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

肠道微生物群在生命的头几年积累了细菌多样性，并在 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，发展的儿童 过敏或哮喘，表现出持续的细菌属耗竭和代谢紊乱 婴儿期。相对于那些疾病发展风险较低的人，相关产物的心烦意乱，早期 生命高危肠道微生物群诱导T-Helper-2细胞扩增和活性，并降低T-Helper-2细胞的频率 体外调节性T细胞。因此，这意味着非常早期的肠道微生物群，通过微生物衍生 代谢物，以与儿童时期的疾病或健康相一致的方式塑造新生免疫功能。我们的 最近的研究表明，哮喘高危婴儿的胎粪微生物群(至少有一个 哮喘父母)与低风险新生儿不同，表现出显著延迟的细菌 生命第一年的多样化轨迹，暗示着垂直传播的基础 肠道微生物和随后的肠道微生物群和免疫发展。因此，人类肠道微生物群 似乎坚持了初级演替的原则，在物种多样化的过程中保持了原始 生态系统，其核心是创始人(或先驱)物种(即那些最先殖民的物种)塑造的宗旨 生态系统条件以及随后物种积累的速度和轨迹。因此，我们 假设在那些防止过敏和哮喘发展的儿童中，特定的早期肠道 微生物菌株，更具体地说，它们的代谢产物，促进免疫耐受，从而形成 随后的免疫和微生物在整个儿童时期的发育，防止疾病的发育。 P3旨在建立在我们之前研究的基础上，并使用以下两个库中的样本解决这一假设 已知10年过敏性致敏和哮喘结果的患者，并预期收集 本P01中的纵向样本来自过敏性哮喘高危儿童的母婴对偶 2岁时表现型(HiRAAP)或过敏性哮喘低风险表型(LoRAAP)。P3提议 鉴定早期肠道微生物衍生的代谢物，促进与保护相关的免疫功能 预防儿童过敏性哮喘的发展，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菌的形成免疫功能和预防疾病的能力 小鼠呼吸道过敏性致敏作用。这项研究将增进我们对肠道微生物菌株和 他们的产品针对儿童过敏性哮喘的发展提供保护性免疫，并作为一种 这是该疾病初级预防的基础。

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.