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

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/10469405
• 关键词: 16S ribosomal RNA sequencing; Affect; Antibiotics; Bacteria; Bifidobacterium; Biological Markers; Child; Childhood; Chronic; Clinical; Clinical Trials; Colon; Complex; Coupled; Crohn' s disease; Data; Development; Diagnosis; Disease; Early Intervention; Event; Exhibits; Exposure to; Family; Fathers; Feces; Feeding behaviors; First Degree Relative; Fostering; Gastrointestinal tract structure; Genetic Predisposition to Disease; Germ-Free; Health; Health Status; Human Milk; Immune; Immune system; Immunoglobulin Class Switching; Incidence; Individual; Infant; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Intestines; Leukocyte L1 Antigen Complex; Life; Light; Maternal Health; Maternal-Fetal Transmission; Memory B-Lymphocyte; Metabolic; Metagenomics; Mothers; Mucosal Immunity; Mucositis; Mucous Membrane; Mus; Outcome; Pathogenesis; Patients; Persons; Pharmaceutical Preparations; Play; Pregnancy; Pregnancy Complications; Pregnant Women; Prospective Studies; Prospective cohort; Proteins; Proteobacteria; Proteomics; Regulatory T-Lymphocyte; Risk; Risk Factors; Role; Sampling; Shapes; Source; Testing; Time; Ulcerative Colitis; Umbilical Cord Blood; Validation; Woman; bacterial community; cohort; commensal microbes; disease diagnosis; disease transmission; disorder control; disorder risk; early life exposure; gut colonization; gut dysbiosis; gut inflammation; gut microbiome; gut microbiota; healthy pregnancy; high risk; inflammatory marker; insight; maternal microbiota; metabolomics; microbial; microbial colonization; microbiome; microbiome composition; microbiome research; microbiota; novel strategies; offspring; oral microbiome; postnatal; pregnant; prospective; recruit; reproductive; transmission process; vaginal microbiome

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.

摘要 炎症性肠病(IBD)是一种慢性胃肠道疾病，是由肠道失血引起的 粘膜对共生微生物区系的耐受性导致慢性炎症。重要的是，IBD 妇女在育龄期间会受到影响，25%的妇女在初次诊断后怀孕。这个 肠道中的细菌组成，或微生物组，已成为IBD的一个重要决定因素 发病机制。此外，越来越多的证据表明，早期生活中的暴露可能会调节IBD的风险。 孕妇的健康状况和孕期的微生物群组成可能会影响婴儿的肠道 并在塑造免疫系统方面起着至关重要的作用。我们证明了孕妇 与IBD和他们的婴儿相比，他们的IBD患者和他们的婴儿的微生物区系明显不那么多样化，更容易发炎 无IBD控制，当IBD母亲所生的3个月大的婴儿接种到 无菌小鼠，会引发免疫系统失衡。然而，它在很大程度上仍不为人所知。 母体IBD和其他早期生活事件如何影响后代的微生物群组装和粘膜 豁免权。因此，这项建议的目标是1)追踪源自或 由母体肠道微生物区系、脐带血中的细菌代谢物和炎性 患有和不患有IBD的母亲所生婴儿肠道中的母乳蛋白质；2)确定 母体IBD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，以及3)验证患有IBD的母亲所生婴儿的细菌菌株或代谢物是否丰富 使用两个独立的队列，在诊断IBD之前，在IBD高危一级亲属中检测到。我们会 展开正在进行的胎粪(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名患有和不患有IBD的孕妇及其婴儿，采集了5500份样本。 我们将使用广泛的数据，包括怀孕期间和许多婴儿的16S rRNA基因测序。 生命头三年的时间点，关于母婴配对的元基因组数据，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、 摄食行为等，以确定微生物群早期定植的来源和预测因素。接下来，给出 粪便钙保护素是IBD高危个体发病率的重要预测因子，我们将对 通过粪便钙保护素评估有无母亲所生婴儿的粘膜炎症程度 IBD。这一多方面的研究将为早期生命微生物群的起源和成熟提供新的线索。 将产妇的健康和疾病设定在最敏感的时期，为免疫系统做好准备。 研究结果在两个独立的前瞻性队列中得到验证，可以帮助开发新的早期策略 采取干预措施，最大限度地减少疾病传播，并促进健康微生物群的发展。

项目成果

Corrigendum to: Influence of Early Life Factors, including breast milk Composition, on the Microbiome of Infants Born to Mothers with and without Inflammatory Bowel Disease.

勘误表：早期生活因素（包括母乳成分）对患有或不患有炎症性肠病的母亲所生婴儿微生物组的影响。

• DOI: 10.1093/ecco-jcc/jjae021
• 发表时间: 2024
• 期刊: Journal of Crohn's & colitis