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：
10517504
负责人：
CATHRYN R NAGLER
金额：
$ 55.48万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-24 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10517504
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 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 Natural Selections Nature Pathology Population Predisposition Prevalence Public Health Publishing Role Societies Source System T cell differentiation T-Lymphocyte Therapeutic Time Work allergic response bacterial community 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，食物过敏的患病率出现了前所未有的增长，在最近十年中，我们已经描述了粘膜的作用。相关共生细菌在保护小鼠免受过敏反应中的作用。微生物群调节人类过敏性疾病，我们用来自以下来源的人类细菌在无菌小鼠中定殖健康或牛奶过敏 (CMA) 婴儿的粪便我们的数据显示细菌定植。来自健康人类婴儿粪便的成分足以保护小鼠免受对牛粪便的过敏牛奶过敏原 b-乳球蛋白 (BLG)，而人类 CMA 婴儿的粪便却无法定植通过分析人类之间差异丰富的操作分类单元（OTU）。粪便捐赠者（4 名健康者，4 名 CMA）我们定义了一个微生物特征来区分 CMA 和人类供体和定植小鼠的健康群体，强调临床相关性我们的回肠肠上皮细胞的 RNASeq 分析显示出差异。表达基因 (DEG) 可以区分所有供体中的健康小鼠和 CMA 定植小鼠。回肠 OTU 与健康定植小鼠回肠中 DEG 的相关性鉴定出梭菌属物种， Anaerostipes caccae，可防止食物过敏反应。我们的研究结果表明，健康婴儿微生物群在预防食物过敏方面的因果作用，并表明调节细菌群落的干预措施可能有助于新型疗法的开发在本提案中，我们将进一步完善我们的 OTU 特征并检查是否存在这种疾病。 CMA 婴儿微生物组是目标 1 中的特应性微生物组。目标 2 将探索健康的肠道如何细菌通过检查食物过敏原对先天淋巴细胞的影响来影响对食物过敏原的反应功能、早期 T/B 启动以及效应 T 细胞分化和迁移。我们描述的无菌模型将提供一个理想的系统来识别关键的宿主微生物有助于维持食物过敏中饮食抗原耐受性的相互作用。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Fecal microbiome and metabolome differ in healthy and food-allergic twins.

健康双胞胎和食物过敏双胞胎的粪便微生物组和代谢组有所不同。

DOI：
10.1172/jci141935
发表时间：
2021-01-19
期刊：
The Journal of clinical investigation
影响因子：
0
作者：
R. Bao;Lauren A. Hesser;Ziyuan He;Xiaoying Zhou;K. Nadeau;C. Nagler
通讯作者：
C. Nagler

Drugging the microbiome.

对微生物组进行药物治疗。

DOI：
发表时间：
2020
期刊：
影响因子：
0
作者：
Nagler; Cathryn R
通讯作者：
Cathryn R

Commensal bacteria signal through TLR5 and AhR to improve barrier integrity and prevent allergic responses to food.

共生细菌通过 TLR5 和 AhR 发出信号，以改善屏障完整性并防止对食物的过敏反应。

DOI：
发表时间：
2023-10-31
期刊：
影响因子：
8.8
作者：
Kemter, Andrea M;Patry, Robert T;Arnold, Jack;Hesser, Lauren A;Campbell, Evelyn;Ionescu, Edward;Mimee, Mark;Wang, Shan;Nagler, Cathryn R
通讯作者：
Nagler, Cathryn R

Origins of peanut allergy-causing antibodies.

引起花生过敏的抗体的起源。

DOI：
发表时间：
2020
期刊：
影响因子：
0
作者：
Wesemann, Duane R;Nagler, Cathryn R
通讯作者：
Nagler, Cathryn R

A Lipopolysaccharide-Enriched Cow's Milk Allergy Microbiome Promotes a TLR4-Dependent Proinflammatory Intestinal Immune Response.

富含脂多糖的牛奶过敏微生物组促进 TLR4 依赖性促炎性肠道免疫反应。

DOI：
发表时间：
2024-02-15
期刊：
影响因子：
0
作者：
Campbell, Evelyn;Hesser, Lauren A;Berni Canani, Roberto;Carucci, Laura;Paparo, Lorella;Patry, Robert T;Nagler, Cathryn R
通讯作者：
Nagler, Cathryn R