MATERNAL OBESITY AND IMMUNE DEVELOPMENTAL PROGRAMMING, ROLE OF THE MICROBIOME

Poor maternal nutrition and obesity during pregnancy have been associated with a higher incidence ofchronic diseases including cardiovascular disorders, childhood asthma and diabetes. Many of thesecomplications 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, duringpregnancy and lactation. It has been demonstrated that the female offspring of HFD-fed mothers havesignificantly higher birth weights and continue to be heavier through at least 6 months of age. However, themale HFD offspring do not show a significant difference in weight relative to their controls suggesting thatthere 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 andcontrol-fed mothers; currently these animals are all under 2 years of age, so developmental delays due tothe in utero environment should still be evident. However, we will also examine pre-natal HFD effects usingtissues that were harvested from fetuses collected by C-section at day 165 of fetal gestation from both HFDand control cohorts. The immune parameters to be examined in Specific Aim I include the following: i) T cellmaturation and selection in the fetal thymus (an early event that is critical for proper development of theadaptive immune system), ii) blood cell subsets reflecting effects on hematopoietic stem cells and lineagedevelopment, 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 whoseexpression patterns are altered by the in utero environment. For all assays, both male and femaleoffspring/fetal materials will be used to address a suspected gender-bias. Given that newborn children areinitially colonized at birth from the maternal microbiome and that immune development is highly dependenton triggers provided by the microbiome, we hypothesize that there will be an underlying mechanistic linkand that both will be affected in concert by the maternal diet during pregnancy. Thus, in Specific Aim II, wewill characterize the diversity and structure of the gut microbiome and determine whether the in uteronutritional status affects these profiles. NHP studies like this one are intended to model human healthchallenges. With approximately 33% of women of child-bearing age characterized as obese, it is indeedcritical to assess the potential developmental consquences of these high risk pregnancies in order todevelop strategies to minimize downstream pathologies.