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

基本信息

批准号：
10185766
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
项目类别：
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/10185766
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 Climacteric Cytoprotection 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 anti-IgE 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

项目摘要

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）已成为一个公共健康问题，影响着相当大一部分人。尽管由于其患病率的惊人增加，控制 FA 流行的努力因有限的措施而受到阻碍了解疾病发病机制，特别是在生命早期肠道菌群失调这一过程中的作用。在那就此而言，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 细胞的分化来增强对 FA 的免疫耐受，该细胞的作用是抑制 FA。 RORgt+ Treg 细胞的早期生命扩张是由梭菌目和拟杆菌目物种的繁殖诱导的断奶期间从母乳转向固体食物。这种扩张受到类抵抗素分子的反调节 beta (RELMb)，在 FA 受试者和小鼠中升高。因此，本提案的重点是阐明生命早期生态失调促进 FA 的机制及其对疾病的长期影响对微生物疗法的持久性和反应。我们假设微生物和免疫学的变化生命早期断奶为诱导对固体食物的耐受性提供了机会之窗受 RELMb 调节，其生态失调导致的失调会促进 FA（目标 1）。我们还假设 RORgt+ Treg 细胞群的无效分化和 Th2 细胞样 Treg 的相互出现我们已确定细胞失衡在 FA 中发挥重要作用，可促进疾病发病机制通过许可 IgE 抗食物和抗细菌抗体反应（目标 2）。最后，我们假设产品以及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+ 来增强 FA 的口服耐受性 Treg 细胞分化（目标 3）。拟议的研究将提供与相关的基本新见解 FA 的发病机制，并为早期生命疾病干预和治疗提供了新的机会。