpv2 knockout animals. TRPV2 expression was abundantly detected in human syncytiotrophoblast cells differentiated from trophoblast stem cells, suggesting a conserved role for TRPV2 in human trophoblast differentiation. Finally in the human placenta, TRPV2 expression was lower in early-onset fetal growth restriction compared to appropriately grown pregnancies. Taken together, our findings identify for the first time the indispensable role of TRPV2 during placental development, arbitrating fetal outcomes.

Endocytosis represents a category of regulated active transport mechanisms. These encompass clathrin-dependent and -independent mechanisms, as well as fluid phase micropinocytosis and macropinocytosis, each demonstrating varying degrees of specificity and capacity. Collectively, these mechanisms facilitate the internalization of cargo into cellular vesicles. Pregnancy is one such physiological state during which endocytosis may play critical roles. A successful pregnancy necessitates ongoing communication between maternal and fetal cells at the maternal-fetal interface to ensure immunologic tolerance for the semi-allogenic fetus whilst providing adequate protection against infection from pathogens, such as viruses and bacteria. It also requires transport of nutrients across the maternal-fetal interface, but restriction of potentially harmful chemicals and drugs to allow fetal development. In this context, trogocytosis, a specific form of endocytosis, plays a crucial role in immunological tolerance and infection prevention. Endocytosis is also thought to play a significant role in nutrient and toxin handling at the maternal-fetal interface, though its mechanisms remain less understood. A comprehensive understanding of endocytosis and its mechanisms not only enhances our knowledge of maternal-fetal interactions but is also essential for identifying the pathogenesis of pregnancy pathologies and providing new avenues for therapeutic intervention.

In recent years, our understanding of the gut microbiome's impact on host physiology and metabolism has grown exponentially. Yet, the specific role of certain microorganisms in regulating gestational health and fetal development remains largely unexplored. During pregnancy, Bifidobacterium represents a key beneficial microbiota genus that provides multiple benefits, including changes in placental development and fetal glycaemia. In this study, using germ-free mice colonized with or without Bifidobacterium breve UCC2003 during pregnancy, we demonstrated that this bacterium is important for controlling fetal brain metabolism. In particular, presence of maternal Bifidobacterium led to reduced levels of nine metabolites (including citrate, 3-hydroxyisobutyrate, and carnitine) in the fetal brain, with concurrent elevated abundance of transporters involved in glucose and branched-chain amino acid uptake. B. breve supplementation was also associated with increased expression of critical metabolic and cellular pathways, including the PI3K-AKT, AMPK, STAT5 and Wnt-β-catenin (including its receptor Frizzled-7) in the fetal brain. Furthermore, maternal-associated Bifidobacterium resulted in HIF-2 protein stabilization and altered a number of genes and proteins involved in cellular growth, axogenesis, and mitochondrial function. These findings highlight that Bifidobacterium breve colonisation of the maternal gut is important for the metabolism and growth of the fetal brain.

According to the Developmental Origins of Health and Disease (DOHaD) hypothesis, exposure to certain environmental influences during early life may be a key determinant of fetal development and short- and long-term offspring health. Indeed, adverse conditions encountered during the fetal, perinatal, and early childhood stages can alter normal development and growth, as well as put the offspring at elevated risk of developing long-term health conditions in adulthood, including chronic kidney disease (CKD) and cardiovascular diseases. Of relevance in understanding the mechanistic basis of these long-term health conditions, are previous findings showing low glomerular number in human intrauterine growth restriction and low birth weight - indicators of a sub-optimal intrauterine environment. In different animal models, the main sub-optimal intrauterine conditions studied relate to maternal dietary manipulations, poor micronutrient intake, prenatal ethanol exposure, maternal diabetes, glucocorticoid and chemical exposure, hypoxia, and placental insufficiency. These studies have demonstrated changes in kidney structure, glomerular endowment, and expression of key genes and signalling pathways controlling endocrine, excretion and filtration function of the offspring. This review aims to summarize those studies to uncover the effects and mechanisms by which adverse gestational environments impact offspring renal and vascular health in adulthood. This is important for identifying agents and interventions that can prevent and mitigate the long-term consequences of an adverse intrauterine environment on the subsequent generation.