膳食干预肠道菌群预防代谢性疾病.ppt

1、膳食干预肠道菌群预防代谢性疾病Dietary Modulation of Gut Microbiota for Preventive management of Metabolic Diseases,赵立平 Liping Zhao上海交通大学生命科学技术学院上海系统生物医学研究中心Shanghai Jiao Tong University,Human Superorganisms正确认识自己的身体“超级生物体”,诺贝尔奖得主-里德伯格, Science 2000,Joshua LederbergNobel Laureate 1958,人体内生活着1-2公斤细菌90%在肠道里,人体的细胞组成10

2、%人细胞+90%细菌细胞,人体的基因组成 2.5万个人的基因3百多万个微生物基因丰富而活跃的代谢活动,肠道菌群人体后天获得的“第二个基因组”Gut Microbiota-Second genome acquired after birth,“慢性病的肠道起源”“人体系统生物学方法”,慢性病的肠道起源Gut Origin of Chronic Diseases,IIya MechnikovNobel Laureate 1908,“Later he took up the study of the flora of the human intestine and developed atheory

3、 that senility is due to poisoning of the body by the products of certain of these bacteria. To prevent the multiplication of these organisms he proposed a diet containing milk fermented by bacilli which produce large amounts of lactic acid and for a time this diet became widely popular.”-http:/nobe

4、lprize.org/,Symbiosis vs. Dysbiosis,“粪毒入血， 百病蜂起”中医观念“Fecal toxins into bloodstream will lead to all kinds of diseases” Concept from Traditional Chinese Medicine (TCM),细胞毒素、遗传毒素、免疫毒素-肝肠循环-肠屏障受损,肠道菌群结构失调与代谢综合征,Cani, 2009,肠道菌群控制能量代谢基因表达,Backhed, F., et al., The gut microbiota as an environmental factor

5、 that regulates fat storage. Proc Natl Acad Sci U S A, 2004. 101:15718-15723. Backhed, F., et al., Mechanisms underlying the resistance to diet-induced obesity in germ-free mice. Proc Natl Acad Sci U S A, 2007. 104: 979-984.Turnbaugh, P.J., et al., An obesity-associated gut microbiome with increased

6、 capacity for energy harvest. Nature, 2006. 444(7122): p. 1027-1031.Turnbaugh, P.J., et al., Diet-induced obesity is linked to marked but reversible alterations in the mouse distal gut microbiome. Cell Host Microbe, 2008. 3: 213-223.,Jeffery Gordon,肥胖,糖尿病,炎性衰老,低度、系统性的慢性炎症,慢性炎症与衰老和老年病的关系Inflammation

7、and Age-related Diseases,代谢性疾病,Endotoxin-the most common immunotoxin内毒素-最常见的免疫毒素,Molecular Inflammation induced by endotoxin内毒素诱导的分子炎症,Inflammation induced by diet-disrupted gut microbiota菌群结构失调诱发慢性炎症,Cani, P.D., Amar, J., Iglesias, M.A., Poggi, M., Knauf, C., Bastelica, D. et al. (2007a) Metabolic

8、endotoxemia initiates obesity and insulin resistance. Diabetes 56: 1761-1772.Cani, P.D., Neyrinck, A.M., Fava, F., Knauf, C., Burcelin, R.G., Tuohy, K.M. et al. (2007b) Selective increases of bifidobacteria in gut microflora improve high-fat-diet-induced diabetes in mice through a mechanism associat

9、ed with endotoxaemia. Diabetologia 50: 2374-2383 Cani, P.D, et al.,(2008) Changes in gut microbiota control metabolic endotoxemia-induced inflamation in high-fat diet-induced obesity and diabetes in mice. Diabetes 57: 1470-1482Cani, P.D, et al.,(2009) Changes in gut microbiota control inflammation i

10、n obese mice through a mechanism involving GLP-2-driven improvement of gut permeability. Gut 58:1091-1103,Apoa-1 knock-out mouseApoa-1 基因敲除鼠,敲除小鼠 Apoa-l gene的策略 (Williamson, 1992, PNAS),Apolipoprotein A-,高密度脂蛋白水平低易感动脉粥样硬化先天性胰岛素抵抗,动物实验,高脂饲料,植物饲料,敲除鼠坏基因,植物饲料,对照鼠好基因,高脂饲料,两种基因 X 两种饲料 饲喂6个月,坏食物,好食物,坏食物,好

11、食物,Food intake,Glucose Tolerance Test,Phenotype Data,好基因+坏食物病得最重！,Diet is shaping gut microbiota饮食决定肠道菌群结构，基因作用很小,新一代革命性测序技术,15,100 台老一代测序仪,30，中心型II度肥胖症患者 （F:M=69:54）,WHO中国临床试验注册中心通过伦理审查并注册，注册号为ChiCTR-TRC-00000353,菌群参与代谢性疾病发展的分子过程,保护肠屏障的细菌种群水平下降，条件致病菌的种群水平上升；肠道的通透性上升；血液中的细菌抗原载荷量升高；炎性水平升高；胰岛素抵抗出现；血糖、

12、血脂、血压调控机制受损。,相关分子标示物的使用,菌群结构的454高通量测序分析肠屏障功能检查乳果糖（lactulose）尿中排泄率甘露醇（mannitol）尿中排泄率比值法 血液中的细菌抗原载荷量脂多糖结合蛋白LBP的浓度测定炎性水平测定C反应蛋白CRPIL-1、IL-6、TNF-和脂联素 胰岛素抵抗测定空腹胰岛素稳态模型的胰岛素抵抗指数（HOMA-IR）=空腹胰岛素（IU/L）空腹血糖（mmol/L）/22.5。,空腹血糖糖化血红蛋白甘油三酯总胆固醇高密度脂蛋白低密度脂蛋白血压谷草转氨酶 丙氨酸氨基转移酶 -谷氨酰转移酶,相关临床标示物的使用,保护肠屏障的细菌增加条件致病菌下降,*,*,*,

13、*,肠屏障功能,P-values 0.05,*,P-values 0.01,*,*,脂多糖结合蛋白（LBP）,P-values 0.05,*,P-values 0.01,*,*,C反应蛋白（CRP）,P-values 0.05,*,P-values 0.01,*,*,炎性因子,P-values 0.05,*,P-values 0.01,*,*,糖稳态,P-values 0.05,*,P-values 0.01,*,*,血脂,P-values 0.05,*,P-values 0.01,*,*,肝功能,P-values 0.05,*,P-values 0.01,*,*,血压,P-values 0.

14、05,*,P-values 0.01,*,*,志愿者体重变化情况,Weight,BMI,-30d 9w 23w Time Point,-30d 9w 23w Time Point,*,*,*,*,*,*,P-values 0.05,kg,kg/m,84.9,80.4,78.0,31.8,30.1,29.0,9周: 减重中位值4.5 kg, 最高 15.5 kg23周: 减重中位值 6.9 kg, 最高 20.3 kg,以菌群为靶点的健康监测新技术,肠道菌群结构检测肠屏障保护菌毒素、抗原产生菌肠道菌毒素检测免疫毒性细胞毒性遗传毒性肠屏障功能检测血液抗原载荷量测定炎性反应检测,内毒素结合蛋白C反应

15、蛋白空腹胰岛素,样品采集情况,基于功能元基因组学的人体系统生物学分析,病前阶段Predisease,疾病早期Early disease,疾病中后期Late disease,Nutrition and life style,drug,基于人体分子测量的病人分型与健康监测Systems trajectory analysis for health management,健康人群Healthy space,通过大规模人群试验发现对疾病有预测作用的生物标示物,平衡膳食 调理菌群,颐养天年 无疾而终,Acknowledgements,Students and StaffChenhong Zhang, N

16、a Fei, Shuiming Xiao, Zhengsheng Xue, Jiaqi Liu, JingJing Wang, Wenmin Long, Jian Shen, Weiying Hua, Xiaoyan Pang, Linghua Wang, Menghui Zhang, Xiaojun Zhang, Youfang Cao, Chaochun WeiCollaboratorsYan Chen, Ruijun Han, INS-SIBS, CASYong Liu, Shoufeng Li, INS-SIBS, CASGuoping Zhao, Shengyue Wang, CHGSCJeremy Nicholson, Imperial College, LondonHuiru Tang, CAS, WuhanLianjuan Li, Zhejiang UniversitySunil Konhar, Nestle Research CenterXiuguo Hua, Li Cui, Ag School, SJTUFunding agenciesMOSTNSFCShanghai Government,