肠道菌—宿主代谢物组的分析平台的建立及应用
摘要
哺乳动物是一个由动物体和体内共生的微生物共同组成的“超级生物体”。体内微生物主要分布在与外界相通的腔道内，其中胃肠道细菌最为复杂、对机体最为重要。肠道菌群与其宿主在长期的进化过程中建立了密切的关系，发挥着重要的生理功能，包括了生物屏障作用、免疫作用、代谢作用、营养作用、抗肿瘤作用等，并影响着机体的生长、发育和老化。哺乳动物体内的肠道菌群与宿主在正常情况下处于微生态平衡，能够维持机体的健康状态；当微生态平衡被破坏，有害的肠道菌容易诱发疾病产生。值得关注的是，肠道菌群是哺乳动物体内重要的代谢“器官”，影响着宿主的整体代谢，当改变其结构，宿主的生理代谢也会发生相应的改变。所以，宿主的代谢受自身基因和肠道菌群基因的双重影响，宿主和菌群之间进行着“共代谢”的过程。
要研究肠道菌群和宿主之间的这一复杂的代谢体系，代谢组学是目前较为有效的研究手段。代谢组学作为一种相对全面、连续动态、无刺激的分析手段，能够客观地检测肠道微生物的代谢物组分及浓度，展示肠道菌的代谢状态。将代谢组学与元基因组学、微生态学方法相结合，并利用多维统计的分析方法，能够深入研究肠道菌群与宿主之间的交互作用，为揭示肠道菌群与哺乳动物机体的健康和疾病之间的关系提供了重要的依据。
本课题建立基于色谱质谱联用技术的代谢物全谱和靶标分析的技术平台，检测大鼠尿液、粪便中肠道菌-宿主的代谢产物，并将开发的分析技术应用于肠道内容物中代谢物组成的空间分布规律，及三聚氰胺毒性与肠道菌群相关性的研究中。主要内容如下：
建立肠道菌-宿主共代谢产物的全谱分析方法。利用超高效液相四级杆飞行时间质谱和气相飞行时间质谱联合的方法作为测试手段，分析用广谱抗生素亚胺培南/西司他丁钠造肠道菌群抑制大鼠模型的尿液和粪便代谢轮廓的动态变化。结果显示202个尿液代谢物和223个粪便代谢物为肠道菌-宿主共代谢产物，这些代谢物相关的机制包括，色氨酸代谢途径、吲哚类物质和褪黑素的补偿机制、酪氨酸苯丙氨酸代谢途径、神经递质类物质和脑-肠轴、短链脂肪酸和糖类物质、中长链脂肪酸和胆酸类物质、寡肽类物质转运加强等。该实验提供了全面的肠道菌群及其宿主共代谢的代谢物信息，证明了代谢物全谱分析方法对肠道菌-宿主共代谢研究的可行性，为研究代谢表型动态变化与微生物组成变化的相关性提供了平台和分子机制的依据。
建立短链脂肪酸和支链氨基酸靶标的分析方法。该方法采用100μL氯甲酸丙酯，在水/丙醇/吡啶（8:3:2）的反应体系中进行衍生，衍生产物通过正己烷两步提取，再通过GC/QMS对样品进行测试。这个方法弥补了代谢组学全谱测试方法对于挥发性物质定量不准确的缺点，是一个精确、简便、稳定的方法，可应用于多种生物样本，为短链脂肪酸和支链氨基酸这两类物质之间以及与肠道菌群代谢的相关性的研究提供了平台。
建立胆酸靶标的分析方法，基于超高效液相三重四级杆质谱联用检测方法对生物样品中的27种胆酸进行定量测试，其中14个游离型胆酸，6个甘氨结合型胆酸，7个牛磺结合型胆酸。该方法具有快速、简便、灵敏，预处理过程简单、重现性好，能够准确定量且具有线性范围宽、重现性好等优点。胆酸靶标分析方法的建立弥补了代谢组学全谱测试方法鉴定结构相似的同分异构体物质的缺陷，为胆酸和肠道菌群代谢的相关性研究提供了平台，对临床及生命科学的研究都有重要意义。
整合代谢组学全谱检测方法、短链脂肪酸靶标分析方法和胆酸靶标分析方法三个测试平台，对大鼠十二指肠、空肠、回肠、盲肠、结肠、直肠六个肠段内容物中的代谢物组成进行测试，探究肠道菌群在肠道中的代谢规律。结果显示了肠道内容物中不同类型的代谢物因肠道菌的分布和数量不同，产生的代谢、吸收、及其生理意义上的差异，小肠的主要功能为吸收食源性的氨基酸和蛋白质，吸收胆碱并转化为脂类物质，吸收结合型胆酸（主要为回肠），调节肠道的渗透压，进行氧化应激的保护；大肠主要通过肠道菌群的代谢转化发挥功能，包括发酵碳水化合物（主要为盲肠）、蛋白质和肽，解离结合型胆酸成游离型胆酸（主要为盲肠和结肠），解离胆碱成为胺类（二甲胺、三甲胺、氧化三甲胺）。该研究提供了肠道菌群在不同肠段区域的基线信息，为理解不同肠段肠道菌的生理功能及其和宿主共代谢提供了理论基础，为疾病诊断和通过肠道菌提供健康调控药物和食物干预提供了重要的依据。
基于肠道菌群代谢组学全谱测试的方法研究三聚氰胺致肾毒性大鼠模型的尿液代谢轮廓，发现大部分浓度有显著变化的物质为肠道菌群相关代谢物；通过广谱抗生素抑制大鼠肠道菌后，三聚氰胺毒性明显降低，肠道菌群相关代谢物的浓度波动变小。实验显示了三聚氰胺的毒性和肠道菌群代谢的相关性。进一步通过肠道菌群和三聚氰胺的体外培养，发现肠道菌群有能力在肠道中通过转氨作用代谢三聚氰胺成为三聚氰酸，两个物质在肾小管内浓缩蓄积，引起肾毒性。在肠道菌群中，存在Klebsiella菌具有较高的转化三聚氰胺的能力。将Klebsiella菌定植于大鼠肠道后，三聚氰胺的毒性明显增加。该实验为三聚氰胺的毒性研究提供了新的依据，同时，为临床研究上人的三聚氰胺结石的形成提供了新的解释。
Mammals are considered as superorganisms as a result of theirclose symbiotic associations with the gut microbiota. Gut microbesexert strong control over the mammalian host and are involved in thematuration and development of the host’s immune system,maintenance of host energy, and metabolic homeostasis. Thecomposition and activities of gut microbiota play important roles inhost health and the imbalance of dysbiosis of the microbiota inducesdifferent diseases. Mammalian metabolism involves integration ofmultiple indigenous metabolic processes which were encoded by thehost genome with those of the microbiome. Thus, the symbiotic gutmicrobiome exerts a strong influence on the metabolic phenotype ofmammalian host and participates in extensive microbial-mammlianco-metabolism.
To gain better insight into the activity and functionality of gutmicrotiota, metabolomics is uniquely suited to assess the highlycomplex metabolic exchanges, opening a direct biochemical windowinto the metabolome. Metabolomics, as an integral part of thesystems biology, is defined as “the quantitative measurement ofmultiparametric time-related metabolic responses of a complexsystem to genetic modification or a pathophysiological intervention.”This platform offers a well-established high-throughput “omics”technology for analysis of the metabolome using an array ofspectroscopic and spectrometric techniques. Integration of gutmicrobial profiling with high-thourghput metabolic phenotyping promises to delineate the microbiome and the host metabolicphenotypes at a global level to uncover their inherent associations.Such studies help to imporve our understanding of the mechanismsunderlying complex host-microbe interactions.
In this dissertation, the untargeted metabolomics platform as wellas targeted analysis of short-chain fatty acids, branched-chain aminoacid and bile acids were developed and validated, characterizing apanel of urinary and fecal metabolites related to microbialmammalian co-metabolism. These approaches were applied in theinvestigations of topographical metabolic signatures of ratgastrointestinal contents and the impact of gut microbiota onmelamine-induced renal toxicity. Main methods and results:
A combined GC/MS and LC/MS untargeted metabolomicsapproach was applied to profile the urinary and fecal metabolitesfrom Wistar rats with gut microbiota suppressed by a broad spectrumantibiotic imipenem/cilastatin sodium. A panel of202urinary and223fecal metabolites were significantly altered as a readout of a gutmicrobial-mammalian co-metabolism, many of which have not beenpreviously reported. This study shows extensive gut microbiotamodulation of host systemic metabolism involving tryptophan,tyrosine and phenylalanine metabolism, short-chain fatty acids,medium and long chain fatty acids, bile acids, oligopeptidestransportation, and possibly a compensatory mechanism ofindole-melatonin production. It appeared that the recovery of theglobal metabolomic changes takes about two-weeks. Given theintegral nature of the mammalian genome and metagenome, thispanel of metabolites will provide a new platform for potentialtherapeutic markers and mechanistic solutions to complex problemscommonly encountered in pathology, toxicology or drug metabolismstudies.
A targeted metabolomic protocol was developed to determineshort-chain fatty acids and branched-chain amino acids using propylchloroformate derivatization followed by GC/MS analysis. Aone-step derivatization using100μL of propyl chloroformate in a reaction system of water, propanol, and pyridine (v/v/v=8:3:2) at pH8provided the optimal derivatization efficiency. The best extractionefficiency of the derivatized products was achieved by a two-stepextraction with hexane. The method exhibited good derivatizationefficiency and recovery for a wide range of concentrations with a lowlimit of detection for each compound and can be applied in differentbiological samples. This is a complementary assay for the untargetedmetabolomics approach, providing a comprehensive metabolicsignature of gut micribiota and host co-metabolism.
A UPLC/TQMS method was established for targeted bile acidsprofiling in biological samples, allowing the simultaneousquantification of27bile acids including14unconjugated,6glycine-conjugated and7taurine-conjugated bile acids. This methodprovides good results in terms of intra-and interday precision,accuracy and linearity. It is also a complementary method forunbiased metabolomics analysis, providing the capability todistinguish isomers with identical m/z values by different daughterions. This method has great values in the investigations of gutmicrobiota metabolism and can readily be extended to clinicalstudies.
Integrating above three metabolomics platforms, the metabolitecomposition of contents in different regions of the intestine of normalrats were analyzed, investigating spatially the metabolism of gutmicrobiota in different regions of the intestine. Statistical analysiswere applied to differentiate metabolomic profiles of different regionsand revealed that the metabolite composition in gut contents weregreatly altered along different parts of the intestine, especiallybetween small intestine and large intestine.
Based on urinary metabilomics approach, the mechanism ofmelamine-induced renal toxicity was investigated. Cyanuric acidserving as an integral component of the kidney stones is producd inthe gut by microbial transformation of melamine. We demonstratethat melamine-induced toxicity in Wistar rats was attenuated after gutmicrobiota suppression, along with increased melamine excretion. We further demonstrated that melamine can be converted to cyanuric acidin vitro by the cultured bacteria from normal rat feces and Klebsiellawas identified in cultivation of fecal samples by16S rDNAsequencing analysis. In addition, the cultures of Klebsiella terrigena,a species of Klebsiella genus, were able to convert melamine tocyanuric acid. Melamine-induced toxicity in kidneys was exacerbatedwhen rats were colonized with K. terrigena. Cyanuric acid wasdetected in kidneys of rats administered melamine alone and theconcentration was significantly increased after Klebsiellacolonization.
要研究肠道菌群和宿主之间的这一复杂的代谢体系，代谢组学是目前较为有效的研究手段。代谢组学作为一种相对全面、连续动态、无刺激的分析手段，能够客观地检测肠道微生物的代谢物组分及浓度，展示肠道菌的代谢状态。将代谢组学与元基因组学、微生态学方法相结合，并利用多维统计的分析方法，能够深入研究肠道菌群与宿主之间的交互作用，为揭示肠道菌群与哺乳动物机体的健康和疾病之间的关系提供了重要的依据。
本课题建立基于色谱质谱联用技术的代谢物全谱和靶标分析的技术平台，检测大鼠尿液、粪便中肠道菌-宿主的代谢产物，并将开发的分析技术应用于肠道内容物中代谢物组成的空间分布规律，及三聚氰胺毒性与肠道菌群相关性的研究中。主要内容如下：
建立肠道菌-宿主共代谢产物的全谱分析方法。利用超高效液相四级杆飞行时间质谱和气相飞行时间质谱联合的方法作为测试手段，分析用广谱抗生素亚胺培南/西司他丁钠造肠道菌群抑制大鼠模型的尿液和粪便代谢轮廓的动态变化。结果显示202个尿液代谢物和223个粪便代谢物为肠道菌-宿主共代谢产物，这些代谢物相关的机制包括，色氨酸代谢途径、吲哚类物质和褪黑素的补偿机制、酪氨酸苯丙氨酸代谢途径、神经递质类物质和脑-肠轴、短链脂肪酸和糖类物质、中长链脂肪酸和胆酸类物质、寡肽类物质转运加强等。该实验提供了全面的肠道菌群及其宿主共代谢的代谢物信息，证明了代谢物全谱分析方法对肠道菌-宿主共代谢研究的可行性，为研究代谢表型动态变化与微生物组成变化的相关性提供了平台和分子机制的依据。
建立短链脂肪酸和支链氨基酸靶标的分析方法。该方法采用100μL氯甲酸丙酯，在水/丙醇/吡啶（8:3:2）的反应体系中进行衍生，衍生产物通过正己烷两步提取，再通过GC/QMS对样品进行测试。这个方法弥补了代谢组学全谱测试方法对于挥发性物质定量不准确的缺点，是一个精确、简便、稳定的方法，可应用于多种生物样本，为短链脂肪酸和支链氨基酸这两类物质之间以及与肠道菌群代谢的相关性的研究提供了平台。
建立胆酸靶标的分析方法，基于超高效液相三重四级杆质谱联用检测方法对生物样品中的27种胆酸进行定量测试，其中14个游离型胆酸，6个甘氨结合型胆酸，7个牛磺结合型胆酸。该方法具有快速、简便、灵敏，预处理过程简单、重现性好，能够准确定量且具有线性范围宽、重现性好等优点。胆酸靶标分析方法的建立弥补了代谢组学全谱测试方法鉴定结构相似的同分异构体物质的缺陷，为胆酸和肠道菌群代谢的相关性研究提供了平台，对临床及生命科学的研究都有重要意义。
整合代谢组学全谱检测方法、短链脂肪酸靶标分析方法和胆酸靶标分析方法三个测试平台，对大鼠十二指肠、空肠、回肠、盲肠、结肠、直肠六个肠段内容物中的代谢物组成进行测试，探究肠道菌群在肠道中的代谢规律。结果显示了肠道内容物中不同类型的代谢物因肠道菌的分布和数量不同，产生的代谢、吸收、及其生理意义上的差异，小肠的主要功能为吸收食源性的氨基酸和蛋白质，吸收胆碱并转化为脂类物质，吸收结合型胆酸（主要为回肠），调节肠道的渗透压，进行氧化应激的保护；大肠主要通过肠道菌群的代谢转化发挥功能，包括发酵碳水化合物（主要为盲肠）、蛋白质和肽，解离结合型胆酸成游离型胆酸（主要为盲肠和结肠），解离胆碱成为胺类（二甲胺、三甲胺、氧化三甲胺）。该研究提供了肠道菌群在不同肠段区域的基线信息，为理解不同肠段肠道菌的生理功能及其和宿主共代谢提供了理论基础，为疾病诊断和通过肠道菌提供健康调控药物和食物干预提供了重要的依据。
基于肠道菌群代谢组学全谱测试的方法研究三聚氰胺致肾毒性大鼠模型的尿液代谢轮廓，发现大部分浓度有显著变化的物质为肠道菌群相关代谢物；通过广谱抗生素抑制大鼠肠道菌后，三聚氰胺毒性明显降低，肠道菌群相关代谢物的浓度波动变小。实验显示了三聚氰胺的毒性和肠道菌群代谢的相关性。进一步通过肠道菌群和三聚氰胺的体外培养，发现肠道菌群有能力在肠道中通过转氨作用代谢三聚氰胺成为三聚氰酸，两个物质在肾小管内浓缩蓄积，引起肾毒性。在肠道菌群中，存在Klebsiella菌具有较高的转化三聚氰胺的能力。将Klebsiella菌定植于大鼠肠道后，三聚氰胺的毒性明显增加。该实验为三聚氰胺的毒性研究提供了新的依据，同时，为临床研究上人的三聚氰胺结石的形成提供了新的解释。
Mammals are considered as superorganisms as a result of theirclose symbiotic associations with the gut microbiota. Gut microbesexert strong control over the mammalian host and are involved in thematuration and development of the host’s immune system,maintenance of host energy, and metabolic homeostasis. Thecomposition and activities of gut microbiota play important roles inhost health and the imbalance of dysbiosis of the microbiota inducesdifferent diseases. Mammalian metabolism involves integration ofmultiple indigenous metabolic processes which were encoded by thehost genome with those of the microbiome. Thus, the symbiotic gutmicrobiome exerts a strong influence on the metabolic phenotype ofmammalian host and participates in extensive microbial-mammlianco-metabolism.
To gain better insight into the activity and functionality of gutmicrotiota, metabolomics is uniquely suited to assess the highlycomplex metabolic exchanges, opening a direct biochemical windowinto the metabolome. Metabolomics, as an integral part of thesystems biology, is defined as “the quantitative measurement ofmultiparametric time-related metabolic responses of a complexsystem to genetic modification or a pathophysiological intervention.”This platform offers a well-established high-throughput “omics”technology for analysis of the metabolome using an array ofspectroscopic and spectrometric techniques. Integration of gutmicrobial profiling with high-thourghput metabolic phenotyping promises to delineate the microbiome and the host metabolicphenotypes at a global level to uncover their inherent associations.Such studies help to imporve our understanding of the mechanismsunderlying complex host-microbe interactions.
In this dissertation, the untargeted metabolomics platform as wellas targeted analysis of short-chain fatty acids, branched-chain aminoacid and bile acids were developed and validated, characterizing apanel of urinary and fecal metabolites related to microbialmammalian co-metabolism. These approaches were applied in theinvestigations of topographical metabolic signatures of ratgastrointestinal contents and the impact of gut microbiota onmelamine-induced renal toxicity. Main methods and results:
A combined GC/MS and LC/MS untargeted metabolomicsapproach was applied to profile the urinary and fecal metabolitesfrom Wistar rats with gut microbiota suppressed by a broad spectrumantibiotic imipenem/cilastatin sodium. A panel of202urinary and223fecal metabolites were significantly altered as a readout of a gutmicrobial-mammalian co-metabolism, many of which have not beenpreviously reported. This study shows extensive gut microbiotamodulation of host systemic metabolism involving tryptophan,tyrosine and phenylalanine metabolism, short-chain fatty acids,medium and long chain fatty acids, bile acids, oligopeptidestransportation, and possibly a compensatory mechanism ofindole-melatonin production. It appeared that the recovery of theglobal metabolomic changes takes about two-weeks. Given theintegral nature of the mammalian genome and metagenome, thispanel of metabolites will provide a new platform for potentialtherapeutic markers and mechanistic solutions to complex problemscommonly encountered in pathology, toxicology or drug metabolismstudies.
A targeted metabolomic protocol was developed to determineshort-chain fatty acids and branched-chain amino acids using propylchloroformate derivatization followed by GC/MS analysis. Aone-step derivatization using100μL of propyl chloroformate in a reaction system of water, propanol, and pyridine (v/v/v=8:3:2) at pH8provided the optimal derivatization efficiency. The best extractionefficiency of the derivatized products was achieved by a two-stepextraction with hexane. The method exhibited good derivatizationefficiency and recovery for a wide range of concentrations with a lowlimit of detection for each compound and can be applied in differentbiological samples. This is a complementary assay for the untargetedmetabolomics approach, providing a comprehensive metabolicsignature of gut micribiota and host co-metabolism.
A UPLC/TQMS method was established for targeted bile acidsprofiling in biological samples, allowing the simultaneousquantification of27bile acids including14unconjugated,6glycine-conjugated and7taurine-conjugated bile acids. This methodprovides good results in terms of intra-and interday precision,accuracy and linearity. It is also a complementary method forunbiased metabolomics analysis, providing the capability todistinguish isomers with identical m/z values by different daughterions. This method has great values in the investigations of gutmicrobiota metabolism and can readily be extended to clinicalstudies.
Integrating above three metabolomics platforms, the metabolitecomposition of contents in different regions of the intestine of normalrats were analyzed, investigating spatially the metabolism of gutmicrobiota in different regions of the intestine. Statistical analysiswere applied to differentiate metabolomic profiles of different regionsand revealed that the metabolite composition in gut contents weregreatly altered along different parts of the intestine, especiallybetween small intestine and large intestine.
Based on urinary metabilomics approach, the mechanism ofmelamine-induced renal toxicity was investigated. Cyanuric acidserving as an integral component of the kidney stones is producd inthe gut by microbial transformation of melamine. We demonstratethat melamine-induced toxicity in Wistar rats was attenuated after gutmicrobiota suppression, along with increased melamine excretion. We further demonstrated that melamine can be converted to cyanuric acidin vitro by the cultured bacteria from normal rat feces and Klebsiellawas identified in cultivation of fecal samples by16S rDNAsequencing analysis. In addition, the cultures of Klebsiella terrigena,a species of Klebsiella genus, were able to convert melamine tocyanuric acid. Melamine-induced toxicity in kidneys was exacerbatedwhen rats were colonized with K. terrigena. Cyanuric acid wasdetected in kidneys of rats administered melamine alone and theconcentration was significantly increased after Klebsiellacolonization.
引文
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