Role of B. infantis in Development of Atopic Diseases

大量的数据，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，农场与食物过敏，哮喘和其他特应性疾病的风险较低有关 living.虽然越来越多的证据表明肠道生态失调先于特应性的发展， 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 在农场生活方式社区是缺乏的。我们在OOM试点研究中的初步数据表明， 富集双歧杆菌，特别是长双歧杆菌亚种。双（即，B。（二）在 与城市/郊区相比， 罗切斯特的婴儿。在美国，大多数母乳喂养的婴儿缺乏B定植。兄弟们， 这表明在现代社会灭绝，而在孟加拉国等国家，殖民与B。infantis 在超过90%的婴儿中发现了大量的。进入北美社区，如 OOM的生活方式可以追溯到100年前，B的比例异常高。美国的殖民化提供了 一个前所未有的机会来评估B的影响。抗过敏的菌种和菌株的差异 潜力 双歧杆菌已被证明主要定植于母乳喂养的婴儿， 与缺乏双歧杆菌的那些相比，由于其改善的屏障功能和 代谢人乳低聚糖（HMO），降低粪便pH值和短链脂肪酸 （SCFA）生产。具体来说，就是B。在肠上皮细胞中， 以及减轻动物模型中的过敏性炎症。B。与增强型疫苗相关的疾病 婴儿的反应，以及粪便中乳酸水平的增加，也在我们的初步研究中看到。 然而，B。大肠杆菌菌株的代谢功能和与保护相关的菌株差异不同 对过敏性疾病的影响尚未得到评估。我们假设，尽管他们的基因组（和 系统发育）相似性，B。大肠杆菌菌株在其代谢表型方面存在显著差异， 对微生物功能的影响。该项目将利用来自NIH资助的一个活跃的 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 粪便样品将被表征为B。基因组和功能差异以及相关的 代谢产物以及它们的抗炎潜力来挑选最有希望的候选菌株。他们将 在特定菌动物模型中进一步筛选它们预防食物过敏的潜力。这些研究 旨在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