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Mechanisms by which intestinal bacteria contribute to maintenance of tolerance in food allergy

肠道细菌有助于维持食物过敏耐受性的机制

基本信息

批准号：
10411606
负责人：
CATHRYN R NAGLER
金额：
$ 5.23万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-12 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10411606
关键词：
Allergens Allergic Allergic Disease Antibiotics Antigens Atopic Dermatitis B-Lymphocytes Bacteria Birth Butyrates Cattle Cell Differentiation process Cell physiology Cesarean section Clinical Consumption Data Development Diet Disease Epithelial Cells Exhibits Family Family member Feces Food Food Hypersensitivity Gene Expression Profiling Generations Genes Germ-Free Gnotobiotic Homeostasis Human Hypersensitivity IgE Immune Incidence Infant Infant formula Intervention Intestines Laboratories Life Link Lymphoid Cell Maintenance Medicine Milk Milk Proteins Modeling Mucous Membrane Mus Nature Pathology Population Predisposition Prevalence Public Health Publishing Role Societies Source System T cell differentiation T-Lymphocyte Therapeutic Time Work allergic response bacterial community base cell motility clinically relevant commensal bacteria commensal microbes dietary differential expression dysbiosis effector T cell experience feeding food allergen host microbiota host-microbe interactions ileum improved intestinal epithelium lifestyle factors member microbial microbial community microbial signature microbiome microbiota microbiota profiles mouse model novel novel therapeutic intervention operational taxonomic units pre-clinical prevent response sample collection transcriptome sequencing

项目摘要

The prevalence of food allergy has experienced an unprecedented increase in Western societies, rising by as much as 20% in a recent ten-year period. We have previously described a role for mucosa- associated commensal bacteria in protection from allergic sensitization in mice. To understand how the microbiota regulates allergic disease in humans, we colonized germ free mice with human bacteria from the feces of healthy or cow’s milk allergic (CMA) infants. Our data shows that colonization with bacteria derived from healthy human infant feces is sufficient to protect mice against sensitization to the cow’s milk allergen b-lactoglobulin (BLG), whereas colonization with feces from human CMA infants fails to protect. By analyzing operational taxonomic units (OTUs) differentially abundant between our human fecal donors (4 healthy, 4 CMA) we have defined a microbial signature that distinguishes the CMA and heathy populations in both the human donors and the colonized mice, emphasizing the clinical relevance of our gnotobiotic model. RNASeq analysis of ileal intestinal epithelial cells revealed differentially expressed genes (DEGs) that distinguished healthy- and CMA-colonized mice across all donors. Correlation of ileal OTUs with DEGs in the ileum of healthy-colonized mice identified a Clostridial species, Anaerostipes caccae, that protected against an allergic response to food. Our findings demonstrate a causal role for the healthy infant microbiota in protection against food allergy and suggest that interventions that modulate bacterial communities may inform the development of novel therapeutic strategies for this disease. In this proposal we will further refine our OTU signature and examine whether the CMA infant microbiome is an atopic microbiome in Aim 1. Aim 2 will explore how healthy intestinal bacteria influence the response to food allergens by examining their impact on innate lymphoid cell function, early T/B priming and effector T cell differentiation and migration. The robust, pre-clinical gnotobiotic models we describe will provide an ideal system in which to identify key host-microbial interactions that contribute to the maintenance of tolerance to dietary antigen in food allergy.

在西方社会，食物过敏的发病率史无前例地上升