Targeting microbial dysbiosis in Food Allergy to restore tolerance

摘要 食物过敏（FA）已成为一个公共卫生问题，影响了相当一部分人口。尽管 由于其流行率的惊人增长，控制FA流行的努力受到了有限的 了解疾病的发病机制，特别是在这一过程中的作用，早期生活肠道生态失调。在这 关于这一点，我们的研究已经确定了免疫调节梭菌目和拟杆菌目物种的关键作用 通过诱导RORgt+ Treg细胞的分化来加强对FA的免疫耐受， FA. RORgt+ Treg细胞的早期生命扩增由梭菌目和拟杆菌目物种中的水华诱导 从母乳到固体食物的断奶过程中。这种扩张是由抵抗素样分子反调节的 β（α Mb），在FA受试者和小鼠中升高。因此，本提案的重点是阐明 早期生活生态失调促进FA的机制及其对疾病的长期影响 持久性和对微生物疗法的反应。我们假设微生物和免疫学变化 在生命的早期断奶为在一个过程中诱导对固体食物的耐受性提供了一个机会窗口 调节，其失调的生态失调促进FA（目的1）。我们还假设， RORgt+ Treg细胞群的无效分化和Th2细胞样Treg的相互出现 细胞的不平衡，我们已经确定在FA中发挥重要作用，促进疾病的发病机制 通过许可IgE抗食物和抗细菌抗体反应（目标2）。最后，我们假设产品 和各个免疫调节细菌菌株的代谢物，包括Toll样受体激活剂、芳基 碳氢化合物受体配体和次级胆汁酸，通过促进RORgt+， Treg细胞分化（Aim 3）。拟议的研究将提供与以下方面有关的基本新见解： FA的发病机制，并提供了新的机会，在早期生活疾病的干预和治疗。

ABSTRACT Food allergy (FA) has become a public health concern, affecting a sizeable segment of the population. Despite the alarming increase in its prevalence, efforts to contain the FA epidemic have been stymied by the limited understanding of disease pathogenesis, especially the role in this process of early life gut dysbiosis. In that regard, our studies have established a critical role for immunomodulatory Clostridiales and Bacteroidales species in enforcing immune tolerance to FA by inducing the differentiation of RORgt+ Treg cells, which act to suppress FA. Early life expansion of RORgt+ Treg cells is induced by the bloom in Clostridiales and Bacteroidales species during weaning from maternal milk to solid food. This expansion is counter-regulated by resistin-like molecule beta (RELMb), which is elevated in FA subjects and mice. Accordingly, the focus of this proposal is to elucidate the mechanisms by which early life dysbiosis promotes FA and its long-term implications in terms of disease persistence and response to microbial therapy. We hypothesize that the microbial and immunological changes ushered by weaning early in life provide a window of opportunity for tolerance induction to solid food in a process regulated by RELMb, whose dysregulation by dysbiosis promotes FA (Aim 1). We also hypothesize that the ineffective differentiation of RORgt+ Treg cell populations and the reciprocal emergence of Th2 cell-like Treg cells, an imbalance we have identified to play a fundamental role in FA, acts to promote disease pathogenesis by licensing IgE anti-food and anti-bacterial antibody responses (Aim 2). Finally, we hypothesize that products and metabolites of individual immunomodulatory bacterial strains, including Toll-like receptors activators, aryl hydrocarbon receptor ligands and secondary bile acids, act to enforce oral tolerance in FA by promoting RORgt+ Treg cell differentiation (Aim 3). The proposed studies will provide fundamental new insights relevant to the pathogenesis of FA and offers novel opportunities in early life disease intervention and therapy.