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最初几年中积累了细菌多样性，并起着至关重要的作用

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.