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

怀孕期间的饮食和母亲肥胖：对母亲 TH17 和 Treg 细胞功能及后代健康的影响

• 批准号: 403349535
• 负责人: Professor Dr. Stefan Bonn
• 金额: --
• 依托单位: Klinik und Poliklinik für Allgemein-, Viszeral- und Thoraxchirurgie
• 依托单位国家: 德国
• 项目类别: Clinical Research Units
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2023-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/403349535?language=en
• 关键词: Diet; during; pregnancy; maternal; obesity

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.

目前，不仅在发达国家，而且在发展中国家，人们都看到前所未有的高糖、高脂肪和高盐饮食成分消费，通常被称为“西方”饮食，这被认为是肥胖的主要原因之一。很明显，越来越多的人由于社会经济状况而“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患有相关的代谢或心血管疾病。有趣的是，肥胖通常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产妇肥胖增加了怀孕并发症的风险，改变了胎儿发育，并导致儿童以后的健康状况不佳。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体肥胖使母体对妊娠的免疫适应，特别是对半同种异体胎儿产生耐受性所需的CD4 T细胞应答，偏向炎症。反过来，这种炎症会导致胎儿发育受损，后代在以后的生活中患炎性疾病的风险更高。考虑到饮食对肠道微生物群的组成具有关键影响，而肠道微生物群又与免疫系统持续相互作用，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群失衡介导。新的多细胞因子命运报告基因和条件性敲除小鼠模型将用于测试母体西方饮食是否通过不同CD4 T细胞亚群的功能改变影响胎儿发育和后代的免疫力。为了了解这些小鼠中饮食诱导变化的分子细节，我们将采用单细胞转录组学，表观遗传学和最先进的计算方法。为了将小鼠模型的机制见解转化为人类的相似性和差异性，我们将使用来自前瞻性妊娠队列PRINCE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关系。这将有助于确定新的治疗靶点，如致病性CD4 T细胞，以开发新的治疗方法，旨在防止后代因出生时的社会环境而遭受终身健康问题。