Role of B. infantis in Development of Atopic Diseases

婴儿双歧杆菌在特应性疾病发展中的作用

基本信息

批准号：
10286718
负责人：
Kirsi Jarvinen-Seppo
金额：
$ 27.07万
依托单位：
UNIVERSITY OF ROCHESTER
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：
2021-06-16 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10286718
关键词：
Acetates Allergic Disease Allergic inflammation Allergic rhinitis American Animal Model Anti-Allergic Agents Anti-Inflammatory Agents Asthma Atopic Dermatitis Attenuated Back Bangladesh Bifidobacterium Bioreactors Breastfed infant Cell Differentiation process Cell Line Cell Maturation Cell physiology Cells Communities Country Data Dendritic Cells Dendritic cell activation Development Disease Epithelial Cells Exposure to Extinction (Psychology)Farming environment Feces Food Hypersensitivity Freezing Funding Future Genome Genomics Gnotobiotic Health Benefit Human Milk Immunity In Vitro Individual Infant Intervention Life Life Style Mennonite Metabolic Metagenomics Modeling Modernization Mouse Strains Mucous Membrane Oligosaccharides Outcome Parents Phylogenetic Analysis Pilot Projects Population Prevention Prevention trial Primary Prevention Probiotics Production Public Health Regulatory T-Lymphocyte Risk Role Shotguns Societies Supplementation T-Lymphocyte Testing United States United States National Institutes of Health Volatile Fatty Acids atopy cohort comparative genomics cytokine experimental study gastrointestinal epithelium gut colonization gut dysbiosis improved in vivo infant gut microbiome intestinal epithelium intraepithelial metabolic phenotype metabolic profile metabolome metabolomics microbiome mouse model prevent response stool sample suburb vaccine response

项目摘要

A large body of data, including our own studies in the Old Order Mennonites (OOM), suggests that living on farms is associated with a lower risk of food allergy, asthma and other atopic diseases, compared to urban living. While increasing evidence indicates that gut dysbiosis precedes the development of atopy, atopic eczema and food allergy/sensitization, the role of infant gut microbiome in protection against atopic diseases in the farm lifestyle communities are lacking. Our preliminary data in the OOM pilot study suggest enrichment of Bifidobacteria, especially Bifidobacterium longum ssp. infantis (i.e., B. infantis) both in the rate of gut colonization as well as in abundance in the OOM compared to urban/suburban Rochester infants. In the United States, the majority of breastfed infants lack colonization with B. infantis, suggesting extinction in modern societies, while in countries such as Bangladesh, colonization with B. infantis is found in >90% of infants in an overwhelming abundance. Access to a North American community, such as the OOM with a lifestyle dating back 100 years and unusually high rates of B. infantis colonization provides an unprecedented opportunity to assess the impact of B. infantis and strain differences for their anti-allergic potential. Bifidobacteria have been shown to predominantly colonize breastfed infants and have major health benefits compared to those lacking Bifidobacteria due to their improved barrier function and ability to metabolize human milk oligosaccharides (HMOs), resulting in lower stool pH and short-chain fatty acid (SCFA) production. Specifically, B. infantis has been shown to be anti-inflammatory in intestinal epithelial cells and to attenuate allergic inflammation in animal models. B. infantis associated with enhanced vaccine responses in infants, and an increase in stool levels of lactate, also seen in our preliminary studies. However, B. infantis strains differ in their metabolic function and strain differences associated with protection against allergic diseases have not been assessed. We hypothesize that despite their genomic (and phylogenetic) similarities, B. infantis strains vary significantly in their metabolic phenotypes with broad implications to microbiome function. This project will utilize stool samples from an active NIH-funded longitudinal infant cohort including OOM farm-life and Rochester urban/suburban infants. Frozen and fresh stool samples will be characterized for B. infantis genomic and functional differences and associated metabolites as well as their anti-inflammatory potential to pick the most promising candidate strains. They will be further down selected in a gnotobiotic animal model for their potential to prevent food allergy. These studies aim to develop strategies for future prevention trials. 1

大量数据，包括我们自己对旧秩序门诺派 (OOM) 的研究，表明生活与城市相比，农场的食物过敏、哮喘和其他特应性疾病的风险较低活的。虽然越来越多的证据表明肠道菌群失调先于特应性的发展，但特应性湿疹和食物过敏/致敏，婴儿肠道微生物组在预防特应性疾病中的作用农场生活方式中缺乏社区。我们在 OOM 试点研究中的初步数据表明双歧杆菌，特别是长双歧杆菌亚种的富集。婴儿（即婴儿双歧杆菌）都在与城市/郊区相比，OOM 中的肠道定植率以及丰度罗切斯特婴儿。在美国，大多数母乳喂养的婴儿缺乏婴儿双歧杆菌定植，这表明在现代社会中已经灭绝，而在孟加拉国等国家，婴儿双歧杆菌的殖民化在 >90% 的婴儿中发现其含量极其丰富。进入北美社区，例如 OOM 的生活方式可以追溯到 100 年前，并且婴儿双歧杆菌定殖率异常高，这提供了这是一个前所未有的机会来评估婴儿双歧杆菌及其菌株差异对其抗过敏的影响潜在的。双歧杆菌已被证明主要定植于母乳喂养的婴儿，并且对健康有重大影响与那些缺乏双歧杆菌的细菌相比，由于双歧杆菌改善了屏障功能和能力，因此具有优势代谢母乳寡糖 (HMO)，导致粪便 pH 值和短链脂肪酸降低（SCFA）生产。具体来说，婴儿双歧杆菌已被证明对肠上皮细胞具有抗炎作用并减轻动物模型中的过敏性炎症。与增强型疫苗相关的婴儿双歧杆菌我们的初步研究中也发现了婴儿的反应以及粪便中乳酸水平的增加。然而，婴儿双歧杆菌菌株的代谢功能和与保护相关的菌株差异不同尚未评估其对过敏性疾病的作用。我们假设尽管他们的基因组（和系统发育）相似性，婴儿双歧杆菌菌株的代谢表型差异显着，具有广泛的对微生物组功能的影响。该项目将利用来自 NIH 资助的活跃机构的粪便样本纵向婴儿队列包括 OOM 农场生活和罗切斯特城市/郊区婴儿。冷冻和新鲜粪便样本将被表征为婴儿双歧杆菌基因组和功能差异以及相关的代谢物及其抗炎潜力，以选择最有希望的候选菌株。他们会由于其预防食物过敏的潜力，在限生动物模型中进一步被选择。这些研究旨在制定未来预防试验的策略。 1