Diet during pregnancy and maternal obesity: effects on the function of maternal TH17 and Treg cells and on subsequent offspring health

对高糖、高脂肪和高盐饮食成分的史无前例的消费，通常被称为“西方”饮食，目前不仅在发达国家，在发展中国家也是如此，被认为是导致肥胖的主要原因之一。很明显，由于社会经济环境的原因，越来越多的人“被迫”食用这种饮食。根据世界卫生组织的数据，2014年，有6亿成年人患有肥胖症。他们中的许多人还被诊断出患有相关的代谢或心血管疾病。有趣的是，肥胖往往与免疫系统的慢性和病理活动有关。此外，流行病学数据表明，怀孕期间食用西方饮食和母亲肥胖增加了怀孕并发症的风险，改变了胎儿发育，并解释了儿童晚年健康状况不佳的原因。该项目旨在阐明这些效应背后的细胞和分子机制。主要的假设是，西方饮食和母亲肥胖扭曲了母亲对怀孕的免疫适应，特别是对半异基因胎儿建立耐受性所需的CD4T细胞反应，转向炎症。反过来，这种炎症会导致胎儿发育受损，并增加后代在以后的生活中患炎症性疾病的风险。考虑到饮食对肠道微生物区系的组成有关键影响，而肠道微生物区系又与免疫系统持续串扰，我们将测试饮食介导的炎症是否由西方饮食介导的母体微生物区系失衡所介导。新的多细胞因子命运报告和条件性基因敲除小鼠模型将被用来测试母体西方饮食是否通过改变不同的CD4T细胞亚群的功能来影响胎儿发育和后代的免疫。为了了解饮食诱导这些小鼠变化的分子细节，我们将使用单细胞转录学、表观遗传学和最先进的计算方法。为了将小鼠模型的机械洞察力转化为人类的相似和不同之处，我们将使用来自预期怀孕队列王子的数据和生物样本。我们的项目将使我们能够确定西方饮食和后代免疫力低下之间的因果联系。这将有助于确定新的治疗目标，如致病的CD4T细胞，开发新的治疗方法，旨在防止后代因其出生的社会环境而不得不遭受终身健康问题。

Unprecedented consumption of high sugar, fat and salt dietary components, commonly referred to as “Western” diet, is currently observed not only in developed countries, but also in developing countries and is considered one of the leading causes of obesity. It is apparent that a growing number of individuals are “forced” to consume this diet due to socioeconomic circumstances. In the year 2014, according to the World Health Organization, 600 million adults suffered from obesity. Many of them were also diagnosed with related metabolic or cardiovascular diseases. Interestingly, obesity is often associated with chronic and pathological activity of the immune system. Furthermore, epidemiological data indicate that consumption of Western diet during pregnancy and maternal obesity increase the risk of pregnancy complications, alter foetal development and account for poor children’s health later in life. This project aims to elucidate the cellular and molecular mechanisms underlying these effects. The main hypothesis is that Western diet and maternal obesity skew the maternal immune adaptation to pregnancy, especially the CD4 T cell response required to mount tolerance towards the semi-allogeneic foetus, towards inflammation. In turn, this inflammation leads to impaired foetal development and higher risk for the offspring to develop inflammatory diseases later in life. Considering that diet has a pivotal impact on the composition of the intestinal microbiota, which in turn is in continuous cross talk with the immune system, we will test if diet-mediated inflammation is mediated by the Western diet mediated imbalance of the maternal microbiota. Novel multi-cytokine fate reporter and conditional knock out mouse models will be used to test if maternal Western diet affects foetal development and offspring’s immunity via an altered function of distinct CD4 T cell subsets. To understand the molecular details of diet-induced changes in these mice, we will employ single cell transcriptomics, epigenetics, and state-of-the-art computational approaches. To translate the mechanistic insights from the mouse models into similarities and differences in humans, we will use data and biological samples from the prospective pregnancy cohort PRINCE. Our project will allow us to identify the causative link between Western diet and poor offspring immunity. This will help to identify new therapeutic targets such as pathogenic CD4 T cells, to develop new therapies, which aim to prevent the offspring having to suffer life-long health problems due to the social circumstances in which they are born.