Maternal obesity and immune developmental programming, role of the microbiome

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ABSTRACT Poor maternal nutrition and obesity during pregnancy have been associated with a higher incidence of chronic diseases including cardiovascular disorders, childhood asthma and diabetes. Many of these complications could be due to common underlying immune deficits elicited in utero by a high fat diet (HFD) and/or complications of the mother's obese state. This will be investigated using a nonhuman primate (NHP) model whereby baboons are fed a high calorie/high fat diet (HFD) prior to breeding, during pregnancy and lactation. It has been demonstrated that the female offspring of HFD-fed mothers have significantly higher birth weights and continue to be heavier through at least 6 months of age. However, the male HFD offspring do not show a significant difference in weight relative to their controls suggesting that there will be a sex bias in developmental effects of maternal obesity/over-feeding during pregnancy. Thus, we will assess immune system ontogeny and function in both male and female offspring of HFD and control-fed mothers; currently these animals are all under 2½ years of age, so developmental delays due to the in utero environment should still be evident. However, we will also examine pre-natal HFD effects using tissues that were harvested from fetuses collected by C-section at day 165 of fetal gestation from both HFD and control cohorts. The immune parameters to be examined in Specific Aim I include the following: i) T cell maturation and selection in the fetal thymus (an early event that is critical for proper development of the adaptive immune system), ii) blood cell subsets reflecting effects on hematopoietic stem cells and lineage development, iii) tissue, serum, and induced cytokines as a measure of increased baseline inflammation, and iv) transcriptome analysis of lymphocytes as an unbiased approach to identify genes whose expression patterns are altered by the in utero environment. For all assays, both male and female offspring/fetal materials will be used to address a suspected gender-bias. Given that newborn children are initially colonized at birth from the maternal microbiome and that immune development is highly dependent on triggers provided by the microbiome, we hypothesize that there will be an underlying mechanistic link and that both will be affected in concert by the maternal diet during pregnancy. Thus, in Specific Aim II, we will characterize the diversity and structure of the gut microbiome and determine whether the in utero nutritional status affects these profiles. NHP studies like this one are intended to model human health challenges. With approximately 33% of women of child-bearing age characterized as obese, it is indeed critical to assess the potential developmental consquences of these high risk pregnancies in order to develop strategies to minimize downstream pathologies.