Role of B. infantis in Development of Atopic Diseases

大量数据，包括我们自己对旧秩序门诺派(OOM)的研究，表明生活在 与城市相比，农场里的人患食物过敏、哮喘和其他过敏性疾病的风险更低 活着。虽然越来越多的证据表明，肠道生态失调先于特应性、特应性 湿疹与食物过敏/致敏：婴儿肠道微生物群在预防特应性疾病中的作用 在农场里，缺乏生活方式社区。我们在OOM试点研究中的初步数据表明 浓缩双歧杆菌，尤其是长双歧杆菌SSP。婴儿(即婴儿双胞菌) 与城市/郊区相比，OOM的肠道定殖率以及肠道丰度 罗切斯特婴儿。在美国，大多数母乳喂养的婴儿没有感染婴儿芽胞杆菌， 暗示着现代社会的灭绝，而在孟加拉国等国家，带有婴儿巴氏杆菌的殖民 在90%的婴儿体内发现，含量高得惊人。进入北美社区，例如 OOM的生活方式可以追溯到100年前，婴儿芽胞杆菌的定殖率异常高，提供了 一个前所未有的机会来评估婴儿芽孢杆菌的影响和菌株差异对他们的抗过敏作用 潜力。 双歧杆菌已被证明主要定植于母乳喂养的婴儿，并有很大的健康 与那些缺乏双歧杆菌的人相比，由于他们改善了屏障功能和能力 代谢人乳低聚糖(HMOS)，导致粪便pH值和短链脂肪酸降低 (SCFA)生产。具体地说，婴儿巴氏杆菌已被证明在肠道上皮细胞中具有抗炎作用。 并减轻动物模型中的过敏性炎症。B.与增强型疫苗相关的婴儿 婴儿的反应，以及大便乳酸水平的增加，也在我们的初步研究中看到。 然而，婴儿芽孢杆菌的菌株在其代谢功能和与保护相关的菌株差异上有所不同。 治疗过敏性疾病的效果还没有得到评估。我们假设，尽管它们的基因组(和 系统发育)相似性，婴儿芽孢杆菌的代谢表型差异很大，具有广泛的 对微生物组功能的影响。该项目将利用NIH资助的一个活跃的粪便样本 纵向婴儿队列包括OOM农场生活和罗切斯特城市/郊区婴儿。冰冻和新鲜 粪便样本将表征婴儿双胞菌的基因组和功能差异，并与 代谢物以及它们的抗炎潜力，以挑选最有希望的候选菌株。他们会 在灵知生菌动物模型中进一步筛选出它们预防食物过敏的潜力。这些研究 目的为未来的预防试验制定战略。 1

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