基于肠道菌群结构与功能分析的支气管哮喘维、西医研究
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摘要
目的：探究支气管哮喘及维医不同异常体液分型支气管哮喘患者肠道菌群多样性及结构组成特征，研究肠道菌群与支气管哮喘的相互关系，及其参与支气管哮喘发病的可能机制，寻找参与支气管哮喘发生发展的重要功能类群；阐明维医异常体液分型，尤其是异常黑胆质体液的生物学基础，肠道菌群与支气管哮喘维吾尔医异常体液分型间的相互关系。
方法：采用病例-对照研究方案，运用16SrRNA V3区PCR-DGGE指纹图谱技术、454焦磷酸高通量测序手段及生物信息学统计方法—PCA、PLS-DA、UniFrac及RDA冗余分析分别开展小样本和大样本支气管哮喘人群的比较研究，分析和展示支气管哮喘患者与对照人群及不同维医病症分型支气管哮喘患者的肠道菌群结构组成特征与差异。
结果：(1) PCR-DGGE分析结果为支气管哮喘患者的肠道菌DNA条带数量（7～31条不等，平均只有17条）少于对照组个体的DNA条带数量（14～36条不等，平均24条），类群多样性显著降低，Shannon–Weaver指数、Simpson_D指数显著低于对照组（P<0.0001）。粪便菌16SrRNA V3区高通量测序数据分析，发现哮喘患者的肠道菌类群数量和丰度都显著降低。多变量方差分析（mannova检验）显示哮喘患者的肠道菌群结构组成有别于对照组（P<0.01）。支气管哮喘状态下，患者肠道菌群的构成发生了改变，两组样本PCA分类具有潜在分离趋势，维汉不同民族哮喘患者的肠道菌群构成存在差异。群落微生态分析手段RDA冗余分析共鉴定出能够解释造成哮喘组与对照组肠道菌群结构组成差异的14个细菌类群（OTUs），经蒙特卡罗检验（MCPP），差异具有统计学意义（P=0.0002），这些具有差异特征的肠道菌类群分属于不同的OTUs，在两组受试人群中的差异表现行为可能与支气管哮喘发生发展有关。(2)异常黑胆质型哮喘患者的肠道菌DNA条带有8～28条，平均16条；非异常黑胆质型哮喘患者的肠道菌DNA条带有7～31条，平均18条；异常黑胆质哮喘组与非异常黑胆质哮喘组间肠道菌群的多样性指数明显低于对照组（P<0.05），但两个分型组间的差异无统计学意义。454测序数据分析发现，异常黑胆质哮喘组（异黑组）的肠道菌群多样性下降，Shannon–Weaver、Simpson_D等多样性指数均低于非异常黑胆质组（P<0.05）。多变量方差分析（mannova检验）显示异黑哮喘组与非黑哮喘组的肠道菌群结构组成有差异（P<0.01），PCA分析显示两组分离趋势明显。为了明确对两组间肠道菌组成差异贡献较大的具体肠道菌关键类群，经RDA冗余分析共鉴定出了23个细菌类群（OTUs）（MCPP，P=0.0002)，是两组间菌群构成差异的最主要体现，属于Bacteroides的OTUs在异黑组中的构成比例显著升高。
结论：研究表明：（1）支气管哮喘患者的肠道菌群在分子水平上发生明显改变，多样性显著降低，肠道菌群的结构改变参与支气管哮喘发生发展，可以反映支气管哮喘的疾病状态，具有预测和监测支气管哮喘发生发展的潜质。（2）支气管哮喘不同维吾尔医学异常体液分型组患者的肠道菌群构成不同，肠道菌群结构改变是支气管哮喘维医异常体液分型理论内涵的表现之一。（3）被鉴定出的分属于不同分类水平的OTUs很可能与异常黑胆质的形成与转归有关，是支气管哮喘异常黑胆质证的具体生物学基础，此研究结果为维医的辨证分型及其理论基础的科学阐述提供了可靠的实验依据。
Objective: To analyze the diversity and structure characteristics of gut microbiotain patients with asthma and find the possible relationship between gut microbiota andasthma disease and to identify the key functional members which participate theasthma；to clarify the foundation of abnormal Hilit differentiation of traditional Uyghurmedicine (TUM). Especially to make further comprehension of the biologic basis forabnormal Savda syndrome of TUM theory.
Methods: In this case-control study project, we recruited control asthma patientswith and without abnormal savda syndrome, and comparatively examined the structureof the gut microbiota in these asthma patients by using PCR-DGGE profile and454pyrosequencing based on the16SrRNA V3region of bacteria to provide an in-depthanalysis of status-related differences of gut microbiota between different statusaccording to two medicine systems within small and large population.
Results:(1) Based on the DGGE profile, the bands (7to31, averagely17) observedin asthma patients were less than that in controls (the value is from14to36, averagely24). The Shannon-Wiener diversity index is markedly lower in asthma patients thancontrols (P<0.0001). Using454pyrosequencing, it shows that the number and richnessof bacteria in the gut were significantly reduced. Combined with multivariate statisticalmethods analysis, it shows that two groups of sample were classified obviously by thestructure of gut microbiota. And the different within two nationalities has a statisticalsignificance.14operational taxonomic units (OTUs) were identified by redundancyanalysis as key variables significantly associated with the structural difference(MCPP，P=0.0002). This different distribution of these OTUs in the two groups ofsubjects may be associated with asthma onset.(2) Based on the DGGE profile,8to28bands (averagely16) were observed in the abnormal savda type asthma, while the value is from7to31, averagely18in the other abnormal hilit type asthma. The diversityindex is markedly lower in abnormal hilit type asthma patients than controls with thenumber of groups and richness decreased notably (P<0.0001), but no statisticalsignificance between the abnormal hilit type asthma groups. By using sequencing, thediversity of gut bacteria in abnormal hilit type asthma patients is decreased and thediversity index (Shannon–Weaver、Simpson_D) are lower than other groups (P<0.05).Combined with multivariate statistical methods analysis, it shows that2groups ofsamples with different syndrome were classified obviously by the structure of gutmicrobiota. Twenty-three operational taxonomic units (OTUs) were identified byredundancy analysis as key variables significantly associated with the structuraldifference （MCPP，P=0.0002). OTUs closely related to Bacteroides was markedlyenrich in the gut microbiota of abnormal savda syndrome patients.
Conclusion: Using16SrRNA V3DNA fingerprinting and high-throughputsequencing technologies, the structure of gut microbiota were analyzed completely. Theresult shows that (1) The gut microbiota of asthma patient proceed remarkably changesat the molecular level to be associated with the gut micobiota diversity decreases andstructure changes notably. It may be related to asthma disease status. It indicates that thegut microbiota has the potential ability to forecast and monitoring the development ofasthma.(2) Our overall findings provides comprehensive data and improved methodsfor studying the theory of syndrome differentiation of TUM. Gut microbiota analysishave greater weight in TUM syndrome classification.(3) The variables (OTUs)belonged to different level might related to the formation and prognosis and one of theSpecific biological performance of abnormal Hilit savda. The gut microbiota analysisbased study could be an potential evidence-based tool for standardization of TUMsyndrome differentiation. This study provide sufficient evidence for study the theory ofTUM syndrome differentiation.
方法：采用病例-对照研究方案，运用16SrRNA V3区PCR-DGGE指纹图谱技术、454焦磷酸高通量测序手段及生物信息学统计方法—PCA、PLS-DA、UniFrac及RDA冗余分析分别开展小样本和大样本支气管哮喘人群的比较研究，分析和展示支气管哮喘患者与对照人群及不同维医病症分型支气管哮喘患者的肠道菌群结构组成特征与差异。
结果：(1) PCR-DGGE分析结果为支气管哮喘患者的肠道菌DNA条带数量（7～31条不等，平均只有17条）少于对照组个体的DNA条带数量（14～36条不等，平均24条），类群多样性显著降低，Shannon–Weaver指数、Simpson_D指数显著低于对照组（P<0.0001）。粪便菌16SrRNA V3区高通量测序数据分析，发现哮喘患者的肠道菌类群数量和丰度都显著降低。多变量方差分析（mannova检验）显示哮喘患者的肠道菌群结构组成有别于对照组（P<0.01）。支气管哮喘状态下，患者肠道菌群的构成发生了改变，两组样本PCA分类具有潜在分离趋势，维汉不同民族哮喘患者的肠道菌群构成存在差异。群落微生态分析手段RDA冗余分析共鉴定出能够解释造成哮喘组与对照组肠道菌群结构组成差异的14个细菌类群（OTUs），经蒙特卡罗检验（MCPP），差异具有统计学意义（P=0.0002），这些具有差异特征的肠道菌类群分属于不同的OTUs，在两组受试人群中的差异表现行为可能与支气管哮喘发生发展有关。(2)异常黑胆质型哮喘患者的肠道菌DNA条带有8～28条，平均16条；非异常黑胆质型哮喘患者的肠道菌DNA条带有7～31条，平均18条；异常黑胆质哮喘组与非异常黑胆质哮喘组间肠道菌群的多样性指数明显低于对照组（P<0.05），但两个分型组间的差异无统计学意义。454测序数据分析发现，异常黑胆质哮喘组（异黑组）的肠道菌群多样性下降，Shannon–Weaver、Simpson_D等多样性指数均低于非异常黑胆质组（P<0.05）。多变量方差分析（mannova检验）显示异黑哮喘组与非黑哮喘组的肠道菌群结构组成有差异（P<0.01），PCA分析显示两组分离趋势明显。为了明确对两组间肠道菌组成差异贡献较大的具体肠道菌关键类群，经RDA冗余分析共鉴定出了23个细菌类群（OTUs）（MCPP，P=0.0002)，是两组间菌群构成差异的最主要体现，属于Bacteroides的OTUs在异黑组中的构成比例显著升高。
结论：研究表明：（1）支气管哮喘患者的肠道菌群在分子水平上发生明显改变，多样性显著降低，肠道菌群的结构改变参与支气管哮喘发生发展，可以反映支气管哮喘的疾病状态，具有预测和监测支气管哮喘发生发展的潜质。（2）支气管哮喘不同维吾尔医学异常体液分型组患者的肠道菌群构成不同，肠道菌群结构改变是支气管哮喘维医异常体液分型理论内涵的表现之一。（3）被鉴定出的分属于不同分类水平的OTUs很可能与异常黑胆质的形成与转归有关，是支气管哮喘异常黑胆质证的具体生物学基础，此研究结果为维医的辨证分型及其理论基础的科学阐述提供了可靠的实验依据。
Objective: To analyze the diversity and structure characteristics of gut microbiotain patients with asthma and find the possible relationship between gut microbiota andasthma disease and to identify the key functional members which participate theasthma；to clarify the foundation of abnormal Hilit differentiation of traditional Uyghurmedicine (TUM). Especially to make further comprehension of the biologic basis forabnormal Savda syndrome of TUM theory.
Methods: In this case-control study project, we recruited control asthma patientswith and without abnormal savda syndrome, and comparatively examined the structureof the gut microbiota in these asthma patients by using PCR-DGGE profile and454pyrosequencing based on the16SrRNA V3region of bacteria to provide an in-depthanalysis of status-related differences of gut microbiota between different statusaccording to two medicine systems within small and large population.
Results:(1) Based on the DGGE profile, the bands (7to31, averagely17) observedin asthma patients were less than that in controls (the value is from14to36, averagely24). The Shannon-Wiener diversity index is markedly lower in asthma patients thancontrols (P<0.0001). Using454pyrosequencing, it shows that the number and richnessof bacteria in the gut were significantly reduced. Combined with multivariate statisticalmethods analysis, it shows that two groups of sample were classified obviously by thestructure of gut microbiota. And the different within two nationalities has a statisticalsignificance.14operational taxonomic units (OTUs) were identified by redundancyanalysis as key variables significantly associated with the structural difference(MCPP，P=0.0002). This different distribution of these OTUs in the two groups ofsubjects may be associated with asthma onset.(2) Based on the DGGE profile,8to28bands (averagely16) were observed in the abnormal savda type asthma, while the value is from7to31, averagely18in the other abnormal hilit type asthma. The diversityindex is markedly lower in abnormal hilit type asthma patients than controls with thenumber of groups and richness decreased notably (P<0.0001), but no statisticalsignificance between the abnormal hilit type asthma groups. By using sequencing, thediversity of gut bacteria in abnormal hilit type asthma patients is decreased and thediversity index (Shannon–Weaver、Simpson_D) are lower than other groups (P<0.05).Combined with multivariate statistical methods analysis, it shows that2groups ofsamples with different syndrome were classified obviously by the structure of gutmicrobiota. Twenty-three operational taxonomic units (OTUs) were identified byredundancy analysis as key variables significantly associated with the structuraldifference （MCPP，P=0.0002). OTUs closely related to Bacteroides was markedlyenrich in the gut microbiota of abnormal savda syndrome patients.
Conclusion: Using16SrRNA V3DNA fingerprinting and high-throughputsequencing technologies, the structure of gut microbiota were analyzed completely. Theresult shows that (1) The gut microbiota of asthma patient proceed remarkably changesat the molecular level to be associated with the gut micobiota diversity decreases andstructure changes notably. It may be related to asthma disease status. It indicates that thegut microbiota has the potential ability to forecast and monitoring the development ofasthma.(2) Our overall findings provides comprehensive data and improved methodsfor studying the theory of syndrome differentiation of TUM. Gut microbiota analysishave greater weight in TUM syndrome classification.(3) The variables (OTUs)belonged to different level might related to the formation and prognosis and one of theSpecific biological performance of abnormal Hilit savda. The gut microbiota analysisbased study could be an potential evidence-based tool for standardization of TUMsyndrome differentiation. This study provide sufficient evidence for study the theory ofTUM syndrome differentiation.
引文
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