Targeting microbial dysbiosis in Food Allergy to restore tolerance

针对食物过敏中的微生物失调以恢复耐受性

• 批准号: 10549764
• 负责人: Talal Amine Chatila
• 金额: $ 60.16万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-25 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10549764
• 关键词: Affect; Agonist; Anti-Bacterial Agents; Antibody Response; Aryl Hydrocarbon Receptor; Automobile Driving; Bacteria; Bacterial Antibodies; Bile Acids; Cell Differentiation process; Cells; Child; Development; Diagnosis; Diet; Dietary Supplementation; Disease; Disease Outcome; Environmental Risk Factor; Epidemic; Epithelial Cells; Exhibits; Failure; Food; Food Hypersensitivity; Human Milk; IgE; Immune; Immune Tolerance; Immune system; Immunoglobulin A; Immunologics; Individual; Infant; Intervention; Licensing; Life; Life Style; Lipid A; Long-Term Effects; Mediating; Metabolism; Modernization; Molecular; Mucous Membrane; Mus; Oral; Pathogenesis; Pathogenicity; Pathway interactions; Play; Population; Prevalence; Process; Production; Public Health; Reaction; Regulation; Regulatory T-Lymphocyte; Role; Solid; Supplementation; TLR4 gene; Th2 Cells; Therapeutic Intervention; Toll-like receptors; Tryptophan; Weaning; aryl hydrocarbon receptor ligand; bile acid metabolism; combinatorial; commensal bacteria; dysbiosis; effective therapy; food allergen; food antigen; gut bacteria; gut dysbiosis; gut microbiome; gut microbiota; human subject; immunoregulation; insight; microbial; microbiota; novel; oral tolerance; prevent; resistin; response

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.

抽象的 食物过敏（FA）已成为公共健康问题，影响了大量人群。尽管 其患病率的令人震惊的增加，遏制FA流行的努力受到了有限的困扰 了解疾病发病机理，尤其是在这种早期肠道营养不良过程中的作用。在那 考虑到，我们的研究已经确定了免疫调节性梭菌和细菌种类的关键作用 通过诱导Rorgt+ Treg细胞的分化来强制对FA的免疫耐受性，这些细胞起作用可抑制 fa。 Rorgt+ Treg细胞的早期寿命膨胀是由梭菌和蛋黄酱物种的Bloom诱导的 从母乳到固体食物的断奶期间。这种膨胀由抵抗素样分子对抗 beta（relmb），在FA受试者和小鼠中升高。因此，该提议的重点是阐明 早期生命疾病促进FA及其在疾病方面的长期影响的机制 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 在生命的早期断奶中引起的迎接为耐受性诱导固体食物的机会窗口 由RERMB调节，RERMB的失调症会促进FA（AIM 1）。我们还假设 Rorgt+ Treg细胞种群的无效分化和Th2细胞样Treg的相互出现 细胞是我们确定在FA中发挥基本作用的失衡 通过许可IgE抗食品和抗细菌抗体反应（AIM 2）。最后，我们假设产品 单个免疫调节性细菌菌株的代谢产物，包括收费受体激活剂，芳基 碳氢化合物受体配体和二级胆汁酸，通过促进Rorgt+来实现FA的口服耐受性 Treg细胞分化（AIM 3）。拟议的研究将提供与该研究有关的基本新见解 FA的发病机理，并为早期生命疾病干预和治疗提供了新的机会。