Gut Microbial Factors in Farming Lifestyle and Allergic Sensitization

项目摘要/摘要--项目1 特应性疾病，包括特应性皮炎(AD)、食物过敏(FA)、过敏性鼻炎和哮喘 影响美国儿童的常见慢性疾病，预防策略在很大程度上仍然存在 不成功。而有农业生活方式的婴儿患哮喘的风险降低，这包括接触 生命早期的多样性微生物群，在这种生活方式下预防AD和FA的微生物机制 仍在接受调查。还研究了多种细菌代谢物与特应性疾病的关系。 疾病：短链脂肪酸(SCFA)，可诱导抗炎结肠树突起分化， 色氨酸代谢，调节上皮屏障通透性，或胆汁酸，调节T细胞 固有层的分化。我们公布的初步结果表明，与婴儿相比， 旧秩序门诺派(OOM)的传统农业社区来自罗切斯特(ROC)市区/郊区 防止特应性疾病，并拥有独特的肠道细菌群落，包括富含 双歧杆菌和梭状芽孢杆菌，表明生活方式和早期生活微生物群加速 免疫活性，可能在特应性疾病中起到保护作用。这项提议的目标是 确定肠道微生物组及其副产物如何在婴儿体内发育以调节特应性疾病的风险， 确定微生物和代谢物生物标志物以筛查高危婴儿，并评估相关机制 具有保护性的先天和获得性免疫标志物以及皮肤屏障完整性和微生物群 项目2和3的数据。我们的中心假设是，没有发育的婴儿的微生物群 AD和FA调节细菌代谢物库，提供保护或特应性疾病的风险。我们 假设非特应性城市Rochester婴儿和OOM婴儿的肠道微生物群将在 具有抗炎特性和与短链脂肪酸产生相关的基因的物种，乳酸 代谢，色氨酸和胆汁酸代谢，以及肠道微生物组加速成熟 与特应性婴儿进行比较。同时，我们还将评估OOM和ROC婴儿的粪便代谢组， 并测试其与特应性结局的关系：我们假设色氨酸、短链脂肪酸和胆汁 特应性和非特应性婴儿之间的酸将是不同的，微生物组和非特应性婴儿之间的相关性 代谢组也将根据健康结果而有所不同。最后，我们将评估纵向 肠道微生物组和代谢组的发展以识别随时间有相似变化的婴儿组 与特应性疾病以及项目2和3中的生物标记物有关的研究。 我们的策略将确定新的细菌和代谢物生物标志物，这些生物标志物与保护或风险 这将为今后微生物干预措施的发展提供便利。

PROJECT SUMMARY/ABSTRACT – PROJECT 1 Atopic diseases, including atopic dermatitis (AD), food allergy (FA), allergic rhinitis, and asthma, are the most common chronic medical conditions affecting children in the US, and prevention strategies remain largely unsuccessful. While the risk of asthma is reduced in infants with a farming lifestyle, which includes exposure to a diverse microbiome in early life, the microbial mechanisms of protection against AD and FA under this lifestyle are still being investigated. Multiple bacterial metabolites have been also explored for their connection with atopic disease: short-chain fatty acids (SCFA), which can induce the differentiation of anti-inflammatory colonic Tregs, tryptophan metabolism, which modulates epithelial barrier permeability, or bile acids, which regulate T-cell differentiation in the lamina propria. Our published and preliminary results demonstrate that, compared to infants from urban/suburban Rochester (ROC), the traditional agrarian community of Old Order Mennonites (OOM) are protected against atopic diseases and harbor a distinct gut bacterial community, including an enrichment in Bifidobacteria and Clostridia species, suggesting that lifestyle and early life microbiome accelerate immunocompetence and might play a protective role in atopic diseases. The goals of this proposal are to determine how the gut microbiome and its byproducts develop in infants to modulate the risk of atopic diseases, to identify microbial and metabolite biomarkers to screen high-risk infants, and to assess mechanisms associated with protective innate and adaptive immune markers and skin barrier integrity and microbiome by integration of data with Projects 2 and 3. Our central hypothesis is that the microbiome of infants who do not develop AD and FA modulates the bacterial metabolite pool that confers protection or risk of atopic disease. We hypothesize that the gut microbiome of non-atopic urban Rochester infants and OOM infants will be enriched in species with anti-inflammatory properties and genes related to short-chain fatty acid production, lactic acid metabolism, and tryptophan and bile acid metabolism, as well as an accelerated gut microbiome maturation compared with atopic infants. In parallel, we will also assess the fecal metabolome of OOM and ROC infants, and test its association with atopic outcomes: we hypothesize that tryptophan, short-chain fatty acids and bile acids will be differential between atopic and non-atopic infants, and that correlations between microbiome and metabolome will also be differential based on health outcomes. Finally, we will evaluate the longitudinal development of the gut microbiome and metabolome to identify groups of infants with similar changes over time that are associated with atopic disease, as well as with biomarkers from Projects 2 and 3. The rational design of our strategy will identify novel bacterial and metabolite biomarkers that are associated with protection or risk of atopic disease, and which will facilitate the development of microbial interventions in the future.