口腔微生态失衡在放化疗所致口腔黏膜炎发生发展中的作用及机制研究

Oral mucositis is the most common adverse event in head and neck cancer patients undergoing radiochemotherapy. There has been lack of effective preventive or therapeutic measures for oral mucositis, making it become an urgent clinical problem. The relationship between microbiota and radiochemotherapy-induced mucositis has recently become one of the research highlights. However, the present researches are unable to clarify whether the shift of oral flora during radiochemotherapy is the secondary change to oral mucositis or is one of the reasons causing oral mucositis. We have previously, using high-throughput sequencing technique, analyzed the dynamic characteristics of the shift patterns of oral mirobiota in patients with nasopharyngeal cancers during radiochemotherapy. Based upon our previous study, we will further use metagenomic and bioinformatics analysis approaches to decipher the oral microbial characteristics of patients with oral mucositis as well as the relationship between oral flora changes and the occurrence and development of oral mucositis. Also, animal models and in vitro experiments will be performed to verify the existence of “radiochemotherpy-‘oral microbial dysbiosis’-‘oral mucositis’” effect chain. Furthermore, molecular level studies will be performed to unravel the molecular mechanisms of microbiota involved in the occurrence and development of oral mucositis. We believe this project will not only further our knowledge about the pathogenesis of oral mucositis, but also provide novel strategies for developing new preventive or therapeutic measures for oral mucositis.

口腔黏膜炎是头颈部肿瘤患者接受放化疗时最常见的并发症，目前仍缺乏有效的防治手段，是亟待解决的临床问题。微生物与放化疗所致黏膜炎间的关系是目前研究热点之一，现有研究无法回答放化疗期间的菌群变化是口腔黏膜炎发生后的继发性改变还是导致口腔黏膜炎发生发展的重要因素。针对此科学问题，本项目拟基于前期高通量测序技术对鼻咽癌患者放化疗期间口腔微生物群落结构动态变化规律解析的基础上，进一步结合宏基因组学技术及生物信息学分析方法，揭示口腔黏膜炎患者口腔微生物群落结构与功能特点，分析放化疗期间的菌群变化与口腔黏膜炎发生发展的关系，基于动物和体外实验验证“放化疗－口腔微生态失衡－口腔黏膜炎”作用链的存在，应用芯片技术及分子生物学技术探索微生物因素参与口腔黏膜炎发生发展的分子机制。这将有助于我们进一步认识口腔黏膜炎的发病机制，为口腔黏膜炎的防治提供新思路，具有重大的理论意义和应用价值。

口腔黏膜炎是头颈部肿瘤患者接受放化疗时最常见的并发症，目前缺乏有效的防治手段，是亟待解决的临床问题。口腔微生物因素在口腔黏膜炎发生发展中起重要作用。本研究采用高通量测序技术系统解析了35名鼻咽癌经放疗患者口腔微生群落结构与功能的动态变化，发现放疗导致鼻咽癌患者口腔微生态失衡，包括口腔微生物群落结构、组成及功能的显著变化；放疗所致口腔微生态失衡与放射性口腔黏膜炎发生密切相关，口腔微生物群落结构及组成的稳定性有利于黏膜健康。同时，成功构建了放射性口腔黏膜炎动物模型。基于动物实验，我们研究发现放射性口腔黏膜炎小鼠口腔菌群结构与组成发现改变，表现为厌氧菌含量增高，降低厌氧菌代谢相关基因napA的表达量增加。益生菌唾液链球菌K12可通过减少厌氧菌含量，降低厌氧菌代谢相关基因napA的表达量，改善口腔微生态平衡；影响放射性口腔黏膜炎小鼠模型黏膜上皮NF-ĸB信号通路，增加口腔黏膜基底层细胞增生，降低细胞凋亡，从而改善小鼠放射性口腔黏膜炎严重程度。本研究结果为口腔黏膜炎的临床防治提供了一定的实验基础