2型糖尿病肿瘤小鼠模型的建立及其肠道菌群分析  

Establishment of a type 2 diabetes-tumor mouse model and analysis of its intestinal flora

作　　者：康洁 李春青[1,2] 高雪惠 许慧彬 陈川[1,2] 罗都强[1,2] KANG Jie;LI ChunQing;GAO XueHui;XU HuiBin;CHEN Chuan;LUO DuQiang(School of Life Sciences,Hebei University,Baoding 071002,China;Institute of Life Sciences and Green Development,Hebei University,Baoding 071002,China)

机构地区：[1]河北大学生命科学学院,保定071002 [2]河北大学生命科学与绿色发展研究院,保定071002

出　　处：《中国科学：生命科学》2021年第9期1308-1318,共11页Scientia Sinica(Vitae)

基　　金：国家重点研发计划(批准号:2017YFD0201400,2017YFD0201401)资助。

摘　　要：研究发现,糖尿病患者会增加罹患某些癌症的风险,并且这两种疾病都会影响宿主肠道菌群的平衡.本文通过构建2型糖尿病-肿瘤小鼠模型来研究肿瘤和糖尿病的关系,并通过16S r RNA基因分析小鼠的肠道菌群变化,以及肠道菌群对疾病的影响.研究使用链脲佐霉素(streptozocin,STZ)和高脂饲料构建小鼠2型糖尿病模型,随后接种肝癌细胞系(HuH-7),构建好的糖尿病肿瘤模型血糖明显升高并且肿瘤生长迅速.糖尿病肿瘤模型小鼠的肿瘤生长速度明显高于对照肿瘤组,证明糖尿病确实可以促进肝癌细胞的生长.进一步研究发现,糖尿病肿瘤小鼠的炎症以及相关因子如TNFα,IL-1β,IL-6,TLR4和MCP1的表达明显升高.肠道菌群分析发现,糖尿病组厚壁菌门显著升高,拟杆菌门显著降低,糖尿病肿瘤组的炎症和糖尿病相关的菌群Lachnospiraceae,Blautia,Lachnospiraceae_UCG-006,Ruminiclostridium_9,norank_f_Ruminococcaceae和Oscillibacter的水平显著升高,而Alistipes显著降低,但是肿瘤组的菌群变化不明显,揭示肠道菌群变化可能会促进小鼠肿瘤和糖尿病的进展.肠道短链脂肪酸和炎症与糖尿病密切相关.本研究发现,与肿瘤组相比,糖尿病肿瘤组的肠道短链脂肪酸,如乙酸、丙酸和异丁酸浓度明显降低,戊酸和异戊酸水平没有变化,而丁酸浓度明显升高.本研究构建了糖尿病肿瘤模型并研究其肠道菌群的组成变化,对于研究糖尿病和肿瘤的关系有一定意义,为通过肠道菌群干预疾病奠定了基础.Studies have found that diabetic patients have a greater risk of cancer,and both diseases affect the balance of host intestinal flora.We used streptozotocin and a high-fat diet to establish a mouse model of type 2 diabetes then inoculated the nude mice with hepatoma cell lines(Huh-7).The tumor volume of the diabetic tumor mice model was significantly higher than that of the control tumor group,which proved that diabetes could indeed promote liver tumor growth.Further study found that the m RNA expression of inflammation and related factors,such as TNFα,IL-1β,IL-6,TLR4,and MCP1,significantly increased in diabetic tumor mice.Intestinal microflora analysis showed that Firmicutes in the diabetic tumor group significantly increased and Bacteroides significantly decreased.In the diabetic tumor group,the microflora associated with inflammation and diabetes,namely,Lachnospiraceae,Blautia,lachnospiraceae_UCG-006,Ruminiclostridium_9,norank_f_Ruminococcaceae,and Oscillibacter,significantly increased.In contrast,the levels of Alistipes significantly decreased.However,intestinal flora changes in the tumor group were not obvious,which indicated that the changes of intestinal flora caused by diabetes could promote the progress of tumor and diabetes in mice.Intestinal short-chain fatty acids and inflammation were closely related to diabetes.Compared with the tumor group,the concentrations of propionic and isobutyric acids significantly decreased in the diabetic tumor group,while the levels of valeric and isobutyric acids remain unchanged,but the concentration of butyric acid significantly increased in the diabetic tumor group.Therefore,we constructed a diabetic tumor model and studied the compositional changes of its intestinal flora,which has certain significance for studying the relationship between diabetes and tumor and lays the foundation for the intervention of diseases through the intestinal flora.

关 键 词：糖尿病 肿瘤 肝癌 肠道菌群 短链脂肪酸 

分 类 号：R730.2[医药卫生—肿瘤] R587.1[医药卫生—临床医学]