菌群定植对呼吸道免疫耐受功能和特应性进程的作用及机制研究

Allergic rhinitis is closely related to asthma. They are two key links of the"atopic march", and are both associated with the defective of immune tolerance in respiratory system. In our previous study, we have proved that lower microbiota diversity of newborn rats affected the development of the respiratory immune tolerance, promoted allergen sensitivity and the occurrence of asthma, suggesting microbiota colonization is the major factor affecting the development of immune tolerance and "atopic march", but the key microflora affecting the allergic process and its actual role in atopic march are still unclear. In this study, using ignored microbes colonization of the respiratory tract as an entry point, we are going to compare the distinction of nasal microbiota and immune indicators between allergic rhinitis patients and health people, simple allergic rhinitis patients and patients with allergic rhinitis complicated by astnma, aim to look for the key microbiota influencing the occurrence and development of allergic rhinitis，and to establish the microflora-lacking and pulluted air(PM2.5) animal model which simulated the environment of industrial society.Meanwhile we are going to investigate the changing of microbiota in newborn model rats which , and its effect on the development of allergic rhinitis, and to explore the molecular mechanism around the equilibrium conversion of TH2/TH1/TH17 and generation of Treg, then using the key flora to treat rat with allergic rhinitis, to investigate the role of microbiota on stoping atopic march and asthma prevention. So that lay the foundation for the development of efficient immune modulators for the prevention and treatment of allergic diseases.

变应性鼻炎和哮喘关联密切，是"特应性进程"中关键的两个环节，均与呼吸道免疫耐受功能不完善相关。前期研究证明新生鼠菌群丰度降低影响了呼吸道免疫耐受功能的发育，促进对变应原的敏感性和哮喘的发生，提示菌群定植是影响免疫耐受和特应性进程的主要因素，关于影响特应性进程的关键菌群及作用机制有待进一步阐明。本研究以被忽略的呼吸道菌群定植功能为切入点，首先比较变应性鼻炎患者与正常人以及单纯变应性鼻炎患者与合并哮喘患者鼻腔菌群特征和免疫指标的区别，寻找影响变应性鼻炎发生和发展的关键菌群，同时模拟工业社会建立菌群缺失和空气污染（PM2.5）模型，研究新生鼠菌群变化对变应性鼻炎形成的影响，围绕Th2/Th1/Th17的平衡转换和Treg的生成研究作用的分子免疫机制，然后以这些关键菌群调节变应性鼻炎大鼠菌群紊乱，考察其对切断变应性进程和哮喘预防的作用，从新颖的角度为寻找高效稳定防治变应性疾病的免疫调节剂奠定基础。

变应性鼻炎和哮喘关联密切，是"特应性进程"中关键的两个环节，均与呼吸道免疫耐受功能不完善相关。菌群是过敏性疾病发生的影响因素之一，关于菌群对特应性进程的作用及相关机制有待进一步阐明。本研究分析变应性鼻炎患者菌群失调与疾病发生和特应性进程的关系，解析菌群变化对大鼠变应性鼻炎形成和变应性进程的影响及免疫机制，筛选有效菌株，探索调节变应性鼻炎大鼠紊乱菌群对阻断特异性进程、预防哮喘的作用。研究发现变应性鼻炎患者鼻腔菌群发生了明显改变，并且影响了下呼吸道菌群的结构，正常人、变应性鼻炎和哮喘的下呼吸道菌群变化有渐近性变化趋势。研究进一步证实菌群是变应性疾病进程的关键控制因子，通过调节与免疫耐受功能相关的Th1/Th2，Treg/Th17平衡而实现。在此基础上，结合体外实验筛选出具有肠道、呼吸道调节功能的益生菌候选菌株，并证实了肠道、呼吸道调节对特应性进程的缓解作用，对调节时间和调节方法的深入探索建立了涉及皮肤、肠道、呼吸道协同调节的系统调节法，对于特应性进程取得了更好的延缓效果。本研究首次确认菌群是变应性进程的推动和制动因子，筛选出3株具有调节皮肤、肠道和呼吸道菌群的潜质的益生菌，并建立了皮肤、肠道、呼吸道协同作用的最佳调整方式，对于变应性疾病的全面控制，特别是哮喘等严重变应性疾病的有效预防提供了新策略，具有积极的意义。