不同外源扰动因素对肠道菌群组成结构影响的研究
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摘要
人与动物体是由宿主自身与宿主内定植的微生物共同组成的超级生物体。宿主与宿主内微生物共同与外界环境因子相互作用决定机体的健康或疾病状态。外源环境因子如饮食、药物、化学致癌剂等可以引起肠道菌群组成结构的改变,同时,宿主自身也可能对外界刺激做出相应的反应,改变了的肠道菌群与宿主相互作用,决定了生物体新的健康状态。所以研究外界环境因子诱导下,随着生物体健康状态的改变,肠道菌群组成结构所发生的规律性改变,对解析微生物与宿主之间的相互作用关系,更好地了解微生物的作用,评价完整生物体的健康状态等具有非常重要的意义。
     本研究的第一部分以一种化学致癌剂1,2-二甲肼诱导结肠癌癌前病变大鼠模型为研究对象,对结肠癌癌前病变形成过程中,肠道菌群组成的渐进性变化以及经两种中药预防,随结肠癌癌前病变的减轻,肠道菌群组成发生的相应改变进行分析。28只大鼠被随机分成4组,3组采用化学致癌剂二甲肼皮下注射诱导大鼠形成结肠癌癌前病变,其中两组分别给予黄连吴茱萸水提取物以及中药成药金复康对结肠癌癌前病变的形成加以预防,另设健康对照组,不注射致癌剂。采集实验第3,5,9周大鼠的新鲜粪便样本,应用优势细菌(16S rRNA基因的V3区)PCR-DGGE以及拟杆菌、柔嫩梭菌、乳酸菌和双歧杆菌的类群特异性PCR-DGGE方法结合多变量统计分析包括主成分分析(Principal component analysis,PCA)与最小偏二乘判别分析(Partial least squares discriminant analysis,PLS-DA),对大鼠的肠道菌群组成进行动态分析。
     分析结果显示,单纯二甲肼诱导组大鼠的肠道优势细菌与柔嫩梭菌的组成在实验第3周与健康对照组没有明显差异,在实验第5周与健康对照组具有差异趋势,而在实验第9周,当单纯二甲肼诱导大鼠形成(37.7±2.6)个异常隐窝病灶(Aberrant crypt foci,ACF)/全结肠时,其肠道优势细菌与柔嫩梭菌的组成与未见明显ACF的健康对照组具有明显差异,Martens’uncertainty test结合ANOVA检验(p<0.05)结果提示优势细菌中的2条PCR-DGGE条带与柔嫩梭菌的5条PCR-DGGE条带是区分第9周2组动物肠道菌群的重要PCR-DGGE条带,将这些条带进行割胶测序,这些条带为Ruminococcus obeum与Allobaculum stercoricanis等的类似菌。针对部分差异序列设计特异引物,荧光定量PCR的结果证实,实验9周,单纯二甲肼诱导组大鼠的肠道Ruminococcus obeum与Allobaculum stercoricanis的类似菌数量明显高于健康对照组,差异具有统计学意义,与PCR-DGGE结果相符。单纯二甲肼诱导组大鼠肠道中乳酸菌和双歧杆菌的组成没有发生明显改变,其双歧杆菌数量也没有明显改变。本研究结果提示,与健康对照组相比,动态监控疾病高危动物或人群的肠道菌群组成可能会成为一种无损伤性的评估宿主健康状态的方法,肠道菌群组成偏离健康群体的动物,其机体的健康状态可能也发生了改变。
     另外,实验第9周二甲肼诱导结合黄连吴茱萸水提取物处理组大鼠的ACF数量为(16.7±1.2)个ACF/全结肠,二甲肼诱导结合中药成药金复康处理组大鼠的ACF数量为(15.1±2.9)个ACF/全结肠,与单纯二甲肼诱发组相比,两种不同的中药对结肠癌癌前的形成均有一定的预防效果。优势细菌的PCR-DGGE结果为,两种中药组大鼠的肠道优势细菌与单纯二甲肼诱发组具有明显差异。荧光定量PCR的结果为,随ACF数量的下降,两个给药组大鼠的肠道Ruminococcus obeum与Allobaculum stercoricanis类似菌的数量也均明显低于单纯二甲肼诱发组。目前评价药物预防有效性需要解剖动物,记数ACF数量,我们的结果提示,监控动物粪便中Ruminococcus obeum与Allobaculum stercoricanis类似菌的数量具有非损伤性评估化学药物对结肠癌预防效果的潜能。
     本研究第二部分分析了一种益生元物质对人源菌群(human flora-associated,HFA)仔猪大肠各段粘膜黏附菌、内容物细菌与粪便菌群组成的调节作用。样本取自10只HFA仔猪(5只给予益生元,5只作为对照)的盲肠、结肠近端与结肠远端三个位置的内容物和黏膜以及粪便。应用优势细菌(16S rRNA基因的V3区)PCR-DGGE以及柔嫩梭菌、乳酸菌和双歧杆菌的类群特异性PCR-DGGE方法结合多变量统计分析PCA与PLS-DA,对10只HFA仔猪的大肠各段菌群组成情况进行分析。
     大肠各段的优势细菌组成具有一定的空间分布特征,结肠远端黏膜黏附Clostridium sartagoforme的丰度明显高于其它位置,而Streptococcus pasteuri与Faecalibacterium prausnitzii的丰度在结肠远端黏膜中降低。各段内容物与粪便中的优势细菌组成相似,而黏膜与内容物中优势细菌组成存在明显差异,Escherichia coli与一种非培养的细菌(Uncultured bacterium clone E308(DQ 326831))的类似菌在内容物中的丰度高于黏膜黏附菌。柔嫩梭菌的组成也具有一定的空间分布特征,Clostridiaceae bacterium NML的类似菌出现在所有HFA仔猪结肠远端黏膜以及部分HFA仔猪的结肠远端内容物和粪便中,而在盲肠和结肠近端均不存在。大肠内不同部位的生理环境不同可能是各段细菌组成具有一定的空间分布特征的原因,而位置特异性的细菌可能行使着特定的功能,对宿主生理状态的维持起到一定作用。乳酸菌与双歧杆菌的组成简单且没有明显的空间分布差异。本次实验用益生元对HFA仔猪肠道柔嫩梭菌的组成具有明显的调节作用,可以明显增高盲肠与结肠近端内容物中Ruminococcus bromii strain YE282类似菌的丰度。益生元对大肠各部位优势细菌、乳酸菌与双歧杆菌的组成调节能力均不明显。
     本论文的最后一部分研究是针对我们构建HFA仔猪模型过程中遇到的问题及解决方案。我们的两次HFA仔猪实验中的24只受试仔猪中的17只发生严重腹泻最终死亡,经鉴定死亡原因为供体粪便菌悬液中的一种机会致病菌肺炎克雷伯氏菌引起的仔猪感染。目前用于构建HFA小鼠/大鼠的人供体选择标准为表面健康,距离粪便样本采集日至少3个月内没有任何消化系统症状与代谢性疾病,也没有接受过抗生素治疗及添加剂摄入。本实验所用的人供体符合这样的标准还是引起了HFA仔猪死亡。该现象提示,目前应用的供体选择标准对HFA动物的构建还不完善。本研究提出了新的供体粪便菌群悬液安全性评价标准,首先要用培养及分子生物学方法如PCR等对供体粪便菌群悬液中的致病菌与条件致病菌进行检测。其次,使用大剂量(正常剂量的5-10倍)初筛检验合格的供体粪便菌群悬液灌注自然分娩的初生仔猪,灌注至少3天做为预实验。只有预实验中没有遇到问题的供体粪便菌群悬液才能用于HFA仔猪模型的构建。遵循这样的标准,目前为止,我们的HFA仔猪模型没有再遇到大批动物死亡的问题。
The host and the microbiota harboured in the host buildup a whole superorganism. The whole host and microbiota interacts with the environmental factors and affects the health status of the superorganism. Exogenous compounds such as diet, drug or carcinogen may change the structure of intestinal microbiota and the host also may respond to these environmental perturbations. Monitoring the changes of the intestinal microbiota along with the changes of the health status of the superorganism in response to various perturbations will help us understand the role of the intestinal microbiota in the health of the superorganism.
     In the first part of this study, we monitored the gradual shift of intestinal microbiota during the formation of the precancerous lesion of colon cancer induced by the carcinogen 1,2-dimethylhydrazine (DMH) and observed the change of intestinal microbiota when the host was protected with two kinds of Chinese herbs. 28 male Wistar rats weighted 80-100g were divided randomly into four groups. Rats in model group (n=7), Coptidis Rhizoma-Evodiae Fructus herb treated group (n=7) and an oriental prescription consisting of twelve herbs named JFK treated group (n=7) received subcutaneous (s.c.) injection with 1,2-dimethylhydrazine (DMH) and the healthy control group (n=7) with carrier. Coptidis Rhizoma-Evodiae Fructus treated group and JFK treated group were orally dosed with corresponding herbs each day. Fresh feces of the animals in the four groups were collected at the last day of the 3rd, 5th and 9th week of the entire experimental period. V3 region of 16S rRNA gene PCR-DGGE and Bacteroides spp., Clostridium leptum subgroup, Lactic acid bacteria (LAB), Bifidobacterium spp. group specific PCR-DGGE followed by principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA) were used to monitor the structure of the intestinal microbiota of all rats.
     Fingerprints from V3 region of 16S rRNA gene and Clostridium leptum subgroup PCR-DGGE of fecal samples showed that structures of intestinal microbiota between control and only DMH treated rats were similar at 3rd and slightly different at 5th week, but significantly different from each other at 9th week when (37.7±2.6) aberrant crypt foci(ACF)developed in the only DMH treated rats’colons. Martens’uncertainty test followed by ANOVA test (p<0.05) identified two bands of V3 region of 16S rRNA gene PCR-DGGE which were Ruminococcus-like and Allobaculum-like bacteria by sequence and five bands of Clostridium leptum subgroup PCR-DGGE as key variables for discrimination of ACF rats from controls at the 9th week. Species-specific real-time PCR confirmed the significant abundance increase of Ruminococcus-like and Allobaculum-like bacteria in ACF rats at the 9th week. Fingerprints from Bacteroides spp., Lactic acid bacteria (LAB) and Bifidobacterium spp. group specific PCR-DGGE does not show obvious difference between ACF rats and controls at the 9th week. This structural segregation analysis of intestinal microbiota may become a new strategy for assessing heath status of the host. When the structure of the intestinal microbiota away from the controls, the heath status of the host maybe also change.
     In addition, histopathological examination confirmed formation of (16.7±1.2) ACF in Coptidis Rhizoma-Evodiae Fructus herb treated group and (15.1±2.9) ACF in JFK treated group at 9th week and both of the two formulations of Chinese herbal medicine could significantly reduce the number of ACF in colons. PCA score plot of V3 region of 16S rRNA gene PCR-DGGE fingerprint indicated that structure of intestinal microbiota of the two herbal medicine treated groups were shifted away from the only DMH treated group at the 9th week. Result of species-specific real-time PCR indicated that the abundance of the Ruminococcus obeum and Allobaculum-like bacteria in the two herbal treated groups decreased to the level of healthy control group with the decreased number of ACF, while it is significantly different from the only DMH treated group. Quantifying the decreased number of ACF has been used for evaluating chemoprevention efficiency to colon cancer, but it is an invasive method because it need execute the rats. This work indicates that monitoring the amount of Ruminococcus obeum and Allobaculum-like bacteria may be employed as a non-invasive method for evaluating chemoprevention efficiency of these kinds of complex drugs to colon cancer.
     In the second part of this study, we studied the modulation of fructo-oligosaccharides to mucosa associated bacteria and lumen bacteria of different parts of large intestine and fecal bacteria. Samples were taken from mucosa and content of cecum, proximal colon and distal colon and feces of 10 human flora-associated (HFA) piglets (5 piglets receive prebiotic treatment and 5 piglets as control). V3 region of 16S rRNA gene denaturing gradient gel electrophoresis (DGGE) and Bifidobacterium spp, Lactic acid bacteria (LAB), Clostridium leptum subgroup specific PCR-DGGE followed by PCA and PLS-DA were used to analyze the structure of lumen and mucosa associated bacteria in the different parts of the large intestine and the effect of prebiotic on intestial microbiota.
     Clostridium sartagoforme had higher intensity in the mucosa of distal colon and Streptococcus pasteuri and Faecalibacterium prausnitzii had lower intensity in mucosa of distal colon when compared with other parts. Structure of the predominant bacteria among lumen contents in different parts of large intestine and feces was similar, but, significantly different from mucosa associated bacteria. Escherichia coli and an uncultured bacterium clone E308 (DQ326831)-like bacteria had higher intensity in the content when compared with which in the mucosa sample. Clostridiaceae bacterium NML-like bacteria appeared in the mucosa of distal colon of all piglets but not in the cecum and proximal colon. Structure of Bifidobacterium spp. and LAB had no obvious difference among different sampling positions. The prebiotic supplementation in this study showed modulating effects on the structure of C. leptum in the content of cecum and proximal colon. The intensity of Ruminococcus bromii decreased but Ruminococcus bromii strain YE282-like bacteria increased in the prebiotic treated group. Structure of predominant bacteria, Bifidobacterium spp. and LAB had no obvious difference between the prebiotic treated and control group.
     The last part of of this study is about one problem we met during the HFA piglets establishment and how we solved it. For establishment the HFA piglets, human fecal suspension should be orally inoculated to the newborn piglets. 17 of 24 piglets in two litters died in the first two weeks after the first administration of the human fecal suspension and one strain of opportunistic pathogen Kl. pneumoniae from fecal suspension of an apparently healthy human donor caused the fatal infection in HFA piglets. In most previous studies of establishing HFA rats/mice models, fecal suspension was usually obtained from apparently healthy human donor who had no history of either gastrointestinal or metabolic disorders and did not get any prescriptive supplementary diets and drug treatments for 3 months prior to the fecal collection. However, in these two HFA piglets’trials, our donor according to the current standard still cause death of piglets. This study suggests the previous standard for donor is not safe enough for establishment the HFA animals. Here, we recommend a new protocol for evaluating the safety of the human donor’s flora for HFA animal. First, screening for pathogens and some opportunistic pathogens common for neonatal animal infection should be performed with culture or PCR-based methods. Second, preliminary tests should be performed, in which a large amount of the whole fecal flora (5-10 times of normal dosage) prepared for HFA animals should be orally inoculated to naturally born neonatal animals for at least three days (once a day). Only the whole fecal flora, which does not cause problems in the preliminary test, should be used in the following HFA experiment. According to this standard, until now, we did not meet serious problems during the establishment of HFA piglets.
引文
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