肠道菌群（GutMircrobiota≈CNS！）
一片看懂肠道菌群在人体中的作用
一片看懂肠道菌群在人体中的作用日文名：肠内フローラ解明！惊异の细菌パワー中文名：肠道细菌 / 肠道花园类型：医疗健康时长：49min官网：播出时间：2015年2月22日午後9时00分～9时49分腾讯视频链接英语中字版，非会员只能看5分钟，后台回复“肠道细菌”下载1080p英语中字版收藏观看日语中字版，在线可看全片，后台回复“肠道细菌”下载720p日语中字mp4版收藏观看由于面向读者略有不同，两个版本画面也有15分钟许多不同。
如日语还有几段综艺风格的段落。
影片简介在我们的身体中，存在着各种各样的细菌。
尤其在肠道内，存在着一个肠道细菌生态系统，就是所谓的肠道floral(肠道菌群、肠道微生物组)。
其中的细菌种类超过数百种，细菌总量超过了100兆，这是一个什么样的世界呢随着现代科技和医疗技术的发展，科学家发现这个生态系统中的细菌居然跟我们的健康、美容、甚至性格都有着深不可测的关联。
特别是在医疗方面，癌症、糖尿病、抑郁症等疾病都与之有关。
现在在欧美国家正在掀起一场医疗革命，使用一种称为粪便微生物移植的特殊的治疗方法，就可以彻底治愈很多之前无法治愈的顽疾。
随着研究的进一步深入，将来会有更多的疑难杂症会被攻克。
闲言少叙，让我们来了解一下隐藏在我们的身体中的这些不可思议的小伙伴们吧。
图文解读在我们的身体中隐藏着不为人知的秘密，即美容和保持健康的机制。
这里是吸收营养的肠道内部，实际上存在着肉眼无法看到的微小生命。
这是在我们的肠道中居住着的细菌们，它们的数量超过了100兆。
它们被称为肠道生态系统。
floral是花圃的意思。
肠道中的花圃是各种细菌的家园。
现在肠内生态系统的研究使医疗产生了巨大的变化。
全世界的国家接二连三地启动了国家级的项目，使用最先进的基因解析技术，陆续发现了新的细菌。
研究发现这些肠内细菌会影响到全身的健康。
癌症、糖尿病、肥胖症、过敏，之前从未考虑过这些疾病跟肠内细菌有关。
我们已经发现了30多种疾病与肠内生态系统的关系。
肠道菌群名词解释
肠道菌群名词解释肠道菌群是一个复杂的生态系统，由多种细菌、病毒、真菌等微生物组成，主要居住在人类的肠道中。
这些微生物通过与宿主（即人体）的相互作用，对宿主的健康产生重要影响。
肠道菌群在维持人体健康方面发挥着许多作用，包括帮助消化食物、合成维生素、调节免疫系统等。
肠道菌群失衡可能会导致各种健康问题，包括肠道疾病、代谢性疾病、免疫系统疾病等。
近年来，随着人们生活方式的改变，如饮食习惯、卫生习惯和抗生素的滥用等，肠道菌群的平衡逐渐受到破坏，引发了一系列健康问题。
因此，了解肠道菌群的结构和功能，以及如何维护肠道菌群的平衡，对于预防和治疗相关疾病具有重要的意义。
肠道菌群的结构和组成因人而异，受到许多因素的影响，如饮食习惯、生活方式、卫生条件、遗传因素等。
通过对肠道菌群的研究，人们发现了一些与健康和疾病相关的菌群特征，如肥胖人群的肠道菌群与瘦弱人群的肠道菌群存在显著差异；糖尿病患者的肠道菌群中某些益生菌的数量减少，而有害菌的数量增加。
这些发现为人们提供了新的思路和方法来预防和治疗相关疾病。
为了维护肠道菌群的平衡，人们需要采取一系列措施，包括合理饮食、适当运动、保持良好的卫生习惯、避免滥用抗生素等。
同时，针对肠道菌群的研究和应用也在不断深入，如益生菌和益生元的开发和利用、肠道微生物组学的研究等。
这些研究和实践将有助于人们更好地了解肠道菌群，从而更好地维护自己的健康。
综上所述，肠道菌群是一个重要的生态系统，对人类健康产生着深远的影响。
通过深入研究和了解肠道菌群的结构和功能，以及如何维护肠道菌群的平衡，人们可以更好地预防和治疗相关疾病，提高自己的健康水平和生活质量。
同时，随着科技的不断发展，人们对肠道菌群的认识和应用也将不断深入和完善。
在未来的研究中，人们需要进一步探索肠道菌群与人体健康的相互作用机制，以及如何通过调节肠道菌群来改善和治疗各种疾病。
此外，还需要加强肠道微生物组学的研究，以便更深入地了解肠道菌群的组成和功能。
肠道菌群
首都医科大学附属复兴医院
消化科
微生态系统
在人身体的体表及其与外界相通的腔道， 如口腔、 鼻腔系统、 咽喉腔、 眼结
合膜、 肠道及泌尿生殖道等部位都有大量的微生物的存在， 其中一部分为长
期寄居的微生物， 在机体防御机能正常时是无害的， 称为正常菌群或正常微 生物群。 正常菌群对人体有益无害， 而且是必须的。 正常菌群是由相当固定 的细菌组成， 有规律地定居于身体一些特定部位， 成为身体的一个组成部分。 正常菌群数量是巨大的，大约为1014个左右，约400~500种细菌，是人体细胞 总数的10-20倍（一个健康人由1013个动物细胞组成）。按重量计算：人体携 带的微生物总重量约为1271g，其中肠道占1000g，肺：20g，口腔占20g，鼻 占10g，眼1g，阴道29g，皮肤200g。人体微生物总量相当于一个肝脏大小， 产生的酶多于肝脏产生的酶量。
微生态系统-肠道正常菌群
人体携带的微生物细胞主要在肠道，胃肠的微生物量占人体总微生物量的 78.67%，粪便重量的1/3～2/5是微生物。其中90%~99.9％是厌氧菌(厌氧菌约为 需氧菌的 100倍）。在这些细菌中主要包括类杆菌属、真杆菌属、双歧杆菌属 、乳酸杆菌属等至少14个菌属。肠杆菌、肠球菌等需氧菌仅占菌群极少的一部
分。在长期的进化过程中， 通过个体的适应和自然选择， 正常菌群中不同种
类之间， 正常菌群与宿主之间， 正常菌群、 宿主与环境之间， 始终处于动 态平衡状态中， 形成一个互相依存， 相互制约的系统，人体在正常情况下，
正常菌群对宿主不致病。
肠道菌群
正常菌群外， 还有一种称为过路菌群， 又称外籍菌群， 是由非致病性或潜在 致病性细菌所组成，如金黄色葡萄球菌、绿脓杆菌、副大肠杆菌、产气杆菌、变
迈维代谢肠道菌群研究报告
一、研究概述肠道微生物（gut microbiota），也称肠道菌群，指肠道中存在的数量庞大的微生物，这群微生物依靠宿主的肠道生活，同时帮助寄主完成多种生理生化功能。
人体肠道内寄生着10万亿个细菌，它们的基因总数约为人自身基因数目的150倍，肠道菌群也因此称为人体的“第二基因组”。
可以说人体与人体共生微生物构成了超级生物体（superorganism）。
肠道微生物与宿主之间进行密切的信息交流，在代谢、免疫、神经系统调控中起到了重要作用，能影响体重和消化能力、抵御感染和自体免疫疾病的患病风险，还能控制人体对癌症治疗药物的反应。
针对肠道菌群的研究主要分为两个方向，一是菌群结构研究，二是菌群代谢物研究。
二、菌群检测肠道菌群结构检测的方法主要为扩增子检测和宏基因组检测两种方式。
扩增子检测扩增子测序是对特定长度的PCR产物或者捕获片段进行测序，可研究样本中属水平以上的微生物群落组成及其丰度差异。
一般研究肠道菌群使用16S rDNA检测。
宏基因组检测宏基因组，又被称为元基因组，它通过直接从环境样品中提取全部微生物的DNA，构建宏基因组文库，利用基因组学的研究策略研究环境样品所包含的全部微生物的遗传组成及其群落功能。
它是在微生物基因组学的基础上发展起来的一种研究微生物多样性、开发新的生理活性物质（或获得新基因）的新理念和新方法。
宏基因组测序研究摆脱了微生物分离纯培养的限制，扩展了微生物资源的利用空间，为环境微生物群落的研究提供了有效工具。
检测方式对比迈维代谢可提供专业的菌群检测技术服务。
三、菌群代谢研究近年来基于高通量测序的微生物组学研究极大加深了人们对微生物与健康和疾病关系的认识。
然而基因测序方法不能直接测定微生物的功能活性，难以鉴定微生物中的关键功能分子，单独使用无法回答肠道微生物何种成员通过何种方式影响宿主等关键问题。
单一组学研究弊端显现出来，多组学联用的优势逐渐突出。
肠道微生物的代谢组学是以微生物群落所有小分子代谢物为研究对象，可发现肠道微生物随宿主病理生理变化的关键代谢物，为微生物组-宿主互作机制研究提供线索，成为微生物组学研究的重要补充。
肠道微生物的英语单词
肠道微生物的英语单词The Complex World of Gut Microbiota.The gut microbiota, often referred to as the "microbiome" or the "intestinal flora," refers to the vast community of microorganisms that reside within the human gastrointestinal tract. This intricate ecosystem plays a crucial role in maintaining our overall health and well-being. The gut microbiota is composed of a diverse range of bacteria, fungi, viruses, and other microorganisms that coexist in a delicate balance.The human body is estimated to contain trillions of microbial cells, outnumbering the human cells by a ratio of 10 to 1. The majority of these microbial cells reside in the gastrointestinal tract, particularly in the colon. The gut microbiota performs various vital functions, including digesting food, synthesizing vitamins, and regulating the immune system.Functions of the Gut Microbiota.Digestion and Nutrition: The gut microbiota aids in the breakdown of dietary fiber and other complex carbohydrates, releasing short-chain fatty acids (SCFAs) such as acetate, propionate, and butyrate. These SCFAs serve as a source of energy for the host and have been linked to various health benefits, including improved insulin sensitivity and reduced inflammation.Immune System Regulation: The gut microbiota plays a crucial role in shaping and regulating the immune system. It stimulates the development of immune cells and helps maintain a balanced immune response, protecting against both infectious diseases and autoimmune conditions.Barrier Function: The gut microbiota contributes to maintaining the integrity of the gut barrier, which prevents harmful bacteria and toxins from leaking into the bloodstream. A healthy gut microbiota supports tight junctions between gut cells, ensuring a strong barrier against pathogens.Brain-Gut Axis: The gut microbiota also interacts with the brain through the gut-brain axis, influencing mood, cognition, and behavior. This axis involves a complex communication network between the gastrointestinal tract and the central nervous system, which is believed to play a role in conditions like depression, anxiety, and autism.Importance of Gut Microbiota Balance.Disruptions to the gut microbiota, known as "dysbiosis," can lead to various health issues. Changes in the composition of the microbiota can be triggered by various factors, including diet, antibiotics, stress, and chronic illnesses.Diet: The composition of the gut microbiota is significantly influenced by the diet. A diet rich in fiber and diverse in plant-based foods promotes the growth of beneficial bacteria, while a diet high in processed foods and low in fiber can lead to a decrease in microbial diversity and an increase in harmful bacteria.Antibiotics: The use of antibiotics can have a profound impact on the gut microbiota, killing off both harmful and beneficial bacteria. This can lead to a temporary imbalance in the microbiota, allowing opportunistic pathogens to proliferate.Stress: Chronic stress has been shown to alter the gut microbiota composition, leading to an increase in inflammatory markers and a decrease in beneficial bacteria.Chronic Illnesses: Conditions like inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), and obesity have been linked to alterations in the gut microbiota. These changes can contribute to the development and progression of these diseases.Modulating the Gut Microbiota.Given the crucial role of the gut microbiota in maintaining health, there has been increasing interest in modulating its composition through various strategies.Probiotics: Probiotics are live microorganisms that, when administered in adequate amounts, confer a health benefit on the host. They are commonly found in yogurt, fermented foods, and dietary supplements. Probiotics can help restore balance to the gut microbiota, improving digestive health and immune function.Prebiotics: Prebiotics are dietary fibers that promote the growth and activity of beneficial bacteria in the gut. By providing food for the probiotic bacteria, prebiotics can help support a healthy gut microbiota.Dietary Changes: Incorporating a diet rich in fiber, fruits, vegetables, and whole grains can promote the growth of beneficial bacteria and maintain gut microbiota diversity.Conclusion.The gut microbiota plays a pivotal role in maintaining human health and well-being. Its intricate balance ofmicroorganisms is essential for digestion, immune system regulation, and overall physiological functions. Disruptions to this balance can lead to various health issues, emphasizing the importance of maintaining a healthy gut microbiota through diet, lifestyle choices, and probiotic supplementation. As research in this field continues to evolve, so does our understanding of the crucial role the gut microbiota plays in our lives.。
肠道菌群是高血压干预的新靶点
高 压 既是 多种复 杂 因素共 同导致 的临床综 合 “生理器官 ”，其组 成具 有宿 主特异 性 ，并 随宿 主 内外
征 ，也 是心脑血 管疾 病 发 生 发 展 的主 要 及共 同诱 因 环境 的变 化而变化 ，且充分参 与宿 主生 理 、生化 、病 理
和原 因 。现 阶段针 对高 血压发 病机 制 的研 究 主要 围 和药理 的整个过 程 及能量 的提 取 与储存 。肠道 菌 群
ｏｆ ｈｙｐｅ￣ｅｎｓｉｏｎ，ａｌｓｏ ａｂｎｏｒｍａｌｉｔｙ ｏｆ ｔｈｅ ｅｎｅｒｇｙ ａｂｓｏｒｐｔｉｏｎ，ｌｏｗ ｌｅｖｅｌ ｏｆ ｇｕｔ ｄｅｒｉｖｅｄ ｅｎｄｏｔｏｘｉｎ（１ｉｐｏｐｏｌｙｓａｃｃｈａｒｉｄｅ， ＬＰＳ）ａｎｄ ｄｙｓｆｕｎｃｔｉｏｎ ｏｆ ｔｈｅ ｇｕｔ ｂａｒｒｉｅｒ ｍｉｇｈｔ ｐｌａｙ ｔｈｅ ｍｏｓｔ ｉｍｐｏｒｔａｎｔ ｒｏｌｅ ｉｎ ｔｈｉｓ ｐｒｏｃｅｓｓ，ｍｏｒｅｏｖｅｒ，ｔｈｅ ｍｉｃｒｏｂｉｏ—
ｍ ｉｃｒｏｂｉｏｔａ ａｎｄ ｃｉｒｃａｄｉａｎ ｃｌｏｃｋ ｄｉｓｔｕｒｂａｎｃｅ，ｇｕｔ ｍ ｉｃｒｏｂｉｏｔａ ａｎｄ ｃｅｎｔｒａｌ ｂｌｏｏｄ ｐｒｅｓｓｕｒｅ ｒｅｇｕｌａｔｉｏｎ，ｔｈｉｓ ａｒｔｉｃｌｅ ｉｌｌｕｓ— ｔｒａｔｅｓ ｔｈｅ ｃｈａｎｇｅｓ ｏｆ ｔｈｅ ｃｏｍ ｍｕｎｉｔｙ ｃｈａｒａｃｔｅｒｉｓｔｉｃｓ ｏｆ ｇｕｔ ｍ ｉｃｒｏｂｉｏｔａ ｍ ｉｇｈｔ ａｆｆｅｃｔ ｏｎ ｔｈｅ ｏｃｃｕｒｒｅｎｃｅ ａｎｄ ｄｅｖｅｌｏｐｍ ｅｎｔ
４１４
基础 医学 与临床 Ｂａｓｉｃ＆ Ｃｌｉｎｉｃａｌ Ｍｅｄｉｃｉｎｅ
能是高 血压干 预 的新 靶 点 。
及个 体 间的相互 作用 而影 响的 。
１ 高血压控 制中的难点与 困惑
肠道菌群或可帮助抵御寒冷
由 于这 ８ 项 体 育运 动 呈 现 出 的 不 同 社 交 因 素 需 要 ２ 人 或 ，
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毛 球 和 足 球 ． 与 寿 命 得到 最 佳 改 善 相 关 。
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研 究 共
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变 的 水平。 其 原因 或 许 是 微生 物 组 的 缺 失 导致动 ，
物 无 法消 化足够 的 食 物 来 满足 寒冷状 态 下 的 能量 需 求 。
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机体 生 理 和 健 康 领 域 的 认 知 。
肠道微生物The human gut microbiome
REVIEW ARTICLESThe human gut microbiome:current knowledge, challenges,and future directionsMANEESH DAVE,PETER D.HIGGINS,SUMIT MIDDHA,and KEVIN P.RIOUXROCHESTER,MINN;ANN ARBOR,MICH;AND CALGARY,ALBERTA,CANADAThe Human Genome Project was completed a decade ago,leaving a legacy of pro-cess,tools,and infrastructure now being turned to the study of the microbes that re-side in and on the human body as determinants of health and disease,and has beenbranded‘‘The Human Microbiome Project.’’Of the various niches under investiga-tion,the human gut houses the most complex and abundant microbial communityand is an arena for important host–microbial interactions that have both local andsystemic impact.Initial studies of the human microbiome have been largely descrip-tive,a testing ground for innovative molecular techniques and new hypotheses.Methods for studying the microbiome have quickly evolved from low-resolution sur-veys of microbial community structure to high-definition description of composition,function,and ecology.Next-generation sequencing technologies combined withadvanced bioinformatics place us at the doorstep of revolutionary insight into thecomposition,capability,and activity of the human intestinal microbiome.Renewedefforts to cultivate previously‘‘uncultivable’’microbes will be important to the overallunderstanding of gut ecology.There remain numerous methodological challengesto the effective study and understanding of the gut microbiome,largely relating tostudy design,sample collection,and the number of predictor variables.Strategiccollaboration of clinicians,microbiologists,molecular biologists,computational sci-entists,and bioinformaticians is the ideal paradigm for success in thisfield.Meaning-ful interpretation of the gut microbiome requires that host genetic and environmentalinfluences be controlled or accounted for.Understanding the gut microbiome inhealthy humans is a foundation for discovering its influence in various important gas-trointestinal and nutritional diseases(eg,inflammatory bowel disease,diabetes,andobesity),and for rational translation to human health gains.(Translational Research2012;160:246–257)Abbreviations:GI¼gastrointestinal;IBD¼inflammatory bowel disease;IBS¼irritable bowelsyndrome;TRFLP¼terminal restriction fragment length polymorphism;UC¼ulcerative colitisFrom the Division of Gastroenterology and Hepatology,Mayo Clinic, Rochester,Minn;Division of Gastroenterology and Hepatology, Department of Internal Medicine,University of Michigan Medical Center,Ann Arbor,Mich;Division of Biomedical Statistics and Informatics,Department of Health Sciences Research,Mayo Clinic, Rochester,Minn;Department of Medicine,Division of Gastroenterology and Hepatology,Department of Microbiology and Infectious Diseases,Faculty of Medicine,University of Calgary, Calgary,Alberta,Canada.The authors have nofinancial disclosures relevant to this article.Submitted for publication December6,2011;revision submitted May 8,2012;accepted for publication May8,2012.Reprint requests:Kevin P.Rioux,University of Calgary,1863Health Sciences Centre,3330Hospital Drive NW,Calgary,Alberta,Canada T2N4N1;e-mail:kprioux@ucalgary.ca.1931-5244/$-see front matterÓ2012Mosby,Inc.All rights reserved.doi:10.1016/j.trsl.2012.05.003246Humans live in a biosphere where microbes are ubiqui-tous and have existed and evolved over3.8billion years.1 The intestinal tract of humans harbors a complex micro-bial community estimated to contain approximately100 trillion cells,exceeding the number of human cells by a factor of10.2-4This complex community of microbes in the alimentary tract(bacteria,archaea,eukarya,and viruses)is also known as the‘‘gastrointestinal(GI) microbiota.’’5,6Akin to the human genome,which is the sum of all human genes,the term‘‘microbiome’’refersto all of the microbiota in a defined microbial community,which are usually differentiated by their genetic elements.7Metagenomics refers to the functional and compositional analysis of an assemblage of microbes based on molecular study of their collective genomes.8,9 The gut microbiota performs a variety of beneficial functions(Table I),and given their importance in human health and disease,the Human Microbiome Project was launched by the National Institutes of Health to(1) characterize the microbial communities of various niches of the human body(eg,the nasal passages,oral cavity,skin,urogenital system,and GI tract),(2)to de-termine whether individuals share a core human micro-biome,and(3)to explore whether changes in the human microbiome cause or correlate with human disease.10,11 The distal GI tract contains the most abundant and diverse communities of microbes,in continuous interplay with the human host resulting in both local (mucosal and luminal)and systemic(metabolic and nutritional)effects.Therefore,of all microniches being explored by human microbiome researchers,the GI tract holds the most promise for discovery of important new concepts and understanding of the human‘‘superorganism’’and translation to clinical biomarkers and therapies.12There are excellent reviews that have focused on the temporal and spatial development of the human gut mi-crobiota13and their role in health and disease.14The goal of this article is to highlight the current state of knowledge of the human gut microbiome,discuss tech-nical and practical limitations of scientific devices and tools,and map out some of the knowledge gaps in this challengingfield that will be solved by thoughtful scien-tific approaches,advanced sequencing and computa-tional technology,and persistence.TECHNIQUES FOR ANALYZING MICROBIOTA Studies in the1970s using anaerobic culture–based techniques identified more than400to500distinct bac-terial species in the human gut.15Studying the human GI microbiota by cultivation methods has many draw-backs:It produces selective growth of some organisms and thus distorts composition of the natural community.Moreover,approximately60%to80%of gut microbes simply cannot be grown by conventional in vitro tech-niques.16,17In1977,Woese and Fox18described a tech-nique for molecular characterization of bacterial phylogeny based on ribosomal RNA sequence analysis. In particular,the16S rRNA is a molecule that is univer-sally present in bacteria and has highly conserved do-mainsflanking hypervariable sequences that can be used to distinguish bacterial groups.In the early 1980s,various culture-independent molecular tech-niques based on the16S rRNA became available,and during the last3decades they have been used extensively to assess the structure of complex or fastid-ious prokaryotic communities.1Examples of these techniques are terminal restriction fragment length polymorphism(TRFLP),denaturing gradient gel elec-trophoresis,andfluorescent in situ hybridization.19 These bacterial community profiling or‘‘fingerprint-ing’’techniquesfirst involve isolating bacterial DNA from environmental or biological samples.The DNA is amplified by polymerase chain reaction using univer-sal primers that target conserved regions of the16S rRNA gene,and the resulting amplicons contain vari-able regions that discern the constituent members of bacterial communities by electrophoretic or hybridiza-tion techniques.Cloning and then sequencing of the16S rRNA gene in an automated capillary sequencer is a higher-resolution method of studying bacterial phylogeny.20This tech-nique uses Sanger sequencing to produce a long read ( 800base pairs)of the16S rRNA gene,which enables identification of bacteria at a higher-level phylogenetic resolution(ie,genera and species).This relies on robust bioinformatics tools,such as the Ribosomal Database Project.21In the wake of the Human Genome Project,next-generation sequencing technologies have emerged that have increased the depth and speed of phylogenetic cov-erage and decreased the cost through massively parallel sequencing methods.There are various commercial platforms for next-generation sequencing.One of these newer techniques is pyrosequencing that identifies nu-cleotides by the amplitude of light signals generated when luciferin is converted to oxyluciferin during Table I.Biological effects of the gut microbiota on human hostDevelopment of innate and adaptive immunityIntestinal epithelial integrityEnergy sourceVitamin biosynthesis,bile salt transformation,catabolism of dietary glycans(eg,cellulose and pectins)Barrier to colonization by microbial pathogensXenobiotic metabolismTranslational ResearchVolume160,Number4Dave et al247DNA synthesis.22A limitation of this technique in its first iteration was short sequence reads of100to250 base pairs,which have been quickly surpassed by newer methods.There are several companies that manufacture these machines(eg,Roche454[Roche Diagnostics Corp,Indianapolis,Ind],Illumina/Solexa[Illumina Inc,San Diego,Calif],Applied Biosystems,Foster City,Calif).Although the16S rRNA gene sequences obtained by Sanger or next-generation sequencing en-able greater depth and resolution to identify and discern taxa,the identity and thus functional importance of community members may be missed because of a sub-stantial proportion gut microbes match ribosomal se-quences from uncultured bacteria.Also,there is currently no clear consensus on what constitutes a bacte-rial species at a molecular level,23so alternative methods of describing‘‘phylotypes’’are based on oper-ational taxonomical units,groups of sequences that are highly similar to a single reference sequence.24 Despite the enormous progress made in determining microbial community structure using the16S rRNA gene,the basic technique provides no information about bacterial physiology and ecological significance.1An-other novel approach to assess the diversity of microbes is the whole genome shotgun sequencing of community DNA.25This differs from16S RNA sequencing tech-niques in that entire genomes of microbes are sequenced and compared with previously characterized genes to build a picture of functional capability of the micro-biota.This approach helps not only with identification of rare species in a complex community but also with identification of microbial genes that code for metabolic or biologic functions.12The drawback with this tech-nique is that a large amount of DNA is needed(although it can be overcome by whole genome amplification), contamination with host DNA is problematic,and many genes are identified that do not yet have a known function.Hamady and Knight26have published a com-prehensive review of various sequencing techniques used in microbiome investigation.SEQUENCE DATA ANALYSIS AND CHALLENGESAs mentioned earlier,there are2main approaches to surveying the microbiome,16S rRNA sequencing and whole genome sequencing(Fig1).The former uses a small representative region as a marker or proxy and involves evaluating the informative sites of any of the 16S rRNA variable regions.27Similar organisms are represented by clustered reads and used to infer the phy-logenetic and taxonomic identity.The proportion of var-ious types of organisms is used to infer the structure of microbial communities using statistical analysis.The latter approach of assembly involves splitting the DNA into smaller pieces and sequencing them to later assemble into longer contigs.Those are then used to in-fer functional and metabolic pathway information.28 There are huge challenges in analyses of these data. All the next-generation sequencing technologies have improved vastly but still have higher error rates than tra-ditional Sanger sequencing.There are also systematic sources of error depending on the sequencing instru-ment used that can yield noisy data.29,30Qiime31and Mothur32are popular analysis tools for microbial se-quencing data,but there are many pre-and post analysis steps that have a bearing on the eventual results.It is thus vital to have quality checks and data-cleaning steps along the analysisflow to ensure the validity of the end results.The alignment of these short reads,especially to similar sequences,is error prone.A one-off read sup-porting evidence for a particular rare organism or group should thus be treated with caution.Some studies have come up with a leave-one-out analysis to recommend a minimum number of sequence-reads mapping to a par-ticular feature to be confident of the result.33These anal-yses are continually improving as the availability of complete microbial genomes increases.This would mean a larger number of reference genomes that can be used for accurate and efficient bioinformatics analy-sis and better functional interpretation of data.The current tools use traditional statistical techniques with some refinements that do not take into account the inherent complexity in biological systems and are lim-ited by the assumption that predictor variables(ie,gut microbes)are independent of each other.This is clearly not the case,because the human gut microbiota is a com-plex community whose constituents are linked together through complex homeostatic interactions.The solution to deciphering this complexity could be through the use of machine-learning algorithms that include neural net-works,support vector machines,and decision trees.Ma-chine learning is inherently more suited to the study of complex microbial communities because it uses pattern recognition,does not need identification of predictor variables in advance,and becomes increasingly better at prediction with larger volumes of data.34Another problem facing investigators is the huge volume of data that sequencing generates,which can overwhelm available computing resources of an institution.Cloud computing uses the storage and processing capabilities of a network of remote servers hosted on the internet, providing individual investigators paid access to power-ful computing resources suited to the massive data gen-erated by current sequencing methods.The Cloud BioLinux and Amazon Elastic Compute Cloud(http:// /ec2/)are examples of2currently available commercial resources for metagenomic anal-yses.35In addition,the Data Intensive Academic GridTranslational Research248Dave et al October2012is a free computational cloud sponsored by the National Science Foundation and available to researchers in aca-demic and nonprofit institutions.SAMPLING THE GUT MICROBIOTAAlthough the same bacterial phyla predominate in the stomach,small intestine,and colon,their relative com-position and abundance varies considerably.36Meth-odologic factors likely account for some of this variation,including patient selection,sample handling,and choice of molecular and bioinformatics techniques.Next,we provide data on some of the issues that may be confounding human gut microbiota studies.These con-cepts are summarized in Table II .1.What constitutes a normal,healthy human micro-biota?It has long been apparent that the intestinal micro-biota varies significantly from one individual to another,making it impossible to define the ‘‘normal’’or ‘‘healthy’’human gut microbiota.Indeed,it is difficult to define what constitutes a healthy human,and as-sumed absence of overt disease may not be the most re-liable indicator of a healthy microbiota for study purposes.Although it will be a difficult task to accom-plish,future studies could use a set of phenotypic char-acteristics,for example,the Adult Fitness Test launched as a part of President’s Challenge (http://www.adultfi/).This test incorporates aerobic fit-ness,muscular strength,endurance,flexibility,and body composition to determine overall health-related fitness.A ‘‘core microbiota’’has been proposed,37but it re-mains unclear what the essential constituents are,and,instead,a set of core functions of the microbiota may well emerge as the correct unifying concept.38Age has well-described influences on the fecal microbiota,for example,with substantial differences being de-scribed among healthy infants,adults,and the el-derly.39-42Gender differences have also been described.40On a collective scale,it is also apparent that the human gut microbiota differs between various ethnic groups,which likely reflects both genetic and en-vironmental influences.40Environmental influences that likely affect the GI microbiota are wide-reaching,dy-namic,and difficult to control for in the context of human studies.These include diet,medications (espe-cially antibiotic exposure,even if remote),stress,smok-ing,and GI infections.Early studies suggested that the intestinal microbiomes of healthy adults were stable over time,43,44but such studies generally used fingerprinting techniques with low sensitivity and relatively few points of observation over a short period of time.More recent studies using deep sequencing techniques have shown a surprising degree of species-level variability within an individual’s fecalFig rmatics analysis.Translational Research Volume 160,Number 4Dave et al 249microbiota over a short time span of days to weeks,with an individual core microbiota of perhaps only 10%re-maining unchanged in the long term.45This has obvious implications for basic and clinical studies in humans,because our new understanding of the human gut micro-biome as a moving target makes it difficult to ascribe significance to shifts in the microbiome in the presence of significant background temporal variation.2.Is fecal microbiota representative of the resident microbiota of the distal GI tract?A majority of the studies of the human gut micro-biome have analyzed the microbiota of human fecal specimens,given the ease of acquisition,minimal cost,and avoidance of invasive procedures such as colo-noscopy with requirement for fasting and laxative prep-aration.It is widely believed,however,that the highly evolved biofilm communities that are closely associated with the intestinal epithelium are biologically more rel-evant than planktonic microbes that exist in the lumen of the gut or associated with food residue,and,moreover,fecal specimens may not accurately portray the mucosal microbiota.Even within stool,there appears to be sig-nificant differences between microbiota of the liquid fraction compared with that associated with the solid phase (insoluble plant residue and mucin).46Lepage et al 47used a bacterial small subunit RNA fingerprinting technique to demonstrate that the dominant bacterial groups differ between fecal and mucosa-associated mi-crobiota in patients with inflammatory bowel disease (IBD)and healthy controls.In a deep sequencing study of 3healthy individuals,mucosal tissue samples from the cecum,ascending colon,transverse colon,descend-ing colon,sigmoid colon,and rectum were compared with fecal samples taken 1month after colonoscopy.48This study showed that the mucosa-associated micro-biota was different from stool microbiota within an in-dividual,and the authors hypothesized that the fecal microbiota represents a combination of shed mucosal bacteria and the nonadherent luminal population.In ad-dition,the investigators showed that mucosa-associated microbiota had a patchy and heterogeneous distribution within a subject.Rather than a subset of the fecal micro-biota,the mucosa-associated microbiota is composi-tionally distinct from that of stool.49Marteau et al 50compared cecal luminal contents (obtained by fluoro-scopic placement of an orocecal tube)with fecal sam-ples using both culture-based and culture-independent techniques,showing that the fecal flora was different from the cecal flora both qualitatively and quantita-tively.3.What is the optimal method of sampling mucosa–associated microbiota?In view of the limitations of studying stool specimens,investigators have turned to mucosal biopsies of the GI tract collected by endoscopic means as the source spec-imens for microbiome studies.However,endoscopic bi-opsies also have important limitations because fasting and colon cleansing are common prerequisites of endo-scopic biopsy collection,and tissue specimen them-selves are contaminated by luminal microbes in the process of endoscopic collection.During colonoscopy,for example,biopsy forceps are advanced and then with-drawn via the same channel used to suction stool resi-due.To determine the degree of contamination ofTable II.Technical and methodological challenges to studying the human gut microbiotaTechnicalContamination during sample collectionBiases due to varying efficiency of bacterial nucleic acid extractionInherent polymerase chain reaction biases leading to under-representation or failed detection of minor phylotypes 16S rRNA gene does not accurately reflect bacterial abundance (varying copy numbers)Sequencing errorsMolecular techniques cannot discern microbes as dead or alive,autochthonous or allochthonousMethodologicalBroad definitions of healthy human subject Lack of correlative host genotype dataConfounding influences of diet and drugs largely unaccounted forEffect of fasting and pre-colonoscopy bowel cleansing on relevant microbiotaValidity of mucosal biopsies as representation of ‘‘mucosa-associated’’microbiota Deep sequencing vs fingerprinting techniques How is operational taxonomic unit defined Moving target:temporal instabilityMajority of metagenomic studies to date have not yet assessed functional aspects of microbiome Statistical tools for devising adequately powered clinical studies are limitedTranslational Research250Dave et alOctober 2012biopsies during endoscopic collection,we deviseda study comparing standard and sterile sheathed biopsyforceps.51Sheathed forceps were constructed by cover-ing standard endoscopic biopsy forceps with polyethyl-ene tubing.Paired biopsies using standard and sheathedforceps were obtained from the terminal ileum of sub-jects,and mucosa-associated bacteria were character-ized by16S-rDNA polymerase chain reaction andTRFLP.Our study showed no difference in the micro-biota between specimens collected with standard or ster-ile sheathed biopsy forceps within individual subjects.In a unique study by Mai et al,52the fecal microbiotawas studied before and up to8weeks after colonoscopyin a small series of healthy individuals undergoing coloncancer screening.In some patients,there were persistentalterations in the fecal microbiota after colonoscopy,presumably due to the effects of fasting and the unspec-ified colon-cleansing agent.No similar studies havebeen published to replicate these preliminary data orto extend thefindings to a variety of common-use bowelpreparations or to the mucosa-associated microbiota.4.Do sample storage conditions and method of DNAextraction matter?As part of ongoing microbiome studies,samples arebeing collected from subjects and archived in biobanks.A relevant concern is whether storage conditions affectthe diversity of gut microbiota.A16S rRNA pyrose-quencing study showed that short-term storage of upto14days at20 C,4 C,220 C,or280 C did not sig-nificantly affect the microbial composition.53Likewise,Wu et al54showed that there was no significant differ-ence in bacterial composition determined by pyrose-quencing in fecal samples immediately frozen at 280 C or those stored on ice for24or48hours.54Other investigators have revealed concern about the stabilityof stool specimens stored at room temperature,particu-larly in excess of12hours.55The exact method of DNAextraction also seems to be important,with an initialbead-beating step improving the performance of bothphenol-based protocols54and proprietary DNA extrac-tion kits.56Bead beating refers to mechanical disruptionof bacterial cell walls by vigorous mixing with tinyglass beads and improves extraction of cytosolic com-ponents from difficult to lyse bacteria including Firmi-cutes,which are a major component of the human gutmicrobiota.COMPOSITION OF THE GUT MICROBIOTAIt is estimated that up to80%of the bacteria in the hu-man gut cannot be cultivated by conventional tech-niques,largely because of their fastidious nutrient andanaerobic requirements and their complex dependence on one another.17Molecular techniques have signifi-cantly advanced our understanding of the constituentmembers of the human microbiome and have largelysupplanted cultivation-based techniques for study ofthe gut microbiome.The major members of bacterialcommunities in various segments of the human GI tractare illustrated in Figure2.The most diverse and abun-dant microbial communities generally occur in theoral cavity and distal GI tract and have been the focusof most studies,because they are most amenable to sam-pling.However,the relatively simple indigenous micro-biota of the human esophagus,stomach,and smallbowel are relatively unstudied,and these niches presentthe added challenge of trying to discern allochthonousbacteria(‘‘passersby’’from upstream niches that arelikely irrelevant)from autochthonous microbes(repre-senting stable,functionally relevant community‘‘resi-dents’’).The oral cavity contains members of thephyla Firmicutes,Proteobacteria,Bacteroidetes,Acti-nobacteria,and Fusobacteria,which account for99%of all phyla present.The rare phyla belong to SR1,TM7,Cyanobacteria,Spirochaetes,Tenericutes,andSynergistetes.57A pyrosequencing study of samplesfrom distal esophagus showed the presence of membersof6phyla,Firmicutes,Bacteroides,Actinobacteria,Proteobacteria,Fusobacteria,and TM7.The bacteriaStreptococcus,Prevotella,and Veillonella were foundto be the most prevalent,and the community of the distalesophagus was similar to that of the oral cavity58;how-ever,the majority of esophageal organisms could be cul-tivated,unlike those of the oral microbiome.Given theextremely low pH in the stomach,it was originally be-lieved that,with few exceptions(eg,Helicobacter py-lori),the stomach harbored a few transient microbial species and did not have a complex community likethe distal GI tract.3However,in a study of gastric biopsyspecimens from23human subjects using the16S rRNAgene clone library construction,Bik et al12showed thatthere is a diverse community of gastric microbes domi-nated by members of phyla Proteobacteria,Firmicutes,Actinobacteria,Bacteroidetes,and Fusobacteria.Thismicrobial community was significantly different thanthe oral and esophageal community.Another interestingfeature of this study was that the composition of the bac-terial community was not apparently altered by the pres-ence of H.pylori.The microbiota of the human small bowel is relativelyunstudied.By using TRFLP to study samples obtainedfrom3individuals during autopsy,one group showedthat the microbiota of the jejunum and ileum was lesscomplex than that of the colon.The jejunal and ilealsamples contained more facultative anaerobes and noClostridium coccoides and leptum subgroups,in con-trast to cecum and rectosigmoid samples.59Translational ResearchVolume160,Number4Dave et al251Microbial abundance is greatest in the colon with ap-proximately 1011and 1012microbial cells per gram of stool,and the number of microbial genes is 2orders of magnitude greater than that contained by the human host genome itself.2Recent studies of human fecal and colonic biopsy specimens have revealed members of 9distinct phyla (Firmicutes,Bacteroidetes,Actinobacte-ria,Fusobacteria,Proteobacteria,Verrucomicrobia,Cy-anobacteria,Spirochaetes,and VadinBE97).5,48The phyla Firmicutes and Bacteroides are the dominant phyla in the colon.10,38,48In contrast,in the total biosphere there are up to 70bacterial phyla,which highlights the fact that the human GI microbiota is restricted to a small subset of phyla,but with a high degree of species richness and abundance within these core constituent phyla.By using the Illumina Genome analyzer platform,the Metagenome of Human Intestinal Tract Consortium as-sessed the metagenome of fecal specimens obtained from 124healthy patients,overweight patients,obese patients,and patients with IBD from Denmark and Spain.38This is the most comprehensive study of human microbiome from a large group of subjects to date.The investigators were able to estimate that human gut mi-crobiota harbors approximately 1150bacterial phylo-types or species.In addition,they noted 536,112unique genes in each sample,of which 99%were bacte-rial.Approximately 40%of the bacterial genes from each individual were shared with at least half of the in-dividuals of the cohort.These highly conserved genes are involved in degradation and digestion of complex sugars,production of short chain fatty acids,and bio-synthesis of vitamins.Although significant interindivid-ual differences exist in the composition of the gut microbiome of humans,there is an essential functional-ity of gut microbes that support human health and nutri-tion.Thus,the concept of the ‘‘human superorganism’’has emerged,a physiology and homeostasis that are the complex sum of human and microbial gene expres-sion.10One of the goals of the human microbiome project is to ascertain whether we have a core group of microor-ganisms that are shared between individuals.Evidence from recent studies suggests that,rather than acoreFig 2.The dominant phyla in various locations in the human GI tract.By permission of Mayo Foundation for Medical Education and Research.All rights reserved.(Color version of figure is available online.)Translational Research252Dave et alOctober 2012。
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肠道菌群（GutMircrobiota≈CNS！）小白讲实验，带你走进科研殿堂，助你从实验小白变身科研达人实验小白人的胃肠道表面积大约有400平方米（相当于2个网球场的大小），而体内95%的细菌都位于胃肠道中，总量大概有1-2千克，几乎占粪便干重的1/3。
尽管细菌的体积仅仅是细胞的1/10到1/50大小，但是细菌的数量是机体细胞数量的10倍，首尾相连能绕地球两圈半。
从胃到结肠，细菌的数量和代谢强度都是逐渐增加的，因此，结肠是人体中细菌浓度最高，代谢最旺盛的部位。
影响肠道菌群的因素Brain-Gut axis当大脑有应激反应时，可通过肾上腺素能神经途径改变肠道菌群稳态，引起肠道内环境紊乱[1]。
最常见的是应激性肠炎（IBS），即在你紧张的时候可引起急性腹泻的一种疾病。
实验小白将有专刊为大家介绍这种神秘的疾病（“懒驴上磨屎尿多”中的科学知识）。
1.Collins SM, Bercik P: The relationship between intestinal microbiota and the central nervous system in normal gastrointestinal function and disease. Gastroenterology 2009, 136:2003-2014.酒精 & 肠道菌群酒精和乙醛等可增加肠道的通透性，引起肠道菌群紊乱，导致菌群分泌LPS、PGN、flagellin、CpG以及DNA增加，最终改变肝内免疫反应，促进酒精性肝病等肝脏疾病的发生发展。
1. Szabo G: Gut-liver axis in alcoholic liver disease. Gastroenterology 2015, 148:30-36.宿主粪便中的miRNA & 肠道菌群宿主粪便中的miRNA可进入像F.nucleatum和E.coli等肠内细菌，调控其基因的转录，最终影响这些肠内细菌的生长。
粪便中缺少miRNA可导致肠内菌群紊乱，加重大肠炎发展；而移植正常小鼠粪便中的miRNA则可减轻大肠炎症状[1]。
1. Liu S, da Cunha AP, Rezende RM, Cialic R, Wei Z, Bry L, Comstock LE, Gandhi R, Weiner HL: The Host Shapes the Gut Microbiota via Fecal MicroRNA. Cell Host Microbe 2016, 19:32-43.宿主遗传背景 & 肠道菌群2014年cell杂志发文称，同卵双生比异卵双生具有更相似的肠道菌群组成，而且鉴定出多种和遗传有关的肠道细菌种属。
另外，该文章还发现减肥相关肠道细菌（Chtistensenella minuta）.如上图所示，与肥胖的人相比，苗条的人具有更高水平的C.minuta，而无菌小鼠接受C.minuta移植后，小鼠体重减轻。
1. Goodrich JK, Waters JL, Poole AC, Sutter JL, Koren O, Blekhman R, Beaumont M, Van Treuren W, Knight R, Bell JT, et al: Human genetics shape the gut microbiome. Cell 2014, 159:789-799.抗生素/质子泵抑制剂等 & 肠道菌群抗生素和质子泵抑制剂等试剂的大量使用可改变肠道菌群组成。
在我国，抗生素滥用问题十分严重，而兽用抗生素滥用问题更是触目惊心。
1. Modi SR, Collins JJ, Relman DA: Antibiotics and the gut microbiota. J Clin Invest 2014, 124:4212-4218.2. Jackson MA, Goodrich JK, Maxan ME, Freedberg DE, Abrams JA, Poole AC, Sutter JL, Welter D, Ley RE, Bell JT, et al: Proton pump inhibitors alter the composition of the gut microbiota. Gut 2016, 65:749-756.Tfh-IgA & 肠道菌群宿主体内的TLR配体与DC等抗原提呈细胞表面的TLR结合后诱导Tfh细胞产生，进而辅助B细胞产生IgA抗体来调控肠道菌群组成[1-3]。
1. Kubinak JL, Petersen C, Stephens WZ, Soto R, Bake E, O'Connell RM, Round JL: MyD88 signaling in T cells directs IgA-mediated control of the microbiota to promote health. Cell Host Microbe 2015, 17:153-163.2. Proietti M, Cornacchione V, Rezzonico Jost T, Romagnani A, Faliti CE, Perruzza L, Rigoni R, Radaelli E, Caprioli F, Preziuso S,et al: ATP-gated ionotropic P2X7 receptor controls follicular T helper cell numbers in Peyer's patches to promote host-microbiota mutualism. Immunity 2014, 41:789-801.3. Kawamoto S, Maruya M, Kato LM, Suda W, Atarashi K, Doi Y, Tsutsui Y, Qin H, Honda K, Okada T, et al: Foxp3(+) T cells regulate immunoglobulin a selection and facilitate diversification of bacterial species responsible for immune homeostasis. Immunity 2014, 41:152-165.母体IgG和IgA抗体促进子代肠道菌群稳态母体内IgG和IgA抗体协同作用抑制子代体内肠道菌群特异性的CD4+T细胞反应，从而维持子代肠道菌群稳态。
1. Koch MA, Reiner GL, Lugo KA, Kreuk LS, Stanbery AG, Ansaldo E, Seher TD, Ludington WB, Barton GM: Maternal IgG and IgA Antibodies Dampen Mucosal T Helper Cell Responses in Early Life. Cell 2016, 165:827-841.饮食 & 肠道菌群如上图所示，高纤维饮食可以很好的维持母代、子代和孙代的肠道菌群多样性，而低纤维饮食可显著减少母代、子代和孙代的肠道菌群多样性。
而且这种多样性减少的过程是不可逆的[1]。
1. Sonnenburg ED, Smits SA, Tikhonov M, Higginbottom SK, Wingreen NS, Sonnenburg JL: Diet-induced extinctions in the gut microbiota compound over generations. Nature 2016, 529:212-215.肠道菌群的作用肠道菌群除了和肠内疾病的发生发展（如IBD、IBS、克罗恩病、结直肠癌等）有直接关系，和肿瘤、肥胖、糖尿病、关节炎、哮喘等肠外疾病也有密切关系，甚至还能影响机体的行为、学习和记忆等过程。
实验小白这一期重点为大家介绍肠道菌群与这些肠外疾病的关系。
肠道菌群 & 免疫在具体介绍肠道菌群和疾病的关系之前，我们首先总体了解一下肠道菌群是如何调控机体的免疫系统的。
肠道菌群的代谢物肠道菌群的代谢产物中的短链脂肪酸（Short-chain fatty acids）、芳香烃受体的配体（AHR liagands）、多胺类物质（polymines）等都可显著影响机体的免疫功能。
尤其是短链脂肪酸可结合多种GPR分子，诱导Treg细胞和耐受型的DC细胞产生，维持肠道稳态，最终降低Th2、过敏等炎症反应[1]。
1.Rooks MG, Garrett WS: Gut microbiota, metabolites and host immunity. Nat Rev Immunol 2016, 16:341-352.肠道菌群的组分肠道菌群很多自身组分（如LPS、鞭毛蛋白、肽聚糖、甲酰基多肽以及特殊的核酸等）都可调控机体的免疫反应。
例如（如上图所示），肠道拟杆菌的成分PSA经过DC细胞提呈后，诱导Treg细胞产生，同时抑制Th1和Th17细胞反应[1]。
1.Rooks MG, Garrett WS: Gut microbiota, metabolites and host immunity. Nat Rev Immunol 2016, 16:341-352.Gut-Liver axis肠道菌群稳态被环境或免疫等因素破坏后，可产生大量的病原体相关分子模式，这些分子随着门静脉进入肝脏进而与TLR等模式识别受体结合而活化肝内巨噬细胞、星状细胞等固有免疫细胞，最终可导致肝纤维化、肝炎、NAFLD以及肝癌的发生[1]。
1.Chassaing B, Etienne-Mesmin L, Gewirtz AT: Microbiota-liver axis in hepatic disease. Hepatology 2014, 59:328-339.Gut-Brain axis肠道菌群还可通过代谢产物、刺激免疫细胞分泌细胞因子、诱导肠内分泌细胞产生5-HT、影响神经细胞等方式调节大脑活动，最终影响人的行为、心情、学习和记忆等活动[1-2]。
1.Collins SM, Surette M, Bercik P: The interplay between the intestinal microbiota and the brain. Nat Rev Microbiol 2012, 10:735-742.2. Yano JM, Yu K, Donaldson GP, Shastri GG, Ann P, Ma L, Nagler CR, Ismagilov RF, Mazmanian SK, Hsiao EY: Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell 2015, 161:264-276.肠道菌群 & 肿瘤（详细内容请点击这里）肠道菌群 VS. 肿瘤形成在TLR信号存在的卡波氏肉瘤模型中，肠道共生菌产物触发TLR5信号，促进肿瘤生长。