人体肠道菌群结构与宿主代谢的相关性研究
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摘要
人类与其体内共生的微生物共同组成一个“超级生物体”。人体的代谢是由宿主自身基因组调节的各种代谢途径以及微生物基因组调节的代谢过程共同组成,这种宿主与微生物之间的共代谢过程最终调节着宿主的整体代谢。肠道菌群是人体内最复杂和种群数量最高的共生微生物生态系统,无论是健康或者疾病状态下的人体生理代谢特性都不可避免地受到肠道菌群结构变化的影响。因此研究肠道菌群与宿主整体代谢及其慢性代谢性疾病的相关性,寻找影响宿主代谢变化的重要功能成员,能够更好的理解肠道菌群对人体健康和疾病的重要作用。
本研究首先对一个健康、四代的中国家庭7位成员的肠道菌群结构及宿主整体代谢特征进行了详尽的研究,通过对肠道菌群与宿主代谢表型的变化进行关联分析,建立了分析、评价肠道菌群成员对宿主代谢影响的方法。通过构建粪便菌群的细菌通用16S rRNA基因克隆文库分析了该家庭7位成员肠道菌群的多样性和组成结构。在种的水平,中国家庭成员的肠道菌群整体结构与之前已报道的美国人有显著差异。利用拟杆菌属(Bacteroides spp.)类群特异性克隆文库对家庭成员肠道内拟杆菌属的多样性进行分析,结果显示类群特异性文库反映的拟杆菌属的多样性较通用克隆文库高,并发现了很多未知的、新的拟杆菌种类。对肠道内优势细菌、拟杆菌属及柔嫩梭菌亚群的变性梯度凝胶电泳(DGGE)分析结果显示,该家庭成员的肠道菌群结构存在一定的性别差异,并鉴定出与性别相关的种类,例如Bacteroides thetaiotaomicron在男性成员中较女性多。利用核磁共振技术(NMR)对尿液代谢物组成的分析发现,该家庭成员的整体代谢特性也存在一定的性别差异,并鉴定出与性别相关的代谢物,例如3-aminoisobutyrate在男性尿液中较女性多。最后结合多变量统计学方法OPLS将反映肠道菌群结构变化的DGGE数据与反映宿主代谢变化的尿液NMR数据加以联系,寻找肠道菌群结构与宿主代谢的共变化(covariation)特征,并且鉴定出10种与宿主代谢密切相关的重要肠道细菌类型。其中一类重要的细菌Faecalibacterium prausnitzii的种群变化与8种尿液代谢物浓度变化相关,提示了这种细菌可能是肠道菌群中一个影响着宿主多个代谢通路的重要的功能成员。本研究为理解肠道菌群与宿主在代谢水平上的互作关系,理解菌群在各种代谢性疾病发展过程中的作用,奠定了新的方法学基础。
为了深入了解中国人群的肠道菌群结构特征,并进一步研究人体在不同健康状态下,例如患有2型糖尿病、肥胖的人群肠道菌群结构的变化规律,寻找肠道菌群结构变化与慢性代谢性疾病可能的相关性,本研究利用bar coded 454测序技术对来自140例新发2型糖尿病病例及142例与其性别、年龄、居住地1:1匹配的对照人群共316例粪便样品肠道菌群的结构特征进行了详尽的分析。共获得268,578条高质量的16S rRNA基因V3区序列。在门的水平上,中国人群肠道内一共含有属于11个门的细菌,其中以拟杆菌门和厚壁菌门最为优势,比例占肠道内总细菌的90%以上。在种的水平,所有序列根据97%的相似性水平划分为2,136个分类操作单位(operational taxonomic units, OTUs)。人群肠道菌群种水平上的多样性组成呈现显著的个体差异。316例人群样本肠道中没有共有的OTU,而40%的OTU为宿主特异性。对人群肠道菌群多样性组成的整体结构特征进行的主成份分析(PCA)结果显示,该中国人群肠道菌群呈现特殊的“分枝状分布(branch-like structure)”,每个分支上的个体均共有一个或几个优势的细菌种类(OTU)。但是这种特殊的分布与性别、年龄、区域以及疾病状态无显著相关性,提示某些其他未知的因素显著影响肠道菌群的结构。与对照人群相比,糖尿病人群和肥胖人群肠道菌群的整体多样性较低。一些优势类群的比例在两组人群中也存在显著差异,例如拟杆菌门以及其中的拟杆菌科(Bacteroidaceae)、紫单胞菌科(Porphyromonadaceae)及拟杆菌属(Bacteroides)的丰度均在糖尿病人群中较低,而厚壁菌门中最优势的毛螺菌科(Lachnospiraceae)以及其中的罗氏菌属(Roseburia)的丰度较高。而应用基于序列进化距离的比较群落结构差异的UniFrac方法显示,两种人群肠道菌群在种的水平无显著性差异。本研究所揭示的中国人肠道菌群多样性组成为人类元基因组计划提供了重要的参考数据。而肠道菌群特殊的人群分布为理解菌群与各种影响因素,例如饮食、疾病等之间的相互关系提供了启示。
因此,本论文建立了对肠道菌群与宿主代谢关系进行整体分析的方法,表明肠道菌群重要功能成员能够影响宿主的特定的代谢过程;分析了代谢性疾病人群与对照人群肠道菌群的整体结构特征,为理解肠道菌群与人体健康的重要关系提供了基础数据。
Human beings can be considered as“superorganisms”as a result of their close symbiotic associations with the gut microbiota. Human metabolism involves integration of multiple indigenous metabolic processes which were encoded by the host genome with those of the microbiome. This results in extensive transgenomic co-metabolism of many substrates including those involved in host metabolic regulation. In health or disease, gut microbial variations would significantly modulate host physiology and pathology. Therefore, understanding the correlation between gut microbiome with host global metabolism relevant to chronic metabolic diseases, and identification of key functional members which modulate the host metabolism would provide new insights into potential contributions of gut microbiota to human health and disease.
In the first part of this study, we analyzed the gut microbial composition and host global metabolic profiles of a healthy, four-generation, seven-membered Chinese family. A co-variation analysis method which linked the changes of gut microbiome and host metabolic phenotypes was developed to analyze the effects of key members of gut microbiota on host metabolism. Global gut microbiomic structure of the Chinese family was investigated by using bacterial universal 16S rRNA gene clone libraries. At the species level, there are clearly structural differences between the Chinese family gut microbiomes and those reported for American volunteers. In addition,the molecular diversity of Bacteroides spp., a prominent bacterial group in human intestinal microbiota, in the seven family members was also analyzed by using Bacteroides spp. group-specific 16S rRNA gene clone libraries. The diversity of Bacteroides spp. detected by the group-specific libraries was much higher than that of universal libraries,and most of Bacteroides species were uncharacterized. The analysis of the microbial DGGE fingerprints of the 16S rRNA gene V3 region for predominant bacteria and of regions for two specific groups, Bacteroides spp. and Clostridium leptum subgroup, showed a sex-related difference of gut microbial composition in this family cohort. And sex-related bacteria were indentified, e.g. Bacteroides thetaiotaomicron was higher in males of family members. The urinary NMR-based metabolic profiling of this family also showed significant sex-related differences, and 3-aminoisobutyrate was identified as a gender-related metabolite which was higher in the urine samples of male members. We applied a multivariate statistical analysis——OPLS to model the covariation between gut microbiomic structural patterns as reflected by community DGGE fingerprints and host metabotypes as defined by NMR spectroscopic urinary profiling, and pinpointed 10 key functional members of the microbiome that most significantly modulate host metabolism. For example, Faecalibacterium prausnitzii population variation is associated with eight urinary metabolites, indicating that this species is a highly functionally active member of the microbiome, influencing numerous host pathways. This study provides a methodological foundation for understanding the symbiotic metabolic relationship between gut microbiome and human host, and potential significance of gut microbiota in the development of metabolic diseases.
To characterize the human gut microbial structure under various health conditions such as type 2 diabetes and obesity, and understand the potential correlation of gut microbial variation and chronic metabolic diseases, we used bar coded 454 pyrosequencing method to characterize the gut microbiomes of 316 human fecal samples from 140 newly diagnosed type 2 diabetic patients and 142 controls whom are 1:1 match in sex, age and geographical origin with diabetic patients. Totally 268,578 high-quality 16S rRNA gene V3 region sequences were obtained from all the samples. At the division level, there are 11 bacterial phyla in the Chinese human guts, dominated by Bacteroidetes and Firmicutes which account for more than 90% of total gut bacteria. At the species level, all the sequences were assigned into 2,136 operational taxonomic units (OTUs) with 97% identity cutoff. The diversity composition of gut microbiome of the Chinese human cohort at the species level exhibited remarkable inter-individual differences. No common OTU existed in 316 human fecal microbial samples, and 40% of total OTUs are host specific. The principle component analysis (PCA) of global gut microbial structure of Chinese human cohort exhibited a specific“branch-like structure”. The individuals in each branch shared one or several predominant OTUs. However, the specific global structure of human gut microbiome seems not to be related with sex, age, geographical origin and health status, indicating that there would be some unknown factors which strongly influence human gut microbiome. Compared with control people, the global diversity of gut microbiota of diabetic and obese people was lower. And the proportions of several predominant bacterial groups were significantly different in two groups. For instance, the abundances of Bacteroidetes phylum, Bacteroidaceae family, Porphyromonadaceae family and Bacteroides genus were lower in diabetic people, whereas the proportions of Lachnospiraceae family which is the most predominant group in Firmicutes and Roseburia genus in this family were higher than those of control people. However, the UniFrac analysis, a phylogenetic method for comparing microbial communities based on the measurement of phylogenetic distance between sequences, showed no significant differences of gut microbiome in two groups of human cohort at species level. The gut microbial diversity composition of the Chinese human cohort revealed in this study provides reference data for“Human Metagenomic Project”; and the specific distribution of Chinese human gut microbiome provides insights into understanding the relationship of gut microbiota and impact factors, e.g. diet and disease.
In summary, in this study, we developed a global analysis to correlate the gut microbial variation with human host global metabolism, showing that the key functional members of gut microbiome can modulate the host specific metabolic pathways; and we also analyzed the overall structure of gut microbiota of the Chinese human cohort with metabolic diseases and healthy controls. This study provides new insights for understanding the contributions of gut microbiota in human health and disease.
本研究首先对一个健康、四代的中国家庭7位成员的肠道菌群结构及宿主整体代谢特征进行了详尽的研究,通过对肠道菌群与宿主代谢表型的变化进行关联分析,建立了分析、评价肠道菌群成员对宿主代谢影响的方法。通过构建粪便菌群的细菌通用16S rRNA基因克隆文库分析了该家庭7位成员肠道菌群的多样性和组成结构。在种的水平,中国家庭成员的肠道菌群整体结构与之前已报道的美国人有显著差异。利用拟杆菌属(Bacteroides spp.)类群特异性克隆文库对家庭成员肠道内拟杆菌属的多样性进行分析,结果显示类群特异性文库反映的拟杆菌属的多样性较通用克隆文库高,并发现了很多未知的、新的拟杆菌种类。对肠道内优势细菌、拟杆菌属及柔嫩梭菌亚群的变性梯度凝胶电泳(DGGE)分析结果显示,该家庭成员的肠道菌群结构存在一定的性别差异,并鉴定出与性别相关的种类,例如Bacteroides thetaiotaomicron在男性成员中较女性多。利用核磁共振技术(NMR)对尿液代谢物组成的分析发现,该家庭成员的整体代谢特性也存在一定的性别差异,并鉴定出与性别相关的代谢物,例如3-aminoisobutyrate在男性尿液中较女性多。最后结合多变量统计学方法OPLS将反映肠道菌群结构变化的DGGE数据与反映宿主代谢变化的尿液NMR数据加以联系,寻找肠道菌群结构与宿主代谢的共变化(covariation)特征,并且鉴定出10种与宿主代谢密切相关的重要肠道细菌类型。其中一类重要的细菌Faecalibacterium prausnitzii的种群变化与8种尿液代谢物浓度变化相关,提示了这种细菌可能是肠道菌群中一个影响着宿主多个代谢通路的重要的功能成员。本研究为理解肠道菌群与宿主在代谢水平上的互作关系,理解菌群在各种代谢性疾病发展过程中的作用,奠定了新的方法学基础。
为了深入了解中国人群的肠道菌群结构特征,并进一步研究人体在不同健康状态下,例如患有2型糖尿病、肥胖的人群肠道菌群结构的变化规律,寻找肠道菌群结构变化与慢性代谢性疾病可能的相关性,本研究利用bar coded 454测序技术对来自140例新发2型糖尿病病例及142例与其性别、年龄、居住地1:1匹配的对照人群共316例粪便样品肠道菌群的结构特征进行了详尽的分析。共获得268,578条高质量的16S rRNA基因V3区序列。在门的水平上,中国人群肠道内一共含有属于11个门的细菌,其中以拟杆菌门和厚壁菌门最为优势,比例占肠道内总细菌的90%以上。在种的水平,所有序列根据97%的相似性水平划分为2,136个分类操作单位(operational taxonomic units, OTUs)。人群肠道菌群种水平上的多样性组成呈现显著的个体差异。316例人群样本肠道中没有共有的OTU,而40%的OTU为宿主特异性。对人群肠道菌群多样性组成的整体结构特征进行的主成份分析(PCA)结果显示,该中国人群肠道菌群呈现特殊的“分枝状分布(branch-like structure)”,每个分支上的个体均共有一个或几个优势的细菌种类(OTU)。但是这种特殊的分布与性别、年龄、区域以及疾病状态无显著相关性,提示某些其他未知的因素显著影响肠道菌群的结构。与对照人群相比,糖尿病人群和肥胖人群肠道菌群的整体多样性较低。一些优势类群的比例在两组人群中也存在显著差异,例如拟杆菌门以及其中的拟杆菌科(Bacteroidaceae)、紫单胞菌科(Porphyromonadaceae)及拟杆菌属(Bacteroides)的丰度均在糖尿病人群中较低,而厚壁菌门中最优势的毛螺菌科(Lachnospiraceae)以及其中的罗氏菌属(Roseburia)的丰度较高。而应用基于序列进化距离的比较群落结构差异的UniFrac方法显示,两种人群肠道菌群在种的水平无显著性差异。本研究所揭示的中国人肠道菌群多样性组成为人类元基因组计划提供了重要的参考数据。而肠道菌群特殊的人群分布为理解菌群与各种影响因素,例如饮食、疾病等之间的相互关系提供了启示。
因此,本论文建立了对肠道菌群与宿主代谢关系进行整体分析的方法,表明肠道菌群重要功能成员能够影响宿主的特定的代谢过程;分析了代谢性疾病人群与对照人群肠道菌群的整体结构特征,为理解肠道菌群与人体健康的重要关系提供了基础数据。
Human beings can be considered as“superorganisms”as a result of their close symbiotic associations with the gut microbiota. Human metabolism involves integration of multiple indigenous metabolic processes which were encoded by the host genome with those of the microbiome. This results in extensive transgenomic co-metabolism of many substrates including those involved in host metabolic regulation. In health or disease, gut microbial variations would significantly modulate host physiology and pathology. Therefore, understanding the correlation between gut microbiome with host global metabolism relevant to chronic metabolic diseases, and identification of key functional members which modulate the host metabolism would provide new insights into potential contributions of gut microbiota to human health and disease.
In the first part of this study, we analyzed the gut microbial composition and host global metabolic profiles of a healthy, four-generation, seven-membered Chinese family. A co-variation analysis method which linked the changes of gut microbiome and host metabolic phenotypes was developed to analyze the effects of key members of gut microbiota on host metabolism. Global gut microbiomic structure of the Chinese family was investigated by using bacterial universal 16S rRNA gene clone libraries. At the species level, there are clearly structural differences between the Chinese family gut microbiomes and those reported for American volunteers. In addition,the molecular diversity of Bacteroides spp., a prominent bacterial group in human intestinal microbiota, in the seven family members was also analyzed by using Bacteroides spp. group-specific 16S rRNA gene clone libraries. The diversity of Bacteroides spp. detected by the group-specific libraries was much higher than that of universal libraries,and most of Bacteroides species were uncharacterized. The analysis of the microbial DGGE fingerprints of the 16S rRNA gene V3 region for predominant bacteria and of regions for two specific groups, Bacteroides spp. and Clostridium leptum subgroup, showed a sex-related difference of gut microbial composition in this family cohort. And sex-related bacteria were indentified, e.g. Bacteroides thetaiotaomicron was higher in males of family members. The urinary NMR-based metabolic profiling of this family also showed significant sex-related differences, and 3-aminoisobutyrate was identified as a gender-related metabolite which was higher in the urine samples of male members. We applied a multivariate statistical analysis——OPLS to model the covariation between gut microbiomic structural patterns as reflected by community DGGE fingerprints and host metabotypes as defined by NMR spectroscopic urinary profiling, and pinpointed 10 key functional members of the microbiome that most significantly modulate host metabolism. For example, Faecalibacterium prausnitzii population variation is associated with eight urinary metabolites, indicating that this species is a highly functionally active member of the microbiome, influencing numerous host pathways. This study provides a methodological foundation for understanding the symbiotic metabolic relationship between gut microbiome and human host, and potential significance of gut microbiota in the development of metabolic diseases.
To characterize the human gut microbial structure under various health conditions such as type 2 diabetes and obesity, and understand the potential correlation of gut microbial variation and chronic metabolic diseases, we used bar coded 454 pyrosequencing method to characterize the gut microbiomes of 316 human fecal samples from 140 newly diagnosed type 2 diabetic patients and 142 controls whom are 1:1 match in sex, age and geographical origin with diabetic patients. Totally 268,578 high-quality 16S rRNA gene V3 region sequences were obtained from all the samples. At the division level, there are 11 bacterial phyla in the Chinese human guts, dominated by Bacteroidetes and Firmicutes which account for more than 90% of total gut bacteria. At the species level, all the sequences were assigned into 2,136 operational taxonomic units (OTUs) with 97% identity cutoff. The diversity composition of gut microbiome of the Chinese human cohort at the species level exhibited remarkable inter-individual differences. No common OTU existed in 316 human fecal microbial samples, and 40% of total OTUs are host specific. The principle component analysis (PCA) of global gut microbial structure of Chinese human cohort exhibited a specific“branch-like structure”. The individuals in each branch shared one or several predominant OTUs. However, the specific global structure of human gut microbiome seems not to be related with sex, age, geographical origin and health status, indicating that there would be some unknown factors which strongly influence human gut microbiome. Compared with control people, the global diversity of gut microbiota of diabetic and obese people was lower. And the proportions of several predominant bacterial groups were significantly different in two groups. For instance, the abundances of Bacteroidetes phylum, Bacteroidaceae family, Porphyromonadaceae family and Bacteroides genus were lower in diabetic people, whereas the proportions of Lachnospiraceae family which is the most predominant group in Firmicutes and Roseburia genus in this family were higher than those of control people. However, the UniFrac analysis, a phylogenetic method for comparing microbial communities based on the measurement of phylogenetic distance between sequences, showed no significant differences of gut microbiome in two groups of human cohort at species level. The gut microbial diversity composition of the Chinese human cohort revealed in this study provides reference data for“Human Metagenomic Project”; and the specific distribution of Chinese human gut microbiome provides insights into understanding the relationship of gut microbiota and impact factors, e.g. diet and disease.
In summary, in this study, we developed a global analysis to correlate the gut microbial variation with human host global metabolism, showing that the key functional members of gut microbiome can modulate the host specific metabolic pathways; and we also analyzed the overall structure of gut microbiota of the Chinese human cohort with metabolic diseases and healthy controls. This study provides new insights for understanding the contributions of gut microbiota in human health and disease.
引文
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