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) 是一种胃肠道慢性疾病，是由于肠道菌群丧失而引起的。粘膜对共生微生物群的耐受性导致慢性炎症。影响育龄妇女，25% 在初次诊断后怀孕。肠道细菌组成或微生物组已成为 IBD 的重要决定因素此外，越来越多的证据表明，早期接触可能会调节 IBD 的风险。生命后期以及怀孕期间的母亲健康和微生物群组成可能会影响婴儿的肠道我们证明了孕妇的定植并在塑造免疫系统方面发挥着重要作用。与 IBD 患者相比，他们的婴儿的微生物群多样性明显较低，但促炎性微生物群较多无 IBD 对照，并且 IBD 母亲所生的 3 个月大婴儿接种疫苗后的微生物组无菌小鼠会引发免疫系统失衡的发展，但人们对此仍知之甚少。母亲 IBD 和其他早期生活事件如何影响后代的微生物组组装和粘膜因此，本提案的目标是 1) 追踪源自或的特定细菌菌株。由母体肠道微生物群、脐带血中的细菌代谢物和炎症提供信息母乳中的蛋白质定植于患有或未患有 IBD 的母亲所生婴儿的肠道中 2) 确定；母亲 IBD 和其他早期生命事件如何改变初始微生物组和粘膜的启动免疫力，以及 3) 验证 IBD 母亲所生婴儿中富含的细菌菌株或代谢物是否我们将在 IBD 诊断之前使用两个独立队列在高 IBD 风险一级亲属中检测到。扩展正在进行的胎粪（通过微生物组在子宫内传播疾病的机制）这项研究跟踪了 430 名患有或不患有 IBD 的孕妇及其婴儿，收集了超过 5,500 个样本。我们将使用大量数据，包括怀孕期间和婴儿时期的 16S rRNA 基因测序生命前 3 年的时间点、母婴对的宏基因组数据、脐带血代谢组学、和母乳蛋白质组学，加上健康状况、临床信息、药物、分娩方式，喂养行为等，以确定早期微生物定植的来源和预测因子。由于粪便钙卫蛋白是高危人群 IBD 发病率的重要预测因子，我们将描述通过粪便钙卫蛋白评估患有或不患有这种疾病的母亲所生婴儿的粘膜炎症程度 IBD。这项多方面的研究将为早期生命微生物组的起源和成熟提供新的线索。在免疫系统启动最敏感的时期设置孕产妇健康和疾病。研究结果在两个独立的前瞻性队列中得到验证，可以帮助制定早期的新策略最大限度地减少疾病传播并促进健康微生物群发展的干预措施。