1、肠道微生物群与精神障碍郭晓奎上海交通大学基础医学院主要内容微生物群的特性肠道微生物群与人体代谢 ,发育和行为肠道微生物群与精神障碍研究展望肠道微生物群与人体疾病微生物群的 特性人体微生物群Human Microbiota is the aggregate of microorganisms, a microbiome that resides on the surface and in deep layers of skin, in the saliva and oral mucosa, in the conjunctiva, and in the gastrointestinal tract
2、s. They include bacteria, fungi, and archaea. Some of these organisms perform tasks that are useful for the human host. However, the majority have been too poorly researched for us to understand the role they play. 正常菌群（ Flora） 微生物群（ Microbiota） 微生物组（ Microbiome）我国微生物群研究1970年代：余贺教授，魏曦教授等倡议1980年代：中国微
3、生物学会微生态学分会；中国微生态学杂志1990年代：中华预防医学会微生态学分会；生态制剂2000年代：微生物群与肝脏；微生物群的转移2010年代：华大研究院； 国际人体微生物群大会（杭州）Development of the MicrobiotaClemente,et al 2012A NON EXHAUSTIVE OVERVIEW OF HUMAN GUT MICROORGANISMS AMONGBACTERIAL, ARCHAEA, VIRAL, AND EUKARYOTA DOMAINS.GUT MICROBIOTACurr Opin Microbiol. 2011 Feb;14(1)_
4、92A comparison of Gram staining, electron microscopy, and pyrosequencing to determine the proportion of Gram-positive/Gram-negative bacteria in the same stool sampleGUT MICROBIOTAcolonic bacteriaDigestion 2006;73(suppl 1)5GUT MICROBIOTAThe composition of gut microbiota is unique to each individual,
5、just like our fingerprints.1Our gut microbiota contains 1014 of bacteria tentimes more cells than in our body.2There are more than 3 millions microbial genes in our gut microbiota 150 times more genes than in the human genome.3Microbiota, in total, can weigh up to 2 kg.4More than 1,000 different kno
6、wn bacterial species5THE INUENCE OF EXTERNAL FACTORS DETERMINING THE COMPOSITION OF THEHUMAN GUT MICROBIOTA.肠道微生物群与人体代谢 ,发育和行为 互交流共发育 共进化共代谢BIDIRECTIONAL COMMUNICATION BETWEEN GUT MICROBIOTA ANDCOMPONENTS OF THE GUTBRAIN AXIS INFLUENCE NORMAL HOMEOSTASIS. Trends in Neurosciences, 2013, 305Coevolutio
7、n of microbes and human beingsCo-metabolism of microbiota and human beingsDiet-independent and -dependent microbial effects on host metabolismFunctional interactions between the gut microbiota and host metabolismNature 489, 242249 Intestinal immunological defects in germ-free miceGut microbiotaepith
8、elium interaction regulates the homeostasis of the gut immune system.Tripartite interaction controls intestinal homeostasis. 微生物影响宿主神经系统发育出生 4-14 天下丘脑 -垂体 -肾上腺 (HPA)轴抑制状态应激低反应时期在发育早期 , HPA 轴功能的成熟需要有肠道微生物的作用此时 HPA 轴的发育决定成年后 HPA 轴的功能BALB/c 雄性无菌小鼠 HPA 轴对应激的反应增强 , GF 小鼠的血浆促肾上腺皮质激素和皮质醇水平比 SPF 小鼠更易受束缚应激影响
9、， HPA 轴的负反馈能力更弱单一定植婴儿双歧杆菌 能够降低 HPA 应激反 应 ; 单一定植兔源性大肠杆菌显著增加 HPA 应激反应。啮齿类动物MICROBIOTA MAY PLAY A ROLE IN THE RELATION BETWEEN INFLAMMATION ANDANXIETY-LIKE BEHAVIORS.Trends in Neurosciences, 2013, 305Novel evidence shows that the gut microbiota exert a strong inuence over brain developmentDiamond, et a
10、l 2011卫生假说？接触微生物减少免疫系统发育不成熟Treg低不能充分终止炎症反应Th1易失控个体1 型糖尿多发性硬克罗恩病抑郁Th2易失控个体过敏性疾病焦虑MICROBES AFFECT OUR THOUGHTS AND FEELINGS Helicobacter pylori: Infected children performed worse on IQ tests, suggesting a link between H. pylori infection and cognitive development. Lactobacillus helveticus : Healthy hu
11、man volunteers who consumed a probiotic mix of these bacteria exhibited less anxiety and depression. Lactobacilli: Healthy students had fewer of these bacteria present in their stool during a high-stress exam time compared with a less stressful period during the semester长双歧杆菌Bifidobacterium longum鼠鞭
12、虫Trichuris muris轻度和中度的胃肠道炎症更多的焦虑和胆怯行为血浆炎症相关蛋白质水平显著上调其它 CNS 功能相关蛋白质减少（丝氨酸蛋白酶抑制剂 3、表皮生长因子海马 BDNF 表达减少(低海马 BDNF 水平与抑郁和焦虑行为相关纠正行为纠正 BDNF mRNA 表达色氨酸代谢改变犬尿氨酸 /色氨酸比率增加感染 AKR小鼠犬尿氨酸以一种剂量依赖方式改变小鼠行为色氨酸是 5-HT 的前体， 5-HT 是调节大脑情绪和胃肠道功能的重要神经递质肠道微生物可能通过神经途径 (神经递质等 )和免疫途径 (各种细胞因子 ), 改变脑内生化物质构成 , 从而引起抑郁、焦虑等精神问题肠道微生物群与 人体疾病
