应用焦磷酸测序技术对不同人群肠道微生物群落结构的研究
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摘要
由于肠道菌群与人体的健康和一些代谢性疾病的发生有着密切的关系，所以越来越多的研究人员在该领域展开了研究工作。本论文分别对婴儿和中青年人群、藏族牧民和城市居民以及哈萨克族和维吾尔族居民肠道微生物群落结构进行了研究，同时对不同民族居民其肠道菌群是否存在共有的或者特有的种系型进行了探讨。为了初步间接的探讨改变代谢性疾病患者肠道菌群的结构是否会对疾病治疗产生影响，本研究选取对人体肠道菌群具有显著影响作用的益生菌和菊粉为研究对象，通过采用循证医学的研究手段，探讨其在临床应用中是否对高脂血症具有治疗作用。论文的主要研究结果如下：
（1）本部分研究选取中国四川地区5例健康汉族婴儿、6例青年人和6例中年人的粪便样品样品作为研究对象，以454焦磷酸测序技术结合多变量统计学方法检测细菌16S rRNA基因V5-V6区的多样性。通过基于UniFrac的主成分分析（principal componentanalysis，PCoA）和非加权组平均法（Unweighted Pair Group Method with ArithmeticMean，UPGMA)我们发现婴儿样品与中青年样品是完全分离的而部分中青年的样品存在交叠现象。多元方差分析（Multivariate analysis of variance，MANOVA）表明婴儿肠道菌群群落结构与中青年差异显著而中青年肠道菌群群落结构差异不显著。无论是基于加权还是非加权的UniFrac距离分析（weighted and unweighted UniFrac distances）均显示婴儿组内平均UniFrac距离大于青年和中年组，同时中年组和青年组间差异不显著。中青年人肠道中的微生物主要隶属于硬壁菌门（Firmicutes），而婴儿的主要为变形菌门（Proteobacteria），克雷白氏杆菌属（Klebsiella）为多数婴儿肠道中的优势细菌属，而非以往文献报道的双歧杆菌（Bifidobacterium）。上述结果表明，婴儿肠道菌群群落结构明显不同于中青年人，但中青年人肠道菌群群落结构相似，同时婴儿肠道菌群群落结构个体之间的差异要显著大于青年人和中年人。
（2）本部分研究选取28例西藏那曲县境内那曲草原的牧民和15例拉萨的城市居民的粪便样品样品作为研究对象，以454焦磷酸测序技术结合多变量统计学方法检测细菌16S rRNA基因V5-V6区的多样性。虽然基于UniFrac的PcoA分析和UPGMA分析均显示两个人群的样本存在交叠现象，但MANOVA分析显示其肠道菌群群落结构差异显著（P <0.05）。虽然藏族城市居民肠道菌群的多样性和丰度大于藏区居民，但藏区居民组内平均UniFrac距离大于城市居民（P <0.05）。利用偏最小二乘判别分析（Partial least squares discrimination analysis, PLS-DA），我们找出了212个在两类居民肠道菌群结构的差异中最为关键的分类操作单元（Operational taxonomic units，OTU），其中逾1/4的OTUs被鉴定为具有短链脂肪酸产生功能的劳特氏菌属（Blautia）、梭菌属（Clostridium）、考拉杆菌属（Phascolarctobacterium）、罗斯氏菌属（Roseburia）和罕见小球菌属（Subdoligranulum），且其在城市居民中含量显著高于藏区牧民。上述结果表明，在城市和藏区生活的藏族居民其肠道菌群结构是不同的，生活方式对人肠道菌群构成有显著影响作用。
（3）本部分研究选取22例在乌鲁木齐生活的维吾尔族居民和21例哈萨克族居民的粪便样品样品作为研究对象，以454焦磷酸测序技术结合多变量统计学方法检测细菌16S rRNA基因V5-V6区的多样性。虽然基于UniFrac的PcoA分析和UPGMA分析均显示两个人群的样本存在交叠现象，但MANOVA分析显示其肠道菌群群落结构差异显著（P <0.05）。虽然维吾尔族居民肠道菌群的多样性和丰度大于哈萨克族居民，但哈萨克族居民组内平均UniFrac距离大于城市居民（P <0.05）。利用偏最小二乘判别分析（Partial least squares discrimination analysis, PLS-DA），我们找出了69个在两类居民肠道菌群结构的差异中最为关键的分类操作单元（Operational taxonomic units，OTU），其中近1/3的OTUs被鉴定为具有短链脂肪酸产生功能的梭菌属（Clostridium）、罗斯氏菌属（Roseburia）、布劳特氏菌属（Blautia）、罕见小球菌属（Subdoligranulum）、栖粪杆菌属（Faecalibacterium）、拟杆菌属（Bacteroides）和多尔氏菌属（Dorea），且其在维吾尔族居民中含量偏高。上述结果表明，维吾尔族和哈萨克族居民肠道菌群结构是不同的，基因型对人肠道菌群构成有显著影响作用。
（4）将前三部分研究中所涉及的汉族、维吾尔族、哈萨克族及藏族青年居民的样品进行合并分析，研究发现所有92个健康居民肠道均含有的细菌属为11个，包括普氏菌属（Prevotella）、拟杆菌属（Bacteroides）、考拉杆菌属（Phascolarctobacterium），罗斯氏菌属（Roseburia），布劳特氏菌（Blautia），栖粪杆菌属（Faecalibacterium）、梭菌属（Clostridium），罕见小球菌属（Subdoligranulum），瘤胃球菌属（Ruminococcus），粪球菌属（Coprococcus）和韦荣球菌属（Veillonella）。通过基于Manova分析的各民族样品马尔距离聚类分析发现各民族居民肠道菌群群落差异显著。为了进一步分析各民族特有的OTU，我们假设若一个OTU在一个或者多个民族居民的检出率小于5%（若样品数小于20则检出率取0），而在其余一个或者多个民族的检出率大于67%，则认为该OTU为能将各民族居民肠道菌群区分开的关键OTU（key OTU）。结果发现不同民族居民肠道菌群具有其特有或缺失的OTUs，哈萨克族和维吾尔族居民其特有的OTUs主要来自于拟杆菌属（Bacteroides）、罗斯氏菌属(Roseburia)和考拉杆菌属（Phascolarctobacterium），然而汉族和藏族居民其特有OTUs主要为劳特氏菌(Blautia)和普氏菌属（Prevotella）细菌。因此我们可以初步推断纳入本部分研究的92个健康青年人共有少数相同的肠道菌群。
（5）经荟萃分析发现，口服益生乳酸菌及其发酵乳制品具有降低受试者血浆总胆固醇和LDL胆固醇的作用，而对HDL胆固醇和甘油三酯无影响。服用菊粉对高脂血症患者具有降低其血清总胆固醇和LDL胆固醇的作用，而对HDL胆固醇和甘油三酯无影响，此外菊粉对健康居民血脂无调节作用。
A large number of studies have shown that the gut microbiota is closely related tohuman health and metabolism, in particular in metabolic diseases; therefor, the profiling ofhuman gut microbiota has become one of the research hot topics. In this study, we havestudied the effects of age, lifestyle and genotype on the gut microbiota of healthy Chinesepeople, meanwhile we have looked for the phenotypic characteristics that are responsible forthe differentiation between ethnic groups or lifestyles. Although the understanding of thehuman gut microbiota is of great interest due to recently accumulating evidence of its tightassociation with the human health, there is no evidence that a change in the composition ofthese microbes would impact on diseases. Oral probiotic strains and inulin could affectmicrobial environment of the gut microbiota, we conducted a meta-analysis of randomizedcontrolled trials that evaluated the effects of probiotics and inulin consumption on bloodlipids. The main results are described as follows：
(1) We performed a structural survey of the gut microbiota of17healthy individuals (5infants,6young people, and6middle-aged people) by using deep454pyrosequencing of theV5-V6region of the16S ribosomal RNA gene. By combining an Unweighted Pair GroupMethod with Arithmetic Mean (UPGMA) and UniFrac principal component analysis (PCoA),we observed that the fecal microbial communities of the infant individuals were distinct fromthose of the other individuals (P>0.001). Multivariate analysis of variance showed that thedifference between the young and middle-aged individuals was not significant. The UniFracdistance metric indicated that the interpersonal variation was significantly greater among theinfants than among the young and middle-aged people (P>0.05). Firmicutes was identifiedas the predominant phylum in the young and middle-aged people, whereas Proteobacteriawas the most abundant in the infants (P>0.05). Contrasting to the findings of other studies,Klebsiella, rather than Bifidobacterium, was identified as the most abundant microbial genusin the infant samples. There were significant differences in the phylogenetic composition ofthe gut microbiota of the healthy Chinese infants and adults, but high similarities in thestructure of the gut microbiota of young and middle-aged people. Interpersonal variation wassignificantly greater among the infants than among the young or middle-aged people.
(2) We compared the fecal microbiota of urban (N=15) and pastoral (N=28) residents inTibet. By using high-throughput16S rDNA sequencing and biochemical analyses, we foundthat although UPGMA and PCoA analysis both showed an overlapping of a few of thesamples,, the difference between the two groups was significant, as shown by Manovaanalysis (P <0.05). UniFrac distance metrics indicated that the interpersonal variation wassignificantly greater among the pastoral residents than the urban ones, meanwhile the meancommunity richness and diversity were higher in the pastoral residents. By Partial LeastSquare Discriminate Analysis (PLS-DA), we identified212OTUs as key phenotypes thatresponded to lifestyle, and more than a quarter of them were Blautia, Clostridium,Phascolarctobacterium, Roseburia and Subdoligranulum. By using Mann-Whitney test, wefound that the bacterial-derived short-chain fatty acids (SCFA) were enriched in urban residents as compared to the pastoral subjects. Thus, we could conclude that the gut microbialcommunities of the pastoral residents were distinct from that of the urban residents, and theirlifestyle had a significant effect on the gut community composition.
(3) We compared the fecal microbiota of the Uygurs (N=28) and Kazakhs (N=15) livingin Urumqi. By using high-throughput16S rDNA sequencing and biochemical analyses, wefound that although UPGMA and PCoA analysis both showed an overlapping of a few of thesamples, the difference between the two groups was significant, as shown by Manova analysis(P <0.05). UniFrac distance metric indicated that the interpersonal variation was significantlygreater among the Kazakhs, meanwhile the mean community richness and diversity werehigher in the Uygurs. By PLS-DA Analysis, we identified69OTUs as key phenotypes thatresponded to genotype, and more than one third of them were Clostridium, Roseburia, Blautia,Subdoligranulum, Faecalibacterium, Bacteroides, and Dorea, By using Mann-Whitney test,we found that these bacterial short-chain fatty acids (SCFA) were enriched in the Uygurs.Thus, we could conclude that the gut microbial communities of the Kazakhs were distinctfrom that of the Uygurs, and genotype had a significant effect on the gut communitycomposition.
(4) We collectively analyzed the gut microbiota in the92healthy young adults which hadbeen studied in part (1) to part (3). At the genus level, eleven taxa, which contained knownshort-chain fatty acids (SCFAs)-producing capacity, were universally present in all theindividuals. These included Phascolarctobacterium, Faecalibacterium, Blautia, Clostridium,and Ruminococcus. Canonical analysis of principal coordinates based on the unweightedUniFrac metric revealed that the volunteers clustered together mainly according to their ethnicbackground. A total of57OTUs were selected as the potential contributors to the ethnicbackground-driven structural variation. By the criterion that each selected OTU should bepresent in less than5%samples in at least one ethnic group but in more than67%samples inone or more of other groups, it appeared that the distinctiveness of the gut microbiotastructure in the Kazakh and Uygur ethnic groups was largely due to the absence of lineageswithin the genera Phascolarctobacterium, Bacteroides, and Roseburia. In addition, a differentset of OTUs was absent, including those within the genera Blautia and Prevotella.Interestingly, the Han and Tibetan showed a contrasting phenomenon. Thus, all92individualsshared a few common components, and any individual shared many components with a fewother individuals. However, very little was shared across all individuals.
(5) Based on meta-analysis, we concluded that the consumption of oral probioticsexerted beneficial effects on the total cholesterol and LDL cholesterol for subjects with high,borderline high and normal cholesterol levels. Moreover, a diet rich in inulin was beneficial tothe plasma total and LDL cholesterol, as well as triglyceride concentration of hyperlipidemicsubjects, but had no effect on the plasma lipid in normolipidemic subjects.
（1）本部分研究选取中国四川地区5例健康汉族婴儿、6例青年人和6例中年人的粪便样品样品作为研究对象，以454焦磷酸测序技术结合多变量统计学方法检测细菌16S rRNA基因V5-V6区的多样性。通过基于UniFrac的主成分分析（principal componentanalysis，PCoA）和非加权组平均法（Unweighted Pair Group Method with ArithmeticMean，UPGMA)我们发现婴儿样品与中青年样品是完全分离的而部分中青年的样品存在交叠现象。多元方差分析（Multivariate analysis of variance，MANOVA）表明婴儿肠道菌群群落结构与中青年差异显著而中青年肠道菌群群落结构差异不显著。无论是基于加权还是非加权的UniFrac距离分析（weighted and unweighted UniFrac distances）均显示婴儿组内平均UniFrac距离大于青年和中年组，同时中年组和青年组间差异不显著。中青年人肠道中的微生物主要隶属于硬壁菌门（Firmicutes），而婴儿的主要为变形菌门（Proteobacteria），克雷白氏杆菌属（Klebsiella）为多数婴儿肠道中的优势细菌属，而非以往文献报道的双歧杆菌（Bifidobacterium）。上述结果表明，婴儿肠道菌群群落结构明显不同于中青年人，但中青年人肠道菌群群落结构相似，同时婴儿肠道菌群群落结构个体之间的差异要显著大于青年人和中年人。
（2）本部分研究选取28例西藏那曲县境内那曲草原的牧民和15例拉萨的城市居民的粪便样品样品作为研究对象，以454焦磷酸测序技术结合多变量统计学方法检测细菌16S rRNA基因V5-V6区的多样性。虽然基于UniFrac的PcoA分析和UPGMA分析均显示两个人群的样本存在交叠现象，但MANOVA分析显示其肠道菌群群落结构差异显著（P <0.05）。虽然藏族城市居民肠道菌群的多样性和丰度大于藏区居民，但藏区居民组内平均UniFrac距离大于城市居民（P <0.05）。利用偏最小二乘判别分析（Partial least squares discrimination analysis, PLS-DA），我们找出了212个在两类居民肠道菌群结构的差异中最为关键的分类操作单元（Operational taxonomic units，OTU），其中逾1/4的OTUs被鉴定为具有短链脂肪酸产生功能的劳特氏菌属（Blautia）、梭菌属（Clostridium）、考拉杆菌属（Phascolarctobacterium）、罗斯氏菌属（Roseburia）和罕见小球菌属（Subdoligranulum），且其在城市居民中含量显著高于藏区牧民。上述结果表明，在城市和藏区生活的藏族居民其肠道菌群结构是不同的，生活方式对人肠道菌群构成有显著影响作用。
（3）本部分研究选取22例在乌鲁木齐生活的维吾尔族居民和21例哈萨克族居民的粪便样品样品作为研究对象，以454焦磷酸测序技术结合多变量统计学方法检测细菌16S rRNA基因V5-V6区的多样性。虽然基于UniFrac的PcoA分析和UPGMA分析均显示两个人群的样本存在交叠现象，但MANOVA分析显示其肠道菌群群落结构差异显著（P <0.05）。虽然维吾尔族居民肠道菌群的多样性和丰度大于哈萨克族居民，但哈萨克族居民组内平均UniFrac距离大于城市居民（P <0.05）。利用偏最小二乘判别分析（Partial least squares discrimination analysis, PLS-DA），我们找出了69个在两类居民肠道菌群结构的差异中最为关键的分类操作单元（Operational taxonomic units，OTU），其中近1/3的OTUs被鉴定为具有短链脂肪酸产生功能的梭菌属（Clostridium）、罗斯氏菌属（Roseburia）、布劳特氏菌属（Blautia）、罕见小球菌属（Subdoligranulum）、栖粪杆菌属（Faecalibacterium）、拟杆菌属（Bacteroides）和多尔氏菌属（Dorea），且其在维吾尔族居民中含量偏高。上述结果表明，维吾尔族和哈萨克族居民肠道菌群结构是不同的，基因型对人肠道菌群构成有显著影响作用。
（4）将前三部分研究中所涉及的汉族、维吾尔族、哈萨克族及藏族青年居民的样品进行合并分析，研究发现所有92个健康居民肠道均含有的细菌属为11个，包括普氏菌属（Prevotella）、拟杆菌属（Bacteroides）、考拉杆菌属（Phascolarctobacterium），罗斯氏菌属（Roseburia），布劳特氏菌（Blautia），栖粪杆菌属（Faecalibacterium）、梭菌属（Clostridium），罕见小球菌属（Subdoligranulum），瘤胃球菌属（Ruminococcus），粪球菌属（Coprococcus）和韦荣球菌属（Veillonella）。通过基于Manova分析的各民族样品马尔距离聚类分析发现各民族居民肠道菌群群落差异显著。为了进一步分析各民族特有的OTU，我们假设若一个OTU在一个或者多个民族居民的检出率小于5%（若样品数小于20则检出率取0），而在其余一个或者多个民族的检出率大于67%，则认为该OTU为能将各民族居民肠道菌群区分开的关键OTU（key OTU）。结果发现不同民族居民肠道菌群具有其特有或缺失的OTUs，哈萨克族和维吾尔族居民其特有的OTUs主要来自于拟杆菌属（Bacteroides）、罗斯氏菌属(Roseburia)和考拉杆菌属（Phascolarctobacterium），然而汉族和藏族居民其特有OTUs主要为劳特氏菌(Blautia)和普氏菌属（Prevotella）细菌。因此我们可以初步推断纳入本部分研究的92个健康青年人共有少数相同的肠道菌群。
（5）经荟萃分析发现，口服益生乳酸菌及其发酵乳制品具有降低受试者血浆总胆固醇和LDL胆固醇的作用，而对HDL胆固醇和甘油三酯无影响。服用菊粉对高脂血症患者具有降低其血清总胆固醇和LDL胆固醇的作用，而对HDL胆固醇和甘油三酯无影响，此外菊粉对健康居民血脂无调节作用。
A large number of studies have shown that the gut microbiota is closely related tohuman health and metabolism, in particular in metabolic diseases; therefor, the profiling ofhuman gut microbiota has become one of the research hot topics. In this study, we havestudied the effects of age, lifestyle and genotype on the gut microbiota of healthy Chinesepeople, meanwhile we have looked for the phenotypic characteristics that are responsible forthe differentiation between ethnic groups or lifestyles. Although the understanding of thehuman gut microbiota is of great interest due to recently accumulating evidence of its tightassociation with the human health, there is no evidence that a change in the composition ofthese microbes would impact on diseases. Oral probiotic strains and inulin could affectmicrobial environment of the gut microbiota, we conducted a meta-analysis of randomizedcontrolled trials that evaluated the effects of probiotics and inulin consumption on bloodlipids. The main results are described as follows：
(1) We performed a structural survey of the gut microbiota of17healthy individuals (5infants,6young people, and6middle-aged people) by using deep454pyrosequencing of theV5-V6region of the16S ribosomal RNA gene. By combining an Unweighted Pair GroupMethod with Arithmetic Mean (UPGMA) and UniFrac principal component analysis (PCoA),we observed that the fecal microbial communities of the infant individuals were distinct fromthose of the other individuals (P>0.001). Multivariate analysis of variance showed that thedifference between the young and middle-aged individuals was not significant. The UniFracdistance metric indicated that the interpersonal variation was significantly greater among theinfants than among the young and middle-aged people (P>0.05). Firmicutes was identifiedas the predominant phylum in the young and middle-aged people, whereas Proteobacteriawas the most abundant in the infants (P>0.05). Contrasting to the findings of other studies,Klebsiella, rather than Bifidobacterium, was identified as the most abundant microbial genusin the infant samples. There were significant differences in the phylogenetic composition ofthe gut microbiota of the healthy Chinese infants and adults, but high similarities in thestructure of the gut microbiota of young and middle-aged people. Interpersonal variation wassignificantly greater among the infants than among the young or middle-aged people.
(2) We compared the fecal microbiota of urban (N=15) and pastoral (N=28) residents inTibet. By using high-throughput16S rDNA sequencing and biochemical analyses, we foundthat although UPGMA and PCoA analysis both showed an overlapping of a few of thesamples,, the difference between the two groups was significant, as shown by Manovaanalysis (P <0.05). UniFrac distance metrics indicated that the interpersonal variation wassignificantly greater among the pastoral residents than the urban ones, meanwhile the meancommunity richness and diversity were higher in the pastoral residents. By Partial LeastSquare Discriminate Analysis (PLS-DA), we identified212OTUs as key phenotypes thatresponded to lifestyle, and more than a quarter of them were Blautia, Clostridium,Phascolarctobacterium, Roseburia and Subdoligranulum. By using Mann-Whitney test, wefound that the bacterial-derived short-chain fatty acids (SCFA) were enriched in urban residents as compared to the pastoral subjects. Thus, we could conclude that the gut microbialcommunities of the pastoral residents were distinct from that of the urban residents, and theirlifestyle had a significant effect on the gut community composition.
(3) We compared the fecal microbiota of the Uygurs (N=28) and Kazakhs (N=15) livingin Urumqi. By using high-throughput16S rDNA sequencing and biochemical analyses, wefound that although UPGMA and PCoA analysis both showed an overlapping of a few of thesamples, the difference between the two groups was significant, as shown by Manova analysis(P <0.05). UniFrac distance metric indicated that the interpersonal variation was significantlygreater among the Kazakhs, meanwhile the mean community richness and diversity werehigher in the Uygurs. By PLS-DA Analysis, we identified69OTUs as key phenotypes thatresponded to genotype, and more than one third of them were Clostridium, Roseburia, Blautia,Subdoligranulum, Faecalibacterium, Bacteroides, and Dorea, By using Mann-Whitney test,we found that these bacterial short-chain fatty acids (SCFA) were enriched in the Uygurs.Thus, we could conclude that the gut microbial communities of the Kazakhs were distinctfrom that of the Uygurs, and genotype had a significant effect on the gut communitycomposition.
(4) We collectively analyzed the gut microbiota in the92healthy young adults which hadbeen studied in part (1) to part (3). At the genus level, eleven taxa, which contained knownshort-chain fatty acids (SCFAs)-producing capacity, were universally present in all theindividuals. These included Phascolarctobacterium, Faecalibacterium, Blautia, Clostridium,and Ruminococcus. Canonical analysis of principal coordinates based on the unweightedUniFrac metric revealed that the volunteers clustered together mainly according to their ethnicbackground. A total of57OTUs were selected as the potential contributors to the ethnicbackground-driven structural variation. By the criterion that each selected OTU should bepresent in less than5%samples in at least one ethnic group but in more than67%samples inone or more of other groups, it appeared that the distinctiveness of the gut microbiotastructure in the Kazakh and Uygur ethnic groups was largely due to the absence of lineageswithin the genera Phascolarctobacterium, Bacteroides, and Roseburia. In addition, a differentset of OTUs was absent, including those within the genera Blautia and Prevotella.Interestingly, the Han and Tibetan showed a contrasting phenomenon. Thus, all92individualsshared a few common components, and any individual shared many components with a fewother individuals. However, very little was shared across all individuals.
(5) Based on meta-analysis, we concluded that the consumption of oral probioticsexerted beneficial effects on the total cholesterol and LDL cholesterol for subjects with high,borderline high and normal cholesterol levels. Moreover, a diet rich in inulin was beneficial tothe plasma total and LDL cholesterol, as well as triglyceride concentration of hyperlipidemicsubjects, but had no effect on the plasma lipid in normolipidemic subjects.
引文
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