Project 3 Identification of Microbial Founder Species and Metabolic Products that Promote Microbiota and Immune Development Resilient to Childhood Allergy and Asthma

肠道微生物组在生命的最初几年积累细菌多样性，并在其中发挥关键作用。 在免疫发育中的作用，包括通过产生微生物衍生的代谢物， 如短链和多不饱和脂肪酸。我们和其他人已经证明， 过敏性致敏或哮喘，表现出一致的细菌属消耗和代谢紊乱， 婴儿期。相对于那些处于疾病发展低风险的人， 生活高风险肠道微生物组诱导辅助性T细胞2的扩增和活性，并降低 体外调节性T细胞。因此，这意味着非常早期的肠道微生物组，通过微生物来源的 代谢产物，以与儿童疾病或健康一致的方式塑造新生免疫功能。我们 最近的研究表明，哮喘高危婴儿的胎粪微生物组（至少有一个 哮喘父母）与低风险新生儿不同，并表现出显著延迟的细菌感染。 在生命的第一年多样化的轨迹，涉及垂直传播的基础差异， 肠道微生物和随后的肠道微生物组和免疫发育。因此，人类肠道微生物组 似乎坚持初级演替的原则，在原始的物种多样化的过程中， 生态系统，其核心是创始者（或先驱）物种（即那些首先殖民的物种）， 生态系统条件以及随后物种积累的速度和轨迹。我们因此 假设在那些预防过敏和哮喘发展的儿童中， 微生物组菌株，更具体地说，它们的代谢产物，促进免疫耐受， 随后在整个儿童期免疫和微生物发育，防止疾病发展。 P3旨在建立在我们以前的研究基础上，并使用来自 已知10年过敏性致敏和哮喘结局并前瞻性收集的WHEALS 本P01中来自过敏性哮喘高危儿童的母婴配对的纵向样本 表型（HiRAAP）或过敏性哮喘低风险表型（LoRAAP）。P3建议 鉴定促进与保护相关的免疫功能的早期肠道微生物衍生代谢物 针对儿童期过敏性哮喘的发展，确定其微生物来源，并根据 这些发现测试了一种新的微生物多生物素的能力，以塑造免疫功能， 小鼠气道过敏性致敏。这项研究将推进我们对肠道微生物菌株和 他们的产品对儿童过敏性哮喘的发展具有保护性免疫力， 为疾病的初级预防奠定基础。

The gut microbiome accumulates bacterial diversity over the first several years of life, and plays a critical role in immune development including immune tolerance via production of microbial-derived metabolites such as short chain and polyunsaturated fatty acids. We and others have demonstrated that children who develop allergic sensitization or asthma, exhibit consistent bacterial genera depletions and metabolic perturbations in infancy. Relative to those at low-risk of disease development, the associated products of the perturbed, early life high-risk gut microbiome induce expansion and activity of T-helper 2 cells and reduce the frequency of regulatory T cells in vitro. Thus, the implication is that the very early-life gut microbiome, via microbial-derived metabolites, shapes nascent immune function in a manner consistent with disease or health in childhood. Our most recent studies indicate that the meconium microbiome of high-risk for asthma infants (with at least one asthmatic parent) is distinct from that of low-risk neonates, and exhibits a significantly delayed bacterial diversification trajectory over the first year of life, implicating differences in vertically transmitted foundational gut microbes and subsequent gut microbiome and immune development. Thus, the human gut microbiome appears to adhere to the tenets of primary succession, the process of species diversification in a pristine ecosystem, central to which is the tenet that founder (or pioneer) species, (i.e. those that first colonize), shape ecosystem conditions and thus the pace and trajectory of subsequent species accumulation. We thus hypothesize that in those children protected against allergy and asthma development, specific early-life gut microbiome strains, and more specifically, their metabolic products, promote immune tolerance which shapes subsequent immune and microbial development throughout childhood protecting against disease development. P3 aims to build upon our previous studies and address this hypothesis using both banked samples from WHEALS for which 10-year allergic sensitization and asthma outcomes are known, and prospectively collected longitudinal samples in this P01 from mother-infant dyads in children with a High Risk for Allergic Asthma Phenotype (HiRAAP) or Low Risk for Allergic Asthma Phenotype (LoRAAP) at age 2 years. P3 proposes to identify early-life gut microbial derived metabolites that promote immune functions associated with protection against allergic asthma development in childhood, identify their microbial source, and develop and, based on these findings, test a novel microbial polybiotic for its capacity to shape immune function and protect against airway allergic sensitization in mice. This study will advance our knowledge of how gut microbial strains and their products program protective immunity against childhood allergic asthma development, and serve as a foundation for primary prevention of the disease.