Nutrition and immunity in pregnancy: maternal responses and consequences for offspring

怀孕期间的营养和免疫：母亲的反应及其对后代的影响

• 批准号: MR/W007711/1
• 负责人: Sinead English
• 金额: $ 115.23万
• 依托单位: University of Bristol
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FW007711%2F1
• 关键词: Nutrition; immunity; pregnancy; maternal; responses

During pregnancy, the mother's immune system faces the task of protecting both the mother and her foetus. Mothers rely on nutrients to maintain their physiological condition and immune system, and also to nourish their developing offspring. A key question is: when mothers face challenges to their physiological state, how do they allocate energy to protect themselves and their offspring? When does this result in adverse outcomes, such as pre-term birth?To date, most research on pregnancy exposures involves long-term studies in humans or experiments on laboratory rodents or larger mammals. We have a solid understanding of how nutrition or infections in pregnancy influence birth timing and offspring development. Remarkably few studies have considered the interaction between nutrition and infections, potentially owing to the scale and complexity of studies involved, or because we have yet to develop a clear conceptual framework to develop testable hypotheses about this interaction.Here, I propose a project which tackles these two challenges head on: first, to develop a formal framework on the interplay between nutrition and infection in pregnancy, informed by evolutionary theory, and to test predictions using insect models of pregnancy, in parallel with analysis of datasets from contrasting human populations. I will first conduct a scoping review of human and animal model studies to identify the pathways linking nutrition, pathogen exposure and inflammatory responses in pregnant mothers, and consequences for offspring. I will then develop mathematical models to examine causality: how do energy trade-offs between defending against pathogens or nourishing offspring explain the optimal immune response across pregnancy stages?This formal framework will inform experiments in insects, which are extremely amenable with well-studied mechanisms, including highly conserved immune pathways found in vertebrates. Most research on insect immunity has focused on egg-laying Drosophila. I will use insects which experience pregnancy - tsetse flies and Pacific beetle cockroaches - to yield new insights on the complex interplay between maternal immune responses and nutrition. Both species exhibit almost mammalian pregnancy, nourishing their young with a milk-like substance from modified organs in utero. At the same time, they are evolutionary distant with contrasting diets, thus providing a unique opportunity to study both the specific and general machineries of pregnancy. I will expose pregnant females on diets varying in quantity or quality directly to pathogens, or indirectly activate their immune system. I will then measure responses of mothers and consequences for their young, in terms birth timing, body size and changes in physiology and gene expression.Lastly, I will examine patterns in two human cohort studies, in divergent contexts: the Children of the 90s study in the Bristol region, where diet quality and reported infections align with maternal socio-economic status, and data from the rural West Kiang region in The Gambia, a low-resource setting with strong seasonality in infections and food availability. I will compare how infections at different stages of pregnancy affect offspring, in terms of pre-term birth, child growth and later health, and how such effects change with maternal nutritional state.This project will provide fundamental insights into how maternal nutrition and immune responses interact to determine pregnancy outcomes and longer-term consequences for offspring, across diverse organisms. In the longer term, it can also inform policy to improve birth outcomes: for example, if immune activation in pregnancy cause an increased risk of pre-term birth, what are the nutritional interventions that could reduce this risk? Vaccines result in a mild immune response: what are the risks to mothers and offspring if administered early or late in pregnancy, and do these vary between under- or over-nourished mothers?

在怀孕期间，母亲的免疫系统面临着保护母亲和胎儿的任务。母亲依靠营养来维持生理状态和免疫系统，并滋养发育中的后代。一个关键问题是：当母亲面临生理状态的挑战时，她们如何分配精力来保护自己和后代？什么时候会导致不良后果，例如早产？迄今为止，大多数关于妊娠暴露的研究都涉及对人类的长期研究或对实验室啮齿动物或大型哺乳动物的实验。我们对怀孕期间的营养或感染如何影响出生时间和后代发育有着深入的了解。很少有研究考虑营养与感染之间的相互作用，这可能是由于所涉及研究的规模和复杂性，或者因为我们尚未开发出一个清晰的概念框架来对这种相互作用提出可检验的假设。在这里，我提出了一个项目来应对这两个挑战：首先，以进化论为基础，开发一个关于妊娠期营养与感染之间相互作用的正式框架，并使用昆虫模型来测试预测。 怀孕，同时分析对比人群的数据集。我将首先对人类和动物模型研究进行范围审查，以确定孕妇营养、病原体暴露和炎症反应之间的联系途径，以及对后代的影响。然后，我将开发数学模型来检验因果关系：防御病原体或滋养后代之间的能量权衡如何解释整个怀孕阶段的最佳免疫反应？这个正式的框架将为昆虫实验提供信息，昆虫非常适合经过充分研究的机制，包括在脊椎动物中发现的高度保守的免疫途径。大多数昆虫免疫研究都集中在产卵果蝇上。我将利用经历过怀孕的昆虫——采采蝇和太平洋甲虫蟑螂——来对母体免疫反应和营养之间复杂的相互作用产生新的见解。这两个物种都表现出几乎哺乳动物的怀孕状态，用子宫内经过改造的器官产生的类似牛奶的物质来滋养它们的幼崽。同时，它们在进化上与对比饮食相距甚远，从而为研究怀孕的特定和一般机制提供了独特的机会。我会让怀孕女性接受不同数量或质量的饮食，直接接触病原体，或间接激活她们的免疫系统。然后，我将衡量母亲的反应及其对孩子的影响，包括出生时间、体型以及生理和基因表达的变化。最后，我将在不同的背景下检查两项人类队列研究的模式：布里斯托尔地区的 90 年代儿童研究，其中饮食质量和报告的感染与母亲的社会经济地位一致，以及来自资源匮乏的冈比亚西江农村地区的数据 感染和食物供应具有强烈季节性的环境。我将比较怀孕不同阶段的感染如何影响后代，包括早产、儿童生长和后期健康，以及这些影响如何随母亲营养状态而变化。该项目将提供关于母亲营养和免疫反应如何相互作用的基本见解，以确定不同生物体的妊娠结局和对后代的长期影响。从长远来看，它还可以为改善出生结果的政策提供信息：例如，如果怀孕期间的免疫激活导致早产风险增加，那么可以降低这种风险的营养干预措施是什么？疫苗会产生温和的免疫反应：如果在怀孕早期或晚期接种，对母亲和后代有哪些风险？营养不良或营养过度的母亲之间的风险是否有所不同？