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

• 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
• 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

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，包括我们自己的旧阶门诺派（OOM）的研究，表明生活 与城市相比 活的。越来越多的证据表明，肠道营养不良先于特亚特氏病的发展 湿疹和食物过敏/敏化，婴儿肠道微生物组在保护特应疾病中的作用 在农场生活方式社区中缺乏。我们在OOM试点研究中的初步数据建议 双歧杆菌的富集，尤其是双歧杆菌SSP。婴儿（即B. infantis）都在 与城市/郊区相比 罗切斯特婴儿。在美国，大多数母乳喂养的婴儿缺乏婴儿芽孢杆菌的定殖， 暗示在现代社会中灭绝，而在孟加拉国等国家 / 在> 90％的婴儿中发现了压倒性的丰度。进入北美社区，例如 具有生活方式的OOM可追溯到100年，而Infantis殖民的率异常高。 一个前所未有的机会，可以评估婴儿芽孢杆菌的影响和应变差异对其抗过敏性的影响 潜在的。 双歧杆菌已被证明主要是在母乳喂养的婴儿中定居 与缺乏双歧杆菌的障碍功能和能力相比 代谢人牛奶寡糖（HMOS），导致粪便较低和短链脂肪酸 （SCFA）生产。具体而言，肠B。在肠上皮细胞中已显示为抗炎 并减轻动物模型中的过敏性炎症。 B. Infantis与增强的疫苗有关 在我们的初步研究中也可以看到婴儿的反应，以及乳酸粪便水平的升高。 但是，婴儿芽孢杆菌菌株的代谢功能和应变差异与保护相关 针对过敏性疾病尚未评估。我们假设尽管它们具有基因组（并且 系统发育）相似性，婴儿芽孢杆菌菌株在其代谢表型中的差异显着差异 对微生物组函数的影响。该项目将利用活跃的NIH资助的粪便样品 纵向婴儿队列，包括OOM农场生活和罗切斯特城市/郊区婴儿。冷冻而新鲜 粪便样品的特征是胎B. infantis基因组和功能差异以及相关的功能差异 代谢物以及它们的抗炎潜力，以选择最有希望的候选菌株。他们会的 在gnotobiotic动物模型中选择进一步选择，以防止食物过敏。这些研究 旨在制定未来预防试验的策略。 1