Akkermansia muciniphila新菌株与乳酸杆菌协同调控吲哚-3-乙酸在治疗抗生素相关性肠炎中的机制

Fecal microbiota transplantation (FMT) is an important strategy for the treatment of antibiotic associated colitis (AAC). However, due to its aesthetics limitation and the difficulty of mass production, it is a hot field in searching for new probiotics and synthetic microbiota to partially replace FMT. In our previous study, a new type of probiotics Akkermansia muciniphila (A. muciniphila), urinary Nrf2 protein and indole derivatives were found to be significantly increased in patients who achieved significant clinical efficacy from FMT. We isolated 4 Chinese A. muciniphila strains from FMT healthy donors and confirmed their ability to metabolize indole-3-acetic acid (IAA). In addition, the co-culture of A. muciniphila and Lactobacillus could increase IAA metabolism, but there exist differences among different strains. We therefore proposed the hypothesis: the new strain of A. muciniphila could co-act with Lactobacilli to enhance the production of IAA, which could act on the nuclear factor E2related factor 2 (Nrf2) antioxidant stress signaling pathway. This study will aim to investigate the combined effects and anti-inflammation mechanism of A. muciniphila and Lactobacilli co-metabolizing IAA to act on Nrf2 pathway based on researches of animal models, intestinal epithelial organoid, lentivirus vector and multi-omics. It would provide an important theoretical evidence for the clinical application of synthetic microbiota transplantation.

粪菌移植（FMT）是治疗抗生素相关性肠炎的重要手段，但因其美学、难以量产等不足，寻找新型益生菌或部分替代FMT的配方菌群移植已成热点。本项目前期发现FMT治疗有效的患者粪中Akkermansia muciniphila（A. muciniphila）增加、尿蛋白组学示Nrf2蛋白增加、尿磁共振氢谱示吲哚衍生物增加；从FMT健康供体中分离出4株中国人源A. muciniphila菌，并证实其与乳酸杆菌共培养能增加吲哚-3-乙酸（IAA）生成。遂假设：A. muciniphila新菌株能与乳酸杆菌共作用，增强IAA代谢，介导Nrf2抗氧化应激。拟通过动物模型、肠类器官、慢病毒转染、多组学等技术，研究中国人源A. muciniphila菌株与乳酸杆菌共代谢IAA并活化Nrf2通路在治疗抗生素相关性肠炎中的机制，为配方菌群移植奠定理论基础。

Akkermansia muciniphila是一种具有重要应用前景的下一代益生菌。本研究组发现IBD患者肠道中的A.muciniphila丰度相比于健康人显著降低。建立葡聚糖硫酸钠（Dextran sulfate sodium, DSS）诱导的小鼠结肠炎模型用以模拟炎症性肠病（inflammatory bowel disease, IBD），进一步用AKK新菌株灌胃干预，来阐述其与IBD之间的因果关系，探究AKK新菌株发挥的保护作用及其机制。本研究组在研究过程中对研究计划依据领域进展做出适当调整，以确保在领域内的领先性。主要开展了以下研究：1、探索80名健康人和100名IBD患者接受WMT治疗前后AKK菌定植率及相对丰度和疗效。揭示了与健康人相比，溃疡性结肠炎患者肠道内AKK菌定植率和相对丰度均显著降低。同时提示WMT对IBD的疗效与AKK菌密切相关，有效组IBD患者治疗后的AKK菌定植率和相对丰度呈上升趋势。2、成功分离筛选出2株具有自主知识产权的中国人源新型AKK益生菌株，并完成其生物学功能鉴定，为进一步用于临床制药奠定了重要基础。3、探究AKK新菌株对DSS小鼠肠炎的影响及其作用机制，挖掘其与乳酸杆菌、吲哚衍生物、Nrf2之间的联系，为组合的配方菌群移植应用于临床治疗提供新的理论基础。