化疗性肠黏膜炎（CIM）是化疗的主要毒性反应。申请人前期研究发现富硒长双歧杆菌DD98（DD98）能够缓解CIM，但机制尚不清楚。研究证明CIM的发生与肠道菌群紊乱相关，肠道菌群代谢产物丁酸能激活Nrf2信号通路促进GSH-Px表达。申请人前期研究发现DD98能提高小鼠肠道有益菌丰度和促进GSH-Px表达、抑制NLRP3表达。我们假设：经DD98修复后的肠道菌群代谢产物通过促进Nrf2的核转移，提高机体抗氧化能力，进而抑制NLRP3激活，减轻CIM。拟从4方面开展研究：1）证明小鼠CIM伴肠道菌群紊乱，菌群紊乱能导致肠道损伤；2）证明DD98通过重建肠道菌群缓解CIM；3）利用无菌小鼠，证明DD98缓解CIM依赖肠道菌群；4）利用NLRP3过表达和Nrf2沉默等技术，证明DD98修复肠道菌群致CIM保护作用依赖Nrf2/ROS/NLRP3通路。

Chemotherapy-induced intestinal mucositis without preventative and control measures is the main toxic reaction of chemotherapy. In our previous study, we found that selenium-enriched Bifidobacterium longum DD98 can alleviate intestinal mucositis caused by CPT-11 and 5-FU. However, the mechanism of alleviating intestinal mucositis has not been elucidated. It has been proved that CIM is associated with gut dysbiosis and that the metabolites of gut microbiota, such as butyrate, can activate the Nrf2 signaling pathway to promote the expression of GSH-Px. We found that DD98 could improve the abundance of beneficial bacteria in the intestinal tract, improve the total antioxidant capacity and inhibit the high expression of NLRP3. Therefore, we propose the hypothesis: the metabolites of gut microbiota restored by DD98 can promote the nuclear transfer of Nrf2, improve the antioxidant capacity, and then inhibit the activation of NLRP3 and thereby relieve CIM.The research will be carried out from four aspects: 1) prove that CIM is accompanied by gut dysbiosis and that gut microbiota impaired by CPT-11 can cause intestinal injury in germ-free mice;2) explore that DD98 can alleviate CIM by restoring gut microbiota;3) validating that DD98 alleviate CIM depending on gut microbiota in germ-free mice;4) clarify that the protective effect of DD98 on restoring gut microbiota depend on the Nrf2/ROS/NLRP3 pathway by silencing Nrf2 and overexpressing NLRP3.