《膳食干预肠道菌群预防代谢性疾病PPT课件》由会员分享，可在线阅读，更多相关《膳食干预肠道菌群预防代谢性疾病PPT课件（57页珍藏版）》请在金锄头文库上搜索。
1、膳食干预肠道菌群预防代谢性疾病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赵立平赵立平 Liping Zhao上海交通大学生命科学技术学院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上海系统生物医学研究中心Shanghai Jiao Tong UniversityHuman Superorganisms正确认识自己的身体正确认识自己的身体“超级生物体超级生物体”诺贝尔奖得主-里德伯格, Science 2000Joshua Leder
2、bergNobel 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%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肠道菌群人体后天获得的人体后天获得的“第二个基因组第二个基因组”Gut Microbiota-Second genome acquired after birth食品食品药品药品人基因组人基因组肠道微生物组肠道微生物组健康健康疾病疾病体体质质亚健康亚健康先天遗传后天养成Shanghai Jiao Tong University“慢性病的肠道起源慢性病的肠道起源”“人体系统生物学方法人体系
3、统生物学方法”Shanghai Jiao Tong University慢性病的肠道起源Gut Origin of Chronic DiseasesIIya MechnikovNobel Laureate 1908“Later he took up the study of the flora of the human intestine and developed atheory that senility is due to poisoning of the body by the products of certain of these bacteria. To prevent the
4、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:/nobelprize.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 d
5、iseases” 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Shanghai Jiao Tong University肠道菌群结构失调与代谢综合征肠道菌群结构失调与代谢综合征Cani, 2009Shanghai Jiao Tong University肠道菌群控制能量代谢基因表达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 that regulates fat storage.
6、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 capacity for energy harvest.
7、 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 Shanghai Jiao Tong University肥胖肥胖糖尿病糖尿病炎性衰老炎性衰老 低度、系统性的慢性炎症低度、系统性的慢性炎症 慢性炎症与衰老和老年
8、病的关系慢性炎症与衰老和老年病的关系Inflammation and Age-related Diseases代谢性疾病代谢性疾病Endotoxin-the most common immunotoxin内毒素-最常见的免疫毒素内毒素Molecular Inflammation induced by endotoxin内毒素诱导的分子炎症Shanghai Jiao Tong UniversityInflammation induced by diet-disrupted gut microbiota菌群结构失调诱发慢性炎症菌群结构失调诱发慢性炎症Cani, P.D., Amar, J., Ig
9、lesias, M.A., Poggi, M., Knauf, C., Bastelica, D. et al. (2007a) Metabolic 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
10、improve high-fat-diet-induced diabetes in mice through a mechanism associated 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: 1470-14
11、82Cani, P.D, et al.,(2009) Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability. Gut 58:1091-1103Shanghai Jiao Tong UniversityApoa-1 knock-out mouseApoa-1 基因敲除鼠基因敲除鼠C57BL/6 miceApoa-1 基因基因敲除敲除Apoa-1-/- mice敲除小鼠敲除小鼠 Ap
12、oa-l gene的策略的策略 (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Shanghai Jiao Tong University动物实验高脂饲料高脂饲料植物饲料植物饲料敲除鼠敲除鼠坏基因植物饲料植物饲料 对照鼠对照鼠好基因高脂饲料高脂饲料 两种基因两种基因 X 两种饲料两种饲料 饲喂饲喂6个月个月坏食物好食物坏食物好食物Shanghai Jiao Tong UniversityFood intakeGlucose Tolerance Test Growth CurvePhenotype Data好基因
13、+坏食物病得最重！Shanghai Jiao Tong UniversityDiet is shaping gut microbiota饮食决定肠道菌群结构，基因作用很小Wt/NC野生型野生型/植物饲料植物饲料Apoa-/- /NC敲除鼠敲除鼠/植物饲料植物饲料Wt/HFD野生型野生型/高脂饲料高脂饲料Apoa-/- /HFD敲除鼠敲除鼠/高脂饲料高脂饲料Shanghai Jiao Tong University新一代革命性测序技术新一代革命性测序技术15100 台老一代测序仪1个技术员，1台新设备NATURE METHODS ，16 | VOL.5 NO.1 | JANUARY 2008 S
14、hanghai Jiao Tong University% of Total Sequences ApoA- -/- high fat dietApoA- -/- normal chow Wild-type high fat dietWild-type normal chow*P0.01 *P0.91LDL- cholesterol （mmol/L）3.42 3.153.420.00-4.16blood pressure（mm Hg）100/140 80/12075/120 80/120Aspartate aminotransferase（U/L）122.0 513110-47LBP (g/m
15、l)(I)8.132.445.76_IL-1beta (pg/ml)(I)0.090.110.07_IL-6 (pg/ml)(I)6.564.392.72_Adiponectin (ng/ml)(A)1839.411925.634145.38_Shanghai Jiao Tong University16S rRNA gene V3-DGGE Pattern M 0d 4w 9w 13w18w 23w PCAShanghai Jiao Tong University0d 4w9w13w18w23wAbundance distribution of predominant phylotypes
16、A pathogenShanghai Jiao Tong UniversityMetagenomic Sequencing以肠道菌群为靶标的慢性病早期营养干预-30天0天4周9周13周18周23周干预期维持期基线（n=163）（n=123）（n=101）（n=93）123位合格志愿者BMI30，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，中国临床试验注册中心通过伦理审查并注册，注册号为注册号为ChiCTR-TRC-00000353 Shanghai Jiao Tong University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
17、，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、血脂、血压调控机制受损。Shanghai Jiao Tong University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。 Shanghai
18、 Jiao Tong University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Shanghai Jiao Tong University保护肠屏障的细菌增加保护肠屏障的细菌增加条件致病菌下降条件致病菌下降* * Shanghai Jiao Tong University肠屏障功能 P-values 0.05*P-values 0.01* *Shanghai Jiao Tong University脂多糖结合蛋白（LBP）P-values 0.05*P-values 0.01* *Shanghai Ji
19、ao Tong UniversityC反应蛋白（CRP）P-values 0.05*P-values 0.01* *Shanghai Jiao Tong University炎性因子P-values 0.05*P-values 0.01* *Shanghai Jiao Tong University 糖稳态P-values 0.05*P-values 0.01* *Shanghai Jiao Tong University血脂P-values 0.05*P-values 0.01* *Shanghai Jiao Tong University肝功能P-values 0.05*P-values
20、0.01* *Shanghai Jiao Tong University血压P-values 0.05*P-values 0.01* *Shanghai Jiao Tong University志愿者体重变化情况 Weight BMI -30d 9w 23w Time Point -30d 9w 23w Time Point * * * * P-values 0.05All vs. -30d 9w vs. 23w * *kgkg/m84.980.478.031.830.129.09周周: 减重中位值减重中位值4.5 kg, 最高最高 15.5 kg23周周: 减重中位值减重中位值 6.9 kg
21、, 最高最高 20.3 kgShanghai Jiao Tong University以菌群为靶点的健康监测新技术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内毒素结合蛋白C反应蛋白反应蛋白空腹胰岛素空腹胰岛素Shanghai Jiao Tong University样品采集情况 StoolUrineBloodUrine for Gut permeability testDun hua fangfirst trial1611616968Dun hua fangsecond
22、 trial70703030Coal central hospital287287123123He ping hospital1961968484Total714714305305Shanghai Jiao Tong University基于功能元基因组学的人体系统生物学分析基于功能元基因组学的人体系统生物学分析ConcentrationPrimary MoleculesSecondary MoleculesResorptionDilutionFiltration1234567ppmhippurateureaallantoincreatininehippurate2-oxoglutaratec
23、itrateTMAOsuccinatefumaratewatercreatininetaurineMetabolism-MetabonomeMicrobiome-MetagenomeProteome-ImmunityVibration, noise, exhaust gasBLOODFecal matterUrine samplesShanghai Jiao Tong University病前阶段病前阶段病前阶段病前阶段PrediseasePredisease疾病早期疾病早期疾病早期疾病早期Early diseaseEarly disease疾病中后期疾病中后期疾病中后期疾病中后期Late d
24、iseaseLate diseaseNutrition and life styleNutrition and life styledrugdrug基于人体分子测量的病人分型与健康监测基于人体分子测量的病人分型与健康监测Systems trajectory analysis for health managementSystems trajectory analysis for health management健康人群健康人群健康人群健康人群Healthy spaceHealthy 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Shanghai Jiao Tong University0306090120150年龄病初病末健康病前健康度濒死平衡膳食平衡膳食 调理菌群调理菌群 颐养天年颐养天年 无疾而终无疾而终
