Project description:We demonstrated that a maternal antibiotic treatment can change intestinal development of the offspring piglets permanently by showing that maternal gestational antibiotic treatment affects intestinal development in offspring piglets for a period of at least seven weeks after the antibiotic treatment in the sows was finished. It was shown that immediately after birth the piglets from amoxicillin treated sows, showed upregulation of genes involved in processes related to ‘tight junctions’ and ‘immunoglobulins’. In addition, these piglets had significantly lower number of goblet cells. Together, this may lead to a gut wall that is more rapidly closed in piglets from amoxicillin treated sows, affecting the uptake of immunoglobulins and the intestinal development. Later in life, around weaning, gene expression and morphological data indicate that the crypts of piglets from amoxicillin treated sows deepen around weaning as an effect of the amoxicillin treatment which in combination with the upregulation of genes involved in cell cycle processes, ribosomal activity and protein degradation might imply that the intestinal development, the subsequent differentiation of cells or the timing of these processes was delayed by the maternal antibiotic treatment.
Project description:Maternal undernutrition during pregnancy followed by ad libitum access to nutrients during postnatal life induces postnatal metabolic disruptions in multiple species. As skeletal muscle is a major metabolic organ, RNAseq was performed on the longissimus dorsi muscles of slaughter-weight adult females that had been exposed to nutrient-restriction in utero.
Project description:Activation of the maternal immune system during pregnancy can fetal development, which can lead to postnatal susceptibility to a wide range of diseases, including cardiovascular, metabolic and psychiatric disorders. During maternal immune activation (MIA), the maternal body must balance its ressources between mounting an immune response and investing resources into continued metabolism and growth : both essential for survival of the fetus and a successful pregnancy. How the placenta responds to MIA over time and how it can protect the fetus is not well understood, and neither are the fetal consequences of MIA. Here, we characterised the response to an induced acute inflammation in maternal lungs over time across maternal and fetal organs, using a combination of omics-methods, imaging and integrative computational analysis. We found that the placenta, unlike other maternal organs, did not react by inducing a typical inflammatory response, but instead initially induced genes associated to strengthen tissue integrity and simultaneously reduced growth to prevent exposure to potential infections. Afterwards, a return to homeostasis was observed, with heightened biosynthesis and expression of endoplasmic reticulum (ER) stress genes. This mechanism likely protects the fetus from inflammation, as we observed no immune response in the fetal liver transcriptome. Instead, we observed metabolic adaptations in the fetus, including a release of docosahexaenoic acid (DHA) Notably, DHA has a crucial function for fetal brain development , and levels of triglyceride and phosphatidylcholine lipids that are necessary for transportation of DHA to the brain were also increased. This metabolic response is likely a combination of the placental MIA response and temporary maternal fasting, caused by MIA-induced fever and lack of nutrient intake. Our study shows, for the first time, the temporal and systemic response to MIA in lungs across maternal and fetal organs.
Project description:Maternal overnutrition increases inflammatory and metabolic disease risk in postnatal offspring. This constitutes a major public health concern due to the increasing prevalence of these diseases yet the mechanisms remain unclear. Here, using nonhuman primate models, we show that maternal Western-style diet (mWSD) exposure is associated with persistent pro-inflammatory phenotypes at the transcriptional, metabolic, and functional levels in bone marrow-derived macrophages (BMDMs) from 3-year-old juvenile offspring and in hematopoietic stem and progenitor cells (HSPCs) from fetal and juvenile bone marrow and fetal liver. mWSD exposure is also associated with increased oleic acid in fetal and juvenile bone marrow and fetal liver. ATAC-seq profiling of HSPCs and BMDMs from mWSD-exposed juveniles supports a model in which HSPCs transmit pro-inflammatory memory to myeloid cells beginning in utero. These findings demonstrate that maternal diet alters long-term immune cell developmental programming in HSPCs with proposed consequences for chronic diseases featuring altered immune/inflammatory activation across the lifespan.
Project description:Adult hematopoietic stem cells (HSCs) respond directly to inflammation and infection, resulting in both acute and persistent changes in quiescence, mobilization, and differentiation. Here we show that fetal HSCs respond to maternal inflammation in utero, and the fetal response drives long-term changes to postnatal hematopoiesis and immunity. Heterogeneous fetal hematopoietic stem and progenitor cells (HSPCs) show divergent responses to maternal immune activation (MIA), including changes in quiescence, expansion, and immune cell output. Single cell transcriptomic analysis of fetal HSPCs reveals specific upregulation of inflammation-responsive genes in discrete populations, in response to upregulated IFNα and IL-1α in the fetal liver cytokine milieu. Postnatally, MIA caused the inappropriate expansion and persistence of transient progenitors, concomitant with increased cellularity and hyper-responsiveness of fetal-derived immune cells. Our investigation demonstrates how inflammation in utero can direct the trajectory of hematopoiesis and immunity by reshaping fetal HSC establishment.
Project description:Adult hematopoietic stem cells (HSCs) respond directly to inflammation and infection, resulting in both acute and persistent changes in quiescence, mobilization, and differentiation. Here we show that fetal HSCs respond to maternal inflammation in utero, and the fetal response drives long-term changes to postnatal hematopoiesis and immunity. Heterogeneous fetal hematopoietic stem and progenitor cells (HSPCs) show divergent responses to maternal immune activation (MIA), including changes in quiescence, expansion, and immune cell output. Single cell transcriptomic analysis of fetal HSPCs reveals specific upregulation of inflammation-responsive genes in discrete populations, in response to upregulated IFNα and IL-1α in the fetal liver cytokine milieu. Postnatally, MIA caused the inappropriate expansion and persistence of transient progenitors, concomitant with increased cellularity and hyper-responsiveness of fetal-derived immune cells. Our investigation demonstrates how inflammation in utero can direct the trajectory of hematopoiesis and immunity by reshaping fetal HSC establishment.