人体小肠微生态研究及肝移植受者肠道微生态研究
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摘要
栖息在人类的微生物的数量达100万亿个,超过人体细胞和生殖细胞的10倍,被称为是人类的“第二基因组”,构成了人体的一个代谢器官,参与机体的代谢,肠道微生物作为体内菌群最多的共生生态系统影响着人类的健康、营养及生长发育。近年来,随着非培养技术的进步,对人类肠道微生态的研究及其对健康与疾病影响的研究呈现空前的增长。越来越多的研究表明,肠道微生态的失衡与许多疾病如肥胖、糖尿病、炎性肠病、过敏性疾病等均有关。然而寄居在人类肠道的微生物达上千种,我们所了解的只是其中的一小部分,因此进一步研究肠道微生物的特征构成,尤其是对既往研究未曾涉及的肠道标本以及特殊人群肠道微生态的变化将有助于我们更为深入的了解微生物在人类健康与疾病中的作用。
本研究第一部分对10位器官捐献者的小肠不同部位的样本进行了研究,在无菌状态下获取空肠上段、空回肠交界处及回肠末端三个部位的肠内容物,提取细菌DNA,应用454焦磷酸测序技术,对小肠内菌群结构特征进行了详细的分析,明确和比较了小肠不同部位肠道菌群多样性及其组成结构,共获得69506条高质量的16S rRNA基因V5-V6区序列,所有序列依据97%相似度水平划分为518个分类操作单元(operational taxonomic units,OTU),在细菌门分类水平丰度较高的有6个已知的门类和一个未分类的门类,包括变形菌门(Proteobacteria)、厚壁菌门(Firmicutes)、放线菌门(Actinobacteria)、TM7门、梭杆菌门(Fusobacteria),拟杆菌门(Bacteroidetes)上述门类细菌覆盖了小肠内85%的细菌微生物,另外检测到7个丰度较低的细菌门类。通过研究表明,人体小肠微生态呈现与生理解剖部位相关的特征性改变,空肠上段与空回肠交界处小肠微生态多样性无明显差异,空肠上段、空回肠交界处小肠微生态多样性与回肠末段小肠微生态多样性相比较存在显著差异。
本研究第二部分对肝移植受者肠道微生态进行了研究,共收集47份粪便标本,包括健康对照组(n=15),肝移植术前组(n=17)、肝移植术后组(n=15)、提取粪便基因组DNA,同样应用454焦磷酸测序技术,共获得527735条万条高质量的16S-rRNA基因序列,1911个OTU。分析结果提示在肝移植术前、术后及正常对照者的所有样本在门类水平分属12个门类,包括厚壁菌门(Firmicutes)、变形菌门(Proteobacteria)、放线菌门(Actinobacteria)、拟杆菌门(Bacteroidetes)、TM7门、蓝藻菌门(Cyanobacteria)、梭杆菌门(Fusobacteria)、疣微菌门(Verrucomicrobia)、柔膜菌门(Tenericutes)、Synergistetes门,古细菌(Archaea)以及未分类细菌。其中厚壁菌门、拟杆菌门和变形菌门占所有细菌的92%。在本研究中肝移植术前患者与健康对照者相比,粪便中变形菌门(Proteobacteria)丰度增加,其中主要是以肠杆菌科(Enterobacteriaceae)明显增加；拟杆菌门(Bacteroidetes)中的普沃氏菌属(Prevotella)丰度明显降低,拟杆菌属(Bacteroides)无明显变化。肝移植术后患者的与术前相比,变形菌门(Proteobacteria)丰度明显减少,其中主要是肠杆菌科(Enterobacteriaceae)减少,而厚壁菌门的丰度增加。肝移植术前术后患者与健康人群之间肠道微生态均存在差异,而肝移植患者术前术后变化更为明显。
本研究通过对器官捐献者小肠微生态的研究,初次用Bar coded454测序描绘人体小肠微生物的种群结构及丰度,并依据生理解剖位置的不同对小肠微生态进行了分析,为进一步研究人类肠道微生态与宿主物质代谢、免疫功能调节及疾病的关系提供重要参考数据。另外本研究通过比较肝移植患者术前术后肠道微生态的变化,初步揭示肝脏移植手术治疗以及免疫抑制治疗等特殊因素对肠道微生态的影响,为进一步的研究提供重要依据。
The number of human microorganism is about100trillion,10times more than the number of somatic cells and germ cells. In this way, human microbiota, regarded as the second human genome, forms an organ which takes part into the metabolism. Human intestinal microbiota, containing the greatest amount of organisms, have a critical influence on human health, nutrition and growth. Recently, with the development of culture-independent techniques, the knowledge about human intestinal microbiota and its effects on health and disease is increasing significantly. Increasingly more evidences show that imbalance of human intestinal microbiota has a closely relationship with many diseases, such as obesity, diabetes, inflammatory bowel disease, allergic diseases and so on. However, despite the existence of thousands of kinds of organisms, we only recognize a very small part of them. Therefore, the study on the characters of human intestinal microbiota, especially on some unstudied intestinal samples or some specific objects, would facilitate us to further understand the role of human intestinal microbiota in health and disease.
In the first part, we studied the intestinal microbiota from10organ donors. Under the sterile condition, the contains from the upper jejunum, jejunoileum junction, and the terminal ileum were colected. Then, DNA was purified. With454pyrosequencing technology, we analyzed the characters of small intestinal microbiota, and compared the composition and diversity of microbiota among different locations. We attained69506high qualified16s rRNA V5-V6sequences. According to97%level of identity, all these sequences were classified into518operational taxonomic units (OTUs). There were6bacterial phylums, whose abundance were above1%, including Firmicutes, Proteobacteria, Actinobacteria, Bacteroidetes, TM7, Cyanobacteria, Fusobacteria, Bacteroidetes and one unclassified bacteria. The phylums mentioned above nearly covered85%organisms in human small intestinal. Besides, several phylums with extremely low abundance were also tested out. According to our study have shown that the conditions of human intestinal microbiota is anatomical location dependent. Human intestinal microbiota in either upper jejunum or jejunoileum junction shows no statistical significance. But the diversity of human intestinal microbiota in upper jejunum and jejunoileum junction is significantly different from that in terminal ileum.
In the second part, we collected47stool specimens from liver transplant recipients in order to study human intestinal microbiota. These specimens were divided into3groups, including healthy control group (n=15), pre-liver trasnplantaton group (pre-LT)(n=17), and post-liver transplantation group (post-LT)(n=15). Then, DNA was purified. With454pyrosequencing technology, we attained527735high qualified16s rRNA sequences and1911OTUs. The results showed that all the specimens from3groups were belonged to12phylums, including Firmicutes, Proteobacteria, Actinobacteria, Bacteroidetes, TM7, Cyanobacteria, Fusobacteria, Verrucomicrobia, Tenericutes, and Synergistetes. And approximate92%of the bacteria from these specimens are from Firmicutes, Bacteroidetes, and Proteobacteria. Compared with the control group, the abundance of Proteobacteria, especially Enterobacteriaceae, in stool specimens from pre-LT group was increased. The abundance of Bacteroidetes was also increased, except for the abundance of Prevotella, which was significantly decreased. Compared with pre-LT group, the abundance of Proteobacteria in stool specimens from post-LT group was declined, while the abundance of Firmicutes was elevated. The differences between control, pre-LT, and post-LT group all reached statistically significance, and the differences between pre-LT, and post-LT group were more significant.
Our study aims to explore the intestinal microbiota in liver transplantation recipients. We first adopt the techniques of Barcoded454sequence to characterize the composition and abundance of human intestinal microbiota, analyze the microbiota from different human intestinal locations, and provide the important parameters for the. further study on association among human intestinal microbiota, host metabolism, immuno-regulation, and relative diseases. Additionally, our study also discuss the changes of intestinal microbiota between pre-LT and post-LT groups, and preliminary disclose the influence of operation and immunosuppressants on intestinal microbiota, providing the critical evidences for the further study.
本研究第一部分对10位器官捐献者的小肠不同部位的样本进行了研究,在无菌状态下获取空肠上段、空回肠交界处及回肠末端三个部位的肠内容物,提取细菌DNA,应用454焦磷酸测序技术,对小肠内菌群结构特征进行了详细的分析,明确和比较了小肠不同部位肠道菌群多样性及其组成结构,共获得69506条高质量的16S rRNA基因V5-V6区序列,所有序列依据97%相似度水平划分为518个分类操作单元(operational taxonomic units,OTU),在细菌门分类水平丰度较高的有6个已知的门类和一个未分类的门类,包括变形菌门(Proteobacteria)、厚壁菌门(Firmicutes)、放线菌门(Actinobacteria)、TM7门、梭杆菌门(Fusobacteria),拟杆菌门(Bacteroidetes)上述门类细菌覆盖了小肠内85%的细菌微生物,另外检测到7个丰度较低的细菌门类。通过研究表明,人体小肠微生态呈现与生理解剖部位相关的特征性改变,空肠上段与空回肠交界处小肠微生态多样性无明显差异,空肠上段、空回肠交界处小肠微生态多样性与回肠末段小肠微生态多样性相比较存在显著差异。
本研究第二部分对肝移植受者肠道微生态进行了研究,共收集47份粪便标本,包括健康对照组(n=15),肝移植术前组(n=17)、肝移植术后组(n=15)、提取粪便基因组DNA,同样应用454焦磷酸测序技术,共获得527735条万条高质量的16S-rRNA基因序列,1911个OTU。分析结果提示在肝移植术前、术后及正常对照者的所有样本在门类水平分属12个门类,包括厚壁菌门(Firmicutes)、变形菌门(Proteobacteria)、放线菌门(Actinobacteria)、拟杆菌门(Bacteroidetes)、TM7门、蓝藻菌门(Cyanobacteria)、梭杆菌门(Fusobacteria)、疣微菌门(Verrucomicrobia)、柔膜菌门(Tenericutes)、Synergistetes门,古细菌(Archaea)以及未分类细菌。其中厚壁菌门、拟杆菌门和变形菌门占所有细菌的92%。在本研究中肝移植术前患者与健康对照者相比,粪便中变形菌门(Proteobacteria)丰度增加,其中主要是以肠杆菌科(Enterobacteriaceae)明显增加；拟杆菌门(Bacteroidetes)中的普沃氏菌属(Prevotella)丰度明显降低,拟杆菌属(Bacteroides)无明显变化。肝移植术后患者的与术前相比,变形菌门(Proteobacteria)丰度明显减少,其中主要是肠杆菌科(Enterobacteriaceae)减少,而厚壁菌门的丰度增加。肝移植术前术后患者与健康人群之间肠道微生态均存在差异,而肝移植患者术前术后变化更为明显。
本研究通过对器官捐献者小肠微生态的研究,初次用Bar coded454测序描绘人体小肠微生物的种群结构及丰度,并依据生理解剖位置的不同对小肠微生态进行了分析,为进一步研究人类肠道微生态与宿主物质代谢、免疫功能调节及疾病的关系提供重要参考数据。另外本研究通过比较肝移植患者术前术后肠道微生态的变化,初步揭示肝脏移植手术治疗以及免疫抑制治疗等特殊因素对肠道微生态的影响,为进一步的研究提供重要依据。
The number of human microorganism is about100trillion,10times more than the number of somatic cells and germ cells. In this way, human microbiota, regarded as the second human genome, forms an organ which takes part into the metabolism. Human intestinal microbiota, containing the greatest amount of organisms, have a critical influence on human health, nutrition and growth. Recently, with the development of culture-independent techniques, the knowledge about human intestinal microbiota and its effects on health and disease is increasing significantly. Increasingly more evidences show that imbalance of human intestinal microbiota has a closely relationship with many diseases, such as obesity, diabetes, inflammatory bowel disease, allergic diseases and so on. However, despite the existence of thousands of kinds of organisms, we only recognize a very small part of them. Therefore, the study on the characters of human intestinal microbiota, especially on some unstudied intestinal samples or some specific objects, would facilitate us to further understand the role of human intestinal microbiota in health and disease.
In the first part, we studied the intestinal microbiota from10organ donors. Under the sterile condition, the contains from the upper jejunum, jejunoileum junction, and the terminal ileum were colected. Then, DNA was purified. With454pyrosequencing technology, we analyzed the characters of small intestinal microbiota, and compared the composition and diversity of microbiota among different locations. We attained69506high qualified16s rRNA V5-V6sequences. According to97%level of identity, all these sequences were classified into518operational taxonomic units (OTUs). There were6bacterial phylums, whose abundance were above1%, including Firmicutes, Proteobacteria, Actinobacteria, Bacteroidetes, TM7, Cyanobacteria, Fusobacteria, Bacteroidetes and one unclassified bacteria. The phylums mentioned above nearly covered85%organisms in human small intestinal. Besides, several phylums with extremely low abundance were also tested out. According to our study have shown that the conditions of human intestinal microbiota is anatomical location dependent. Human intestinal microbiota in either upper jejunum or jejunoileum junction shows no statistical significance. But the diversity of human intestinal microbiota in upper jejunum and jejunoileum junction is significantly different from that in terminal ileum.
In the second part, we collected47stool specimens from liver transplant recipients in order to study human intestinal microbiota. These specimens were divided into3groups, including healthy control group (n=15), pre-liver trasnplantaton group (pre-LT)(n=17), and post-liver transplantation group (post-LT)(n=15). Then, DNA was purified. With454pyrosequencing technology, we attained527735high qualified16s rRNA sequences and1911OTUs. The results showed that all the specimens from3groups were belonged to12phylums, including Firmicutes, Proteobacteria, Actinobacteria, Bacteroidetes, TM7, Cyanobacteria, Fusobacteria, Verrucomicrobia, Tenericutes, and Synergistetes. And approximate92%of the bacteria from these specimens are from Firmicutes, Bacteroidetes, and Proteobacteria. Compared with the control group, the abundance of Proteobacteria, especially Enterobacteriaceae, in stool specimens from pre-LT group was increased. The abundance of Bacteroidetes was also increased, except for the abundance of Prevotella, which was significantly decreased. Compared with pre-LT group, the abundance of Proteobacteria in stool specimens from post-LT group was declined, while the abundance of Firmicutes was elevated. The differences between control, pre-LT, and post-LT group all reached statistically significance, and the differences between pre-LT, and post-LT group were more significant.
Our study aims to explore the intestinal microbiota in liver transplantation recipients. We first adopt the techniques of Barcoded454sequence to characterize the composition and abundance of human intestinal microbiota, analyze the microbiota from different human intestinal locations, and provide the important parameters for the. further study on association among human intestinal microbiota, host metabolism, immuno-regulation, and relative diseases. Additionally, our study also discuss the changes of intestinal microbiota between pre-LT and post-LT groups, and preliminary disclose the influence of operation and immunosuppressants on intestinal microbiota, providing the critical evidences for the further study.
引文
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9. Guarner C, Soriano G. Spontaneous bacterial peritonitis. Semin Liver Dis,1997,17:203-217.
10. Campillo B, Pernet P, Bories PN et al. Intestinal permeability in liver cirrhosis:relationship with severe septic complications. Eur J Gastroenterol Hepatol,1999,11:755-759.
11. Husova L, Lata J, Husa P et al. Bacterial infection and acute bleeding from upper gastrointestinal tract in patients with liver cirrhosis. Hepatogastroenterology,2005,52: 1488-1490.
12. Chen Y, Yang F, Lu H et al. Characterization of fecal microbial communities in patients with liver cirrhosis. Hepatology,2011; 54:562-572.
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14. Y.R. "Xie, S.L. Liu, X Liu, et al. Intestinal Microbiota and Innate Immunity-Related Gene Alteration in Cirrhotic Rats with Liver Transplantation, Transplant Proc,2011, 43(10):3973-3979.
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19.魏晓、王雪松、邵长林,等,乙肝肝硬化患者肠道微生物宏基因组学的研究,军事医学,2011,35(7)：489-493。
20. Wexler, H. M. (2007). Bacteroides:the good, the bad, and the nitty-gritty. Clin. Microbiol. Rev. 20,593-621.
21. Brook, I. (2010). The role of anaerobic bacteria in bacteremia. Anaerobe 16,183-189.
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25. Duncan, S.H., P. Louis, and H.J. Flint, Lactate-utilizing bacteria, isolated from human feces, that produce butyrate as a major fermentation product. Appl Environ Microbiol,2004.70(10):p. 5810-5817.
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