Maternal obesity and immune developmental programming, role of the microbiome

摘要 母亲营养不良和怀孕期间肥胖与更高的发病率有关 慢性疾病，包括心血管疾病、儿童哮喘和糖尿病。其中许多 并发症可能是由高脂肪饮食(Hfd)在子宫内引起的常见的潜在免疫缺陷引起的。 和/或母亲肥胖状态的并发症。这将使用一种非人类灵长类动物进行研究 (NHP)模式，即在繁殖期间，在繁殖前给狒狒喂高卡路里/高脂肪饮食(HFD)。 怀孕和哺乳。已经证明，喂食HFD的母亲的雌性后代有 出生体重显著增加，并在至少6个月大的时候继续增加体重。然而， 男性HFD后代的体重与其对照组相比没有显着差异，这表明 怀孕期间母亲肥胖/过度喂养对发育的影响将存在性别偏见。因此， 我们将评估HFD雄性和雌性后代的免疫系统个体发育和功能 控制喂养的母亲；目前这些动物都在两岁半以下，所以发育延迟是由于 子宫内环境应该仍然是明显的。然而，我们也将使用以下工具检查出生前HFD的影响 从两个HFD患者妊娠第165天剖腹产采集的组织 和控制群组。有针对性地检测的免疫参数包括：1)T细胞 胎儿胸腺的成熟和选择(这是一种早期事件，对胎儿胸腺的正常发育至关重要 适应性免疫系统)，ii)反映对造血干细胞和谱系的影响的血细胞亚群 发展，iii)组织、血清和诱导的细胞因子，作为增加基线炎症的衡量标准， 和四)淋巴细胞的转录组分析，作为一种无偏见的方法，以确定其基因 表达模式会因子宫内环境而改变。对于所有的化验，包括男性和女性 后代/胎儿材料将被用来解决可疑的性别偏见。鉴于新生的孩子 最初在出生时从母体微生物群中定居，免疫发育高度依赖于 在微生物群提供的触发因素上，我们假设将存在潜在的机制联系 这两者都会受到怀孕期间母亲饮食的共同影响。因此，在第二个具体目标中，我们 将表征肠道微生物群的多样性和结构，并确定子宫内的 营养状况会影响这些特征。像这样的NHP研究旨在模拟人类健康 挑战。大约33%的育龄妇女被描述为肥胖，这确实是 关键是评估这些高危妊娠的潜在发育结局，以便 制定策略，将下游病症降至最低。

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.