源于云南农村白族汉氏杆菌在溃疡性结肠炎中的作用及机制研究
批准号:
82060107
项目类别:
地区科学基金项目
资助金额:
34.0 万元
负责人:
孙杨
依托单位:
学科分类:
消化系统免疫相关疾病
结题年份:
2024
批准年份:
2020
项目状态:
已结题
项目参与者:
孙杨
中文摘要
肠道菌群失调在溃疡性结肠炎(UC)发病机制中起重要作用,但关键菌群发挥的功能与宿主免疫间的互作却知之甚少。我们前期发现:①UC患者肠道中汉氏杆菌较健康人显著降低;②云南农村白族UC发病率低于汉族,汉氏杆菌丰度显著升高;③与城市汉族相比,农村白族为粪菌移植(FMT)供体治疗UC,疗效更好,移植后汉氏杆菌丰度显著升高并定植12周以上;④预实验发现汉氏杆菌可能通过调控Th17/Treg平衡减轻DSS诱导的小鼠肠炎。但汉氏杆菌调控Th17/Treg平衡在UC中的具体机制不明。故本项目拟通过:临床水平:扩大样本选择农村白族为FMT供体治疗UC,研究汉氏杆菌的定植水平和Th17/Treg细胞比例;动物水平:探讨其在DSS小鼠肠炎中的防治效应及对Th17/Treg平衡的影响;细胞水平:揭示其调控Th17/Treg平衡的具体机制。最终阐明汉氏杆菌在UC中的作用机理,为探索UC治疗的新靶点提供理论依据。
英文摘要
Gut microbiota dysbiosis plays an important role in the pathogenesis of ulcerative colitis (UC), but few people is known about the interaction between key gut microbiota functions and hosts immune. Preliminary findings: ①The intestinal phascolarctobacterium faecium(P. faecium) of UC patients was significantly lower than that of healthy patients. ②The incidence rate of the Bai ethnic group UC in Yunnan was lower than that of Han ethnic group, and the P. faecium abundance increased significantly. ③ Compared with the urban Han ethnic group, the rural Bai ethnic group was better treated UC which having FMT donor on it, and the P. faecium abundance increased significantly after FMT and was colonized for more than 12 weeks. ④ Pre-experiment showing that P. faecium may attenuate DSS induced enteritis in mice by regulating Th17/Treg balance. But the specific system of P. faecium regulation Th17/Treg balance in the UC is not clear. .1) Clinical studies: Expanding the sample to select the rural Bai ethnic group as the FMT donor treatment UC, studying P. faecium colonization level and Th17/Treg cell proportion;.2) Animal model:To investigate P. faecium control effect in DSS mice and its effect on Th17/Treg balance;.3) Cell culture studies: Revealing the effects and mechanisms of P. faecium regulation Th17/Treg balance..These studies are intended to investigate the mechanism of P. faecium in UC and provides a theoretical basis for exploring new targets of UC therapy.
肠道菌群失调在溃疡性结肠炎(UC)发病机制中起重要作用,但仍有诸多未知功能益生菌未被发现,作用机制未被明确。申请人围绕“汉氏杆菌调控Th17/Treg平衡抑制UC肠道炎症的具体机制”这一关键科学问题开展研究:1)明确汉氏杆菌的定植水平与Th17/Treg平衡的临床相关性;2)探讨汉氏杆菌在预防及减轻DSS小鼠肠炎中的防治效应;3)通过体外细胞与菌群共培养研究汉氏杆菌调控Th17/Treg平衡的具体机制。取得了下述关键数据及重要结果:1)UC患者肠道中汉氏杆菌较健康人显著降低;2)云南农村白族UC发病率低于汉族,汉氏杆菌丰度显著升高;3)与城市汉族相比,农村白族为粪菌移植(FMT)供体治疗UC,疗效更好,移植后汉氏杆菌丰度显著升高并定植12周以上;4)通过无菌小鼠及DSS诱导肠炎小鼠模型,证实了汉氏杆菌在预防及减轻肠炎小鼠中的防治效应;5)明确了汉氏杆菌通过丙酸调控CD4+T细胞稳态激活RORγt+Treg诱导IL-10表达抑制小鼠肠炎的具体机制。在本项目执行过程中,课题组还有如下重要结果发现:1)基于大理白族为粪菌移植供体治疗UC的研究内容,发现了白族供体四界微生物(细菌、噬菌体、真菌、古菌)在抑制UC肠道炎症中的协同作用;2)揭示了汉氏杆菌、普氏栖粪杆菌及青春双歧杆菌等多种益生菌缓解肠炎的分子机制;3)揭示了致病菌编码不同代谢产物通过多种分子机制破坏肠稳态促进UC发生进展的新机制;4)在粪菌移植供体粪便中分离培养出疗效菌株,申报专利。上述研究,以第一/通讯(含共同)在Nat Commun,Cancer Cell,Microbiome,Gut Microbes等杂志发表SCI论著8篇,申报专利3项(已授权1项),以主持获得国家重点研发计划青年科学家立项资助,签订云南白族菌液专利技术转让合同,获云南省科技进步一等奖(3)。本项目最终阐明汉氏杆菌在UC中的作用机理,为探索UC治疗的新靶点提供理论依据。
国内基金
海外基金