Effect of Maternal IBD, Microbiome and Early Life Events on the Bacterial Colonization and Mucosal Immunity in the Offspring

母体 IBD、微生物组和早期生活事件对后代细菌定植和粘膜免疫的影响

基本信息

批准号：
10469405
负责人：
Jose C Clemente
金额：
$ 21.13万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-13 至 2024-07-31
项目状态：
已结题

项目摘要

SUMMARY Inflammatory bowel disease (IBD) is a chronic condition of the gastrointestinal tract that is caused by the loss of mucosal tolerance towards the commensal microbiota resulting in chronic inflammation. Importantly, IBD affects women during their reproductive years and 25% become pregnant after their initial diagnosis. The bacterial composition in the gut, or microbiome, has emerged as an important determinant of IBD pathogenesis. Moreover, increasing evidence suggests that early life exposures may modulate the risk of IBD later in life and that maternal health and microbiota composition during pregnancy may influence the baby’s gut colonization and play an essential role in shaping the immune system. We demonstrated that pregnant women with IBD and their babies have a significantly less diverse and more pro-inflammatory microbiota compared to no-IBD controls, and that the microbiome of 3-month old babies born to IBD mothers, when inoculated into germ-free mice, triggers the development of an imbalanced immune system. Yet, it remains largely unknown how maternal IBD and other early life events affect the offspring’s microbiome assembly and mucosal immunity. Therefore, the objectives of this proposal are to 1) track particular bacterial strains originated from or informed by the maternal gut microbiota, bacterial metabolites in the umbilical cord blood, and inflammatory proteins in the breast milk that colonize the gut of babies born to mothers with and without IBD; 2) determine how maternal IBD and other early life events can modify the priming of the initial microbiome and mucosal immunity, and 3) validate if bacterial strains or metabolites enriched in babies born to mothers with IBD are detected in high IBD risk first degree relatives prior to IBD diagnosis using two independent cohorts. We will expand on the ongoing MECONIUM (MEChanisms Of disease traNsmission In Utero through the Microbiome) study that follows 430 pregnant women with and without IBD and their babies with >5,500 samples collected. We will use extensive data, including 16S rRNA gene sequencing during pregnancy and in babies at numerous time points over the first 3 years of life, metagenomic data on mother-baby pairs, cord blood metabolomics, and breast milk proteomics, coupled with health status, clinical information, medications, mode of delivery, feeding behavior, etc., to identify the sources and predictors of the early microbiome colonization. Next, given that fecal calprotectin is a significant predictor of IBD incidence in high risk individuals, we will characterize the degree of mucosal inflammation, assessed by fecal calprotectin, in babies born to mothers with and without IBD. This multifaceted study will shed new light on the origin and maturation of the early life microbiome in the setting of maternal health and disease during the most sensitive time for the priming of the immune system. Study findings, validated in two independent prospective cohorts, can help develop novel strategies for early interventions to minimize disease transmission, and foster the development of a healthy microbiome.

概括炎症性肠病（IBD）是胃肠道的慢性病，是由损失造成的对共生微生物群的粘膜耐受性，导致慢性感染。重要的是，IBD 在生殖年中影响妇女，并在初次诊断后怀孕25％。这肠道或微生物组中的细菌组成已成为IBD的重要决定因素发病。此外，越来越多的证据表明，早期生活暴露可能会调节IBD的风险生命的后期以及怀孕期间的母校健康和微生物群的组成可能会影响婴儿的肠道殖民化并在塑造免疫系统中起着至关重要的作用。我们证明了孕妇与IBD及其婴儿相比无IBD的控制，以及IBD母亲出生的3个月大婴儿的微生物组，当无菌小鼠，触发了不平衡免疫系统的发展。然而，它仍然很未知 IBD主要和其他早期生活事件如何影响后代的微生物组装和粘膜免疫。因此，该提案的目标是1）跟踪特定的细菌菌株起源于或由母体肠道微生物群，脐带血液中的细菌代谢物和炎症告知母乳中的蛋白质在有或没有IBD的母亲出生的婴儿肠道上定居； 2）确定 IBD主要和其他早期生活事件如何改变初始微生物组和粘膜的启动免疫力和3）验证IBD母亲出生的婴儿富含细菌菌株或代谢产物是在IBD诊断之前使用两个独立队列在IBD诊断之前检测到一级亲戚。我们将扩展正在进行的胎粪（子宫内疾病传播的机理通过微生物组）研究了430名有和没有IBD的孕妇及其婴儿，收集了> 5500个样本。我们将使用广泛的数据，包括怀孕期间的16 s rRNA基因测序以及在许多人中的婴儿时间点在生命的头三年中，母子对的宏基因组数据，脐带血代谢组学，和母乳蛋白质组学，再加上健康状况，临床信息，药物，分娩方式，喂养行为等，以识别早期微生物组定植的来源和预测指标。接下来，给出粪便钙甲染素是高风险个体中IBD事件的重要预测指标，我们将表征粪便炎症程度，由粪便钙骨蛋白评估，在有和没有的母亲出生的婴儿中 IBD。这项多方面的研究将为早期生平微生物组的起源和成熟提供新的启示在最敏感的时期启动免疫系统时，孕产妇健康和疾病的设置。在两个独立的前瞻性队列中验证的研究结果可以帮助制定早期的新策略干预措施以最大程度地减少疾病的传播，并促进健康微生物组的发展。