Nature：人体菌群研究的25个里程碑

本文转载自“热心肠先生”，已获授权

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2019年6月，Nature Milestones 推出专刊，详解人类菌群研究历史上的25个重大里程碑。其内容极为详尽，时间跨度长达70余年，总结了相关领域的几乎一切重要研究。

专刊提供开放下载的 pdf 版，你可以在Nature Milestones 官网下载到。专刊的网页版非常漂亮，如果你想读到原汁原味的英文版，强烈建议点击下面的链接阅读：https://www.nature.com/immersive/d42859-019-00041-z/index.html

我们则将其中最重要的内容翻译成了中文，希望能对你有用。不用谢，我们都是热心肠哦！

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里程碑1：培养厌氧菌

在1944年对牛瘤胃中降解纤维素的微生物的一项研究中，Robert. E. Hungate革命性的滚管方法使厌氧菌的成功培养成为可能。这种沿用至今的培养方法，使人们第一次分离出人类相关的厌氧菌。

原始文献

Hungate, R. E. Studies on cellulose fermentation: I. The culture and physiology of an anaerobic cellulose-digesting bacterium. J. Bacteriol. 48, 499–513 (1944).

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里程碑2：粪菌移植用于治疗艰难梭菌感染

1958年，一项研究报道了使用粪便灌肠成功治疗伪膜性小肠结肠炎。之后，粪菌移植被广泛接受为可成功治疗复发性艰难梭菌感染的抢救疗法。

原始文献

Eiseman B. et al. Fecal enema as an adjunct in the treatment of pseudomembranous enterocolitis. Surgery 44, 854–859 (1958).

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里程碑3：无菌动物中的肠道菌群移植实验

1965年，无菌动物有了一种新用途：将细菌培养物转移到无菌小鼠身上。这样的转移实验对于研究肠道菌群对宿主的影响至关重要。

原始文献

Schaedler, R.W., Dubos, R. & Costello, R. Association of germfree mice with bacteria isolated from normal mice. J. Exp. Med. 122, 77–82 (1965) | Gustafsson, B.E., Midtvedt, T. & Norman. A. Metabolism of cholic acid in germfree animals after the establishment in the intestinal tract of deconjugating and 7α-dehydroxylating bacteria. Acta Pathol. Microbiol. Scand. 72, 433–443 (1968) | Gustafsson, B.E. & Sewander Lanke, L. Bilirubin and urobilins in germfree, ex-germfree and conventional rats. J. Ex. Med. 112, 975–981 (1960) | Umesaki, Y. et al. Segmented filamentous bacteria are indigenous intestinal bacteria that activate intraepithelial lymphocytes and induce MHC class II molecules and fucosyl asialo GM1 glycolipids on the small intestinal epithelial cells in the ex-germ-free mouse. Microbiol. Immunol. 39, 555–562 (1995).

延伸阅读

Johansson, K.R. & Sarles, W.B. Some considerations of the biological importance of intestinal microörganisms. Bacteriol. Rev. 13, 25–45 (1949) | Sommer F. & Bäckhed, F. The gut microbiota — masters of host development and physiology. Nat. Rev. Microbiol. 11, 227–238 (2013).

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里程碑4：菌群影响宿主药物代谢

Peppercorn和Goldman证明，抗炎药物柳氮磺胺吡啶可在普通大鼠中降解，也可在被人类肠道细菌降解，但不能在无菌大鼠中降解，表明肠道菌群在药物转化中起作用。越来越多的研究证实了菌群（不仅限于肠道）在药物代谢中发挥作用，尤其是对药物失活、疗效和毒性的影响。

原始文献

Peppercorn, M. A. & Goldman, P. The role of intestinal bacteria in the metabolism of salicylazosulfapyridine. J. Pharmacol. Exp. Ther. 181, 555–562 (1972).

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里程碑5：生命早期的菌群承递

早在1900年，早期的研究就描述了婴儿体内细菌承递的各个方面，但在1981年，有三项研究着手于定量地表征肠道共生菌的早期获得，并研究了喂养如何塑造我们的初始菌群。

原始文献

Rotimi, V. O. & Duerden, B. I. The development of the bacterial flora in normal neonates. J. Med. Microbiol. 14, 51–62 (1981). | Tompkins, A.M. et al. Diet and the faecal microflora of infants, children and adults in rural Nigeria and urban U.K. J. Hyg. 86, 285–293 (1981). | Daoulas Le Bourdelles, F., Avril, J. L. & Ghnassia, J. C. Quantitative study of the faecal flora of breast- or bottle-fed neonates (transl.). Arch. Fr. Pediatr. 38, 35–39 (1981).

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里程碑6：基于测序的人相关菌群的鉴定

1996年，研究者利用基于序列的方法，对人类相关菌群进行了鉴定。该研究使用16S核糖体RNA测序，分析了人类粪便样本中可培养和非培养细菌的多样性。

原始文献

Wilson, K. H. & Blitchington, R. B. Human colonic biota studied by ribosomal DNA sequence analysis. Appl. Environ. Microbiol. 62, 2273–2278 (1996) | Suau, A. et al. Direct analysis of genes encoding 16S rRNA from complex communities reveals many novel molecular species within the human gut. Appl. Environ. Microbiol. 65, 4799–4807 (1999) | Kroes, I., Lepp, P. W. & Relman, D. A. Bacterial diversity within the human subgingival crevice. Proc. Natl Acad. Sci. USA 96, 14547–14552 (1999) | Eckburg, P. B. et al. Diversity of the human intestinal microbial flora. Science 308, 1635–1638 (2005) | Gill, S. R. et al. Metagenomic analysis of the human distal gut microbiome. Science 312, 1355–1359 (2006).

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里程碑7：成人菌群的稳定性和个体性

1998年，一项研究使用16S核糖体RNA基因扩增和温度梯度凝胶电泳（TGGE）来显示16名成年人粪便细菌的多样性，发现每个人都有独特的微生物群落。研究人员对两个人进行长期监测，发现他们的TGGE特征至少在六个月内是稳定的，并在之后研究了在更长时期内的微生物稳定性。

原始文献

Zoetendal, E. G. et al. Temperature gradient gel electrophoresis analysis of 16S rRNA from human faecal samples reveals stable and host-specific communities of active bacteria. Appl. Environ. Microbiol. 64, 3854–3859 (1998)

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里程碑8：细菌之外：研究宿主相关的其它微生物

病毒、真菌和古生菌也是我们菌群的重要成员，对人类健康有潜在影响。2003年，首次报道了对人类粪便中非培养的病毒群落的宏基因组学分析。

原始文献

Breitbart, M. et al. Metagenomic analyses of an uncultured viral community from human feces. J. Bacteriol. 185, 6220–6223 (2003).

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里程碑9：菌群对粘膜免疫的调控

两项研究揭示了免疫系统如何感知我们的菌群，以及正常条件下细菌是如何调节免疫系统发育的。这些发现为对微生物的免疫应答打开了一个新视角——不是作为宿主防御，而是一种共生的生理过程。

原始文献

Strachan, D. P. Hay fever, hygiene, and household size. BMJ 299, 1259–1260 (1989) | Rakoff-Nahum, S. et al. Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell 118, 229–241 (2004) | Mazmanian, S. K. et al. An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system. Cell 122, 107–118 (2005).

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里程碑10：喂好你的菌群的重要性

我们的肠道微生物组内含有成千上万的基因，它们参与分解食物底物，从中获取能量。2005年的一项研究表明，饮食变化改变了结肠菌群的降解活性。

原始文献

Sonnenburg, J. L. et al. Glycan foraging in vivo by an intestine-adapted bacterial symbiont. Science 307, 1955–1959 (2005).

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里程碑11：通过菌群移植转移宿主表型

研究人员发现，通过粪菌移植可以在小鼠身上复现人类表型。这项首次使用胖人和瘦人粪便的研究，为研究菌群与人类表型之间的机制联系铺平了道路。

原始文献

Turnbaugh, P.J. et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444, 1027–1031 (2006).

延伸阅读

Bäckhed, F. et al. The gut microbiota as an environmental factor that regulates fat storage. Proc. Natl Acad. Sci. USA 101 15718–15723 (2004) | Garrett, W.S. et al. Communicable ulcerative colitis induced by T-bet deficiency in the innate immune system. Cell 131, 33–45 (2007) | Vrieze, A. et al. Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology 143, 913–916 (2012) | Fei, N. et al. An opportunistic pathogen from the gut of an obese human causes obesity in germfree mice. ISME J. 7, 880–884 (2013) | Schulz, M.D. et al. High-fat-diet-mediated dysbiosis promotes intestinal carcinogenesis independently of obesity. Nature 514, 508–512 (2014) | Poutahidis, T. et al. Dietary microbes modulate transgenerational cancer risk. Cancer Res. 75, 1197–1204 (2015) | Collins, S. M. et al. The adoptive transfer of behavioural phenotype via the intestinal microbiota: experimental evidence and clinical implications. Curr. Opin. Microbiol. 16, 240–245 (2013) | Hu, B. et al. Microbiota-induced activation of epithelial IL-6 signaling links inflammasome-driven inflammation with transmissible cancer. Proc. Natl Acad. Sci. USA 110, 9862–9867 (2013).

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里程碑12：饮食 – 菌群互作对人体代谢的影响

从2006年开始，许多研究都强调了饮食可以影响肠道菌群和宿主代谢，这对人类健康以及我们如何通过认识这些相互作用来开发基于营养的治疗方案，具有深远影响。

原始文献

Ley, R. E. et al. Human gut microbes associated with obesity. Nature 444, 1022–1023 (2006).

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里程碑13：定殖抵抗的机制

在早期研究中已观察到定殖抵抗（我们自身菌群抑制病原体侵入的现象），但在2007年，三篇关键论文提供了对该过程机制的初步见解。

原始文献

Corr, S. et al. Bacteriocin production as a mechanism for the anti-infective activity of Lactobacillus salivarius UCC118. Proc. Natl Acad. Sci. USA 104, 7617–7621 (2007) | Lupp, C. et al. Host-mediated inflammation disrupts the intestinal microbiota and promotes the overgrowth of Enterobacteriaceae. Cell Host Microbe 16, 119–129 (2007) | Stecher, B. et al. Salmonella enterica serovar Typhimurium exploits inflammation to compete with the intestinal microbiota. PLoS Biol. 5, 2177–2189 (2007).

延伸阅读

清单过长，略，请下载原始文献查阅

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里程碑14：使用组学技术进行体内的人类菌群功能分析

Eline Klaassens及其同事使用宏蛋白质组学方法分析了非培养的粪便菌群，为菌群提供了第一个分类学鉴定之外的见解。之后，代谢组学和宏转录组学等组学技术被用于大量研究，这也促进了多组学实验分析流程的发展；这些方法目前仍在揭示菌群功能方面发挥重要作用。

原始文献

Klaassens, E. S., de Vos, W. M. & Vaughan, E. E. Metaproteomics approach to study the functionality of the microbiota in the human infant gastrointestinal tract. Appl. Environ. Microbiol. 73, 1388–1392 (2007).

延伸阅读

Verberkmoes, N. C. et al. Shotgun metaproteomics of the human distal gut microbiota. ISME J. 3, 179–189 (2008) | Jansson, J. et al. Metabolomics reveals metabolic biomarkers of Crohn’s disease. PLoS ONE 4, e6386 (2009) | Martin, F. P. et al. Topographical variation in murine intestinal metabolic profiles in relation to microbiome speciation and functional ecological activity. J. Proteome Res. 8, 3464–3474 (2009) | Franzosa, E. A. et al. Relating the metatranscriptome and metagenome of the human gut. Proc. Natl Acad. Sci. USA 111, 2329–2338 (2014) | Bouslimani, A. et al.Molecular cartography of the human skin surface in 3D. Proc. Natl Acad. Sci. USA 112, 2120–2129 (2015) | Heintz-Buschart, A. et al. Integrated multi-omics of the human gut microbiome in a case study of familial type 1 diabetes. Nat. Microbiol. 2, 16180 (2016) | Franzosa, E. A. et al. Gut microbiome structure and metabolic activity in inflammatory bowel disease. Nat. Microbiol. 4, 293–305 (2019).

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里程碑15：抗生素对菌群组成和宿主健康的影响

抗生素不仅会对引起感染的细菌起作用，还会影响原住菌群。 2008年的一项研究显示，健康个体使用环丙沙星，会影响其粪便样本中大约三分之一细菌类群的丰度。

原始文献

Dethlefsen, L. et al. The pervasive effects of an antibiotic on the human gut microbiota, as revealed by deep 16S rRNA sequencing. PLoS Biol. 6, e280 (2008) | Dethlefsen, L, & Relman, D. A. Incomplete recovery and individualized responses of the human distal gut microbiota to repeated antibiotic perturbation. Proc. Natl Acad. Sci. USA 108, 4554–4561 (2011) | Cho, I. et al. Antibiotics in early life alter the murine colonic microbiome and adiposity. Nature 488, 621–626 (2012) | Cox, L. M. et al. Altering the intestinal microbiota during a critical developmental window has lasting metabolic consequences. Cell 158, 705–721 (2014) | Zanvit, P. N. et al. Antibiotics in neonatal life increase murine susceptibility to experimental psoriasis. Nat. Commun. 6, 8424 (2015) | Marra, F. et al. Antibiotic use in children is associated with increased risk of asthma. Pediatrics 123, 1003–1010 (2009) | Arrieta, M. C. et al. Early infancy microbial and metabolic alterations affect risk of childhood asthma. Sci. Transl. Med. 7, 307ra152 (2015) | Russell, S. L. et al. Perinatal antibiotic treatment affects murine microbiota, immune responses and allergic asthma. Gut Microbes 4, 158–164 (2013) | Livanos, A. E. et al. Antibiotic-mediated gut microbiome perturbation accelerates development of type 1 diabetes in mice. Nat. Microbiol. 1, 16140 (2016) | Schulfer, A.F. et al. Intergenerational transfer of antibiotic-perturbed microbiota enhances colitis in susceptible mice. Nat. Microbiol. 3, 234–242 (2018) | Suez, J. et al. Post-antibiotic gut mucosal microbiome reconstitution is impaired by probiotics and improved by autologous FMT. Cell 174, 1406–1423 (2018)

延伸阅读

Willing, C. P. et al. Shifting the balance: antibiotic effects on host-microbiota mutualism. Nat. Rev. Microbiol. 9, 233–243 (2011)

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里程碑16：生物信息学工具助力菌群测序数据分析

以QIIME软件为代表的“菌群生态学定量分析”方法，使对菌群测序产生的海量数据进行分析及解释成为可能。

原始文献

Caporaso, J. G. et al. QIIME allows analysis of high-throughput community sequencing data. Nat. Methods 7, 335–336 (2010).

延伸阅读

Knight, R. et al. Best practices for analysing microbiomes. Nat. Rev. Microbiol. 16, 410–422 (2018).

• Nature综述：手把手教你分析菌群数据

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里程碑17：对大规模人群的菌群分析

21世纪初，宏基因组及高通量测序技术的发展催生了多个分析大规模人群菌群多样性的项目。大规模人群研究极大地提升了我们对菌群多样性的认知，并发现了许多菌群与健康和疾病的潜在关联，激励了更多新研究的开展。

原始文献

Qin, J. N. et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature 464, 59–65 (2010)

延伸阅读

The Human Microbiome Project Consortium. Structure, function and diversity of the healthy human microbiome. Nature 486, 207–214 (2012) | The Human Microbiome Project Consortium. A framework for human microbiome research. Nature 486, 215–221 (2012) | Goodrich, J. K. et al. Human genetics shape the gut microbiome. Cell 159, 789–799 (2014) | Ding, T. & Schloss, P. D. Dynamics and associations of microbial community types across the human body. Nature 509, 357–360 (2014) | Falony, G. et al. Population-level analysis of gut microbiome variation. Science 352, 560–564 (2016) | Zhernakova, A. et al. Population-based metagenomics analysis reveals markers for gut microbiome composition and diversity. Science 352, 365–369 (2016) | Rothschild, D. et al. Environment dominates over host genetics in shaping human gut microbiota. Nature 555, 210–215 (2018) | McDonald, D. et al. Amercian gut: an open platform for citizen science microbiome research. mSystems 3, e00031-18 (2018) | He, Y. et al. Regional variation limits applications of healthy gut microbiome references and disease models. Nat. Med. 24, 1532–1535 (2018). | Fettweis, J. M. et al. The vaginal microbiome and preterm birth. Nat. Med. https://doi.org/10.1038/s41591-019-0450-2 (2019) | Zhou, W. et al. Complex host-microbial dynamics in prediabetes revealed through longitudinal multi-omics profiling. Nature 569, 663–671 (2019) | Lloyd-Price, J. et al. Multi-omics of the gut microbial ecosystem in inflammatory bowel diseases. Nature 569, 655–662 (2019) | Integrative HMP (iHMP) Research Network Consortium. The Integrative Human Microbiome Project. Nature 569, 641–648 (2019)

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里程碑18：菌群-肠-脑轴

2011年，一些实验发现缺乏菌群影响了小鼠的行为、脑基因表达及神经系统的发育。而近期一些人体研究正在揭示菌群与人神经系统之间的潜在关联。

原始文献

Diaz Heijtz, R. et al. Normal gut microbiota modulates brain development and behavior. Proc. Natl Acad. Sci. USA 108, 3047–3052 (2011) | Neufeld, K. M. et al. Reduced anxiety-like behavior and central neurochemical change in germ-free mice. Neurogastroenterol. Motil. 23, 255–264 (2011) | Bercik, P. et al. The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice. Gastroenterol. 141, 599–609 (2011) | Bravo, J. A. et al. Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proc. Natl Acad. Sci. USA 108, 16050–16055 (2011).

延伸阅读

清单过长，略，请下载原始文献查阅

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里程碑19：现代培养方法用以扩展可培养菌群

高通量厌氧培养，使得对多样化的人体肠道菌群成员中的大多数进行培养，并建立培养物集存库成为可能。

原始文献

Goodman, A. L. et al. Extensive personal human gut microbiota culture collections characterized and manipulated in gnotobiotic mice. Proc. Natl Acad. Sci. USA 108, 6252–6257 (2011). 

延伸阅读

Lagier, J. C. et al. Culturing the human microbiota and culturomics. Nat. Rev. Microbiol. 1, 540–550 (2018).

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里程碑20：全球人类微生物组

生活在不同区域的人群有着不同的基因变异，但对菌群的变异了解甚少。为了探究不同人群中的肠道菌群差异，Yatsunenko等人对生活在委内瑞拉亚马逊地区、马拉维农村地区及美国大都市区的不同人群粪便样本中的细菌物种进行了分析鉴定，发现不同地理区域的人群有着明显不同的肠道菌群组成及功能。

原始文献

Yatsunenko, T. et al. Human gut microbiome viewed across age and geography. Nature 486, 222–227 (2012).

延伸阅读

Schnorr, S. L. et al. Gut microbiome of the Hadza hunter-gatherers. Nat. Commun. 5, 3654 (2014) | O’Keefe, S. J. D. et al. Fat, fibre and cancer risk in African Americans and rural Africans. Nat. Commun. 6, 6342 (2014) | Obregon-Tito, A. J. et al. Subsistence strategies in traditional societies distinguish gut microbiomes. Nat. Commun. 6, 6505 (2015) | Nishijima, S. et al. The gut microbiome of healthy Japanese and its microbial and functional uniqueness. DNA Res. 23, 125–133 (2016) | Das, B. et al. Analysis of the gut microbiome of rural and urban healthy Indians living in sea level and high-altitude areas. Sci. Rep. 8, 10104 (2018) | Pasolli, E. et al. Extensive unexplored human microbiome diversity revealed by over 150,000 genomes from metagenomes spanning age, geography, and lifestyle. Cell 176, 649–662 (2019) | Nayfach, S., Shi, Z. J., Seshadri, R., Pollard, K. S. & Kyrpides, N. Novel insights from uncultivated genomes of the global human gut microbiome. Nature https://doi. org/10.1038/s41586-019-1058-x (2019).

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里程碑21：菌群产生的短链脂肪酸诱导调节性T细胞的产生

调节性T细胞（Treg）在维持免疫稳态中起到关键作用。2013年，3项研究发现，菌群产生的短链脂肪酸促进Treg的扩增与分化，揭示了共生菌群通过化学物质与免疫系统互作的机制。

原始文献

Smith, P.M. et al. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 341, 569–573 (2013) | Atarashi, K. et al. Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature 500, 232–236 (2013) | Arpaia, N. et al. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 504, 451–455 (2013).

延伸阅读

Tanoue, T., Atarashi, K. & Honda, K. Development and maintenance of intestinal regulatory T cells. Nat. Rev. Immunol. 16, 295–309 (2016) | Round, J. L. & Mazmanian, S. K. Inducible Foxp3+ regulatory T-cell development by a commensal bacterium of the intestinal microbiota. Proc. Natl Acad. Sci. USA 107, 12204–12209 (2010) | Geuking, M. B. et al. Intestinal bacterial colonization induces mutualistic regulatory T cell responses. Immunity 34, 794–806 (2011) | Lathrop, S. K. et al. Peripheral education of the immune system by colonic commensal microbiota. Nature 478, 250–254 (2011).

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里程碑22：人体菌群产生的抗生素

在人体菌群的基因组中鉴定出抗生素的生物合成基因簇，提示人体菌群可作为抗菌药物的新来源，特定菌种产生的抗菌药物或可用于调节局部菌群群落结构。

原始文献

Donia, M. S. et al. A systematic analysis of biosynthetic gene clusters in the human microbiome reveals a common family of antibiotics. Cell 158, 1402–1414 (2014).

延伸阅读

Zipperer, A. et al. Human commensals producing a novel antibiotic impair pathogen colonization. Nature 535, 511–516 (2016).

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里程碑23：靶向宿主的药物影响菌群种群

常用药物影响胃肠道菌群丰度及细菌基因表达，可对药物治疗后的人体健康产生正面或负面影响。

原始文献

Tsuda A et al. Influence of proton-pump inhibitors on the luminal microbiota in the gastrointestinal tract. Clin. Transl. Gastroenterol. 6, e89 (2015) | Freedberg, D. E. et al. Proton pump inhibitors alter specific taxa in the human gastrointestinal microbiome: a crossover trial. Gastroenterology 149, 883–885 (2015) | Forslund, K. et al. Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature 528, 262–266 (2015).

延伸阅读

Maurice, C. F., Haiser, H. J. & Turnbaugh, P. J. Xenobiotics shape the physiology and gene expression of the active human gut microbiome. Cell 152, 39–50 (2013) | Maier L. et al. Extensive impact of non-antibiotic drugs on human gut bacteria. Nature 555, 623–628 (2018) | Zimmermann, M. et al. Separating host and microbiome contributions to drug pharmacokinetics and toxicity. Science 363, eaat9931 (2019).

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里程碑24：人肠道菌群影响对癌症治疗的应答

在小鼠模型中的早期研究之后，最新研究发现肠道菌群组成影响了黑色素瘤患者、晚期肺癌患者及晚期肾癌患者对免疫检查点抑制剂治疗的应答及肿瘤控制。

原始文献

Routy, B. et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 359, 91–97 (2018) | Gopalakrishnan, V. et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 359, 97–103 (2018) | Matson, V. et al. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science 359, 104–108 (2018).

延伸阅读

Tanoue, T. et al. A defined commensal consortium elicits CD8 T cells and anti-cancer immunity. Nature 565, 600–605 (2019) | Iida, N. et al. Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment. Science 342, 967–970 (2013) | Viaud, S. et al. The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide. Science 342, 971–976 (2013) | Taur, Y. et al. The effects of intestinal tract bacterial diversity on mortality following allogeneic hematopoietic stem cell transplantation. Blood 124, 1174–1182 (2014) | Sivan, A. et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 350, 1084–1089 (2015) | Vétizou, M. et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 350, 1079–1084 (2015).

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里程碑25：宏基因组组装的基因组分析鉴定出了前所未有的人体相关菌群

近期在环境微生物领域中，计算方法的发展使得从宏基因组数据集中重建细菌基因组成为可能。使用这一技术，从全球人群的肠道及其它身体部位鉴定出上千种新的无法培养的候选细菌物种，极大地扩展了已知的系统发育多样性，并提升了对非西方人群的分类。

原始文献

Pasolli, E. et al. Extensive unexplored human microbiome diversity revealed by over 150,000 genomes from metagenomes spanning age, geography, and lifestyle. Cell 176, 649–662 (2019) | Almeida, A. et al. A new genomic blueprint of the human gut microbiota. Nature https://doi.org/10.1038/s41586-019-0965-1 (2019) | Nayfach, S. et al. New insights from uncultivated genomes of the global human gut microbiome. Nature https://doi. org/10.1038/s41586-019-1058-x (2019).

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