运输相关压力对羊新陈代谢影响的代谢组学研究
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摘要
道路运输对家畜身体、内分泌和代谢的影响的研究已有二十多年的历史。在此期间,人们主要通过传统的血液学和生物化学的方法对其进行研究。但是,这些方法对于轻微的代谢扰动并不是十分敏感。
在本文的第一部分中,我们采用了基于核磁共振(NMR)的代谢组学(Metabonomics)的研究方法,研究了12小时和48小时的道路运输对羊新陈代谢的影响。实验中,80只美利奴母羊被分成两批来进行重复实验。每次实验时,羊被运输了12小时(n=20)和48小时(n=20)后到达目的地,我们对那之后三天的恢复期也进行了观察。我们采集了5个时间点的尿液和血液样品,即运输之前,到达目的地时,恢复期24小时,恢复期48小时和恢复期72小时。尿液样品和血清样品的多变量统计分析的结果都表明了道路运输对于羊的代谢产生了明显的影响。代谢轨迹的分析显示,48小时运输实验中的动物的代谢轨迹比12小时实验中的动物的轨迹更为扩展,并且在恢复期的轨迹也更为复杂。这说明了长时间道路运输对动物代谢的造成了更深的影响。结合多变量和单变量统计分析,我们发现在实验过程中很多代谢物都发生了明显的变化,如尿液中的甜菜碱、4-甲酚硫酸、肌氨酸、肌氨酸酐、马尿酸、壬二酸和酰基甘氨酸,以及血液中的葡萄糖、脂蛋白、甜菜碱、缬氨酸、亮氨酸和异亮氨酸等。这些代谢物的变化说明,在运输实验中,羊的肠道和能量代谢发生改变,肌肉发生了分解代谢,并且肾脏代谢可能也发生了变化。在运输过程中和恢复期间,一些酰基甘氨酸和二羧酸的分泌增加了,因而我们认为运输相关压力引起了羊的过氧化物酶体的脂肪酸代谢发生变化。
而本文的第二部分论述了代谢组学研究中一些基本研究,包括：
1.以巴豆酰甘氨酸的鉴定为例,说明如何使用核磁共振、质谱和色谱等分析技术来鉴定未知化合物。尿液作为最重要的生物样品之一,已经被广泛应用于代谢组学的研究。生物体把数以千计的化合物分泌到尿液中,这造成了尿液样品的核磁共振一维氢谱中的信号重叠严重。目前的公共数据库中仅仅包括大约有一千个左右的代谢物的信息,所以在代谢组学的研究中,仍然有大量的重要的代谢物需要被鉴定。在实验中,我们发现有一个未知代谢物是区分不同运输时间作用的关键性的代谢物。为了鉴定这个化合物,我们使用反相高效液相色谱来分离尿液样品,以减轻核磁共振一维氢谱的复杂度。我们成功地将未知化合物分离到单一的组分中。结合该组分的核磁共振和电喷雾飞行时间质谱数据,我们认为此化合物是巴豆酰甘氨酸。我们用合成的巴豆酰甘氨酸的标准物来标记尿液样品,确认了此鉴定的正确性。我们的研究表明多种分析技术的结合在发现和鉴定潜在的生物标志物的中有着重要的作用。
2.优化羊的尿液和血清样品的缓冲液。NMR样品的pH值和盐离子浓度都会对样品中的代谢物的化学位移产生影响,为了消除化学位移变化对多变量统计分析的影响,我们对尿液和血清样品的缓冲液进行了优化。我们比较了生理盐水、0.075M、0.1M、0.25M和0.5M磷酸盐缓冲液等几种缓冲液对羊血清样品pH值和代谢物化学位移的影响,并最终将血清样品的缓冲液定为0.25M的磷酸盐缓冲液。在尿液样品缓冲液的优化过程中,我们也选择了同样浓度的磷酸盐缓冲液。
综上所述,本文的研究说明了基于核磁共振的代谢组学方法在家畜的相关研究中有着广阔的应用前景。
The physical, endocrine and metabolic responses of livestock to road transport have been evaluated by conventional haematological and biochemistry parameters for more than twenty years. However, these measures are relatively insensitive to subtle metabolic adaptations. In this thesis, we applied NMR-based metabonomics to assess system-wide metabolic responses as expressed in urine and serum of a large cohort of animals (n=80) subjected to 12 hour and 48 hour road transport (without food and water), with two replicates. Sera and urine samples were taken at pre-transport, and at 0 h,24 h,48 h, and 72 h post-transport. Our results revealed clear metabolic responses to road transport. The amplification of the response and recovery trajectory in the cohort subjected to the longer duration transport could be observed in both blood serum and urine samples using Multivariate Statistical Analysis (MVSA), which demonstrated the animals transported for 48 hours exhibited a deeper metabolic response to the transport event, and a complex and expanded metabolic trajectory over the 72 h recovery period. Betaine, phenylacetylglycine, creatine/creatinine, hippurate, azelate, and a number of acyl glycines were characterized as key metabolites in urine study. For blood serum study, glucose, lipoprotein, betaine, valine, isoleucine and leucine are responsible for the metabolic changes. Therefore, the profiling of 1H NMR spectra revealed that the transported animals experienced altered gut and energy metabolism, muscle catabolism and possibly a renal response. Intriguingly, the excretion of acyl glycines and a dicarboxylic acid was observed after transport and during recovery, implicating peroxisomal fatty acid oxidation as a metabolic response to transport-induced stress.
We also report the identification of crotonyl glycine, a key metabolite in the metabolic response to long duration road transport. Urine, one of the most important biological samples, has been widely investigated in NMR-based metabonomics studies. Thousands of metabolites are excreted into urine, causing extensive overlap of signals in NMR spectra. Currently, less than one thousand metabolites can be identified through data in publicly available sources, whereas numerous chemical compounds which are potential biomarkers for the clinical application still need to be identified. We found an unknown constituent was important in separating the urine from animals undergoing different treatments. To identify this metabolite, a pool of urine was separated by reversed phase HPLC. The complexity of 1H NMR spectra of the collected fractions was reduced, greatly improving the resolution, and revealing that the unknown metabolite had separated into a single fraction. This fraction was spiked by synthesized crotonyl glycine which proved the identification. Mass determination of parent ion and its fragments by nano ESI-TOF-MS also helped to confirm the identity of crotonyl glycine. Our results demonstrated the combination of analytical methods has a great application in the discovery of potential biomarkers.
To eliminate the influences of pH and ionic strength on chemical shifts variations, we optimized buffers for sheep urine and serum samples. Ten healthy sheep were involved in the analysis. After comparing the effects of saline,0.075 M,0.1 M, 0.25 M, and 0.5 M phosphate buffer on minimizing variations of chemical shifts, we determined the 0.25 M phosphate buffer as the buffer for sheep serum with the consideration of matching and tunning issue of probe. The same buffer was also selected for urine samples.
In conclusion, NMR-based metabonomics combined with statistical analysis can offer fresh insights into livestock research.
在本文的第一部分中,我们采用了基于核磁共振(NMR)的代谢组学(Metabonomics)的研究方法,研究了12小时和48小时的道路运输对羊新陈代谢的影响。实验中,80只美利奴母羊被分成两批来进行重复实验。每次实验时,羊被运输了12小时(n=20)和48小时(n=20)后到达目的地,我们对那之后三天的恢复期也进行了观察。我们采集了5个时间点的尿液和血液样品,即运输之前,到达目的地时,恢复期24小时,恢复期48小时和恢复期72小时。尿液样品和血清样品的多变量统计分析的结果都表明了道路运输对于羊的代谢产生了明显的影响。代谢轨迹的分析显示,48小时运输实验中的动物的代谢轨迹比12小时实验中的动物的轨迹更为扩展,并且在恢复期的轨迹也更为复杂。这说明了长时间道路运输对动物代谢的造成了更深的影响。结合多变量和单变量统计分析,我们发现在实验过程中很多代谢物都发生了明显的变化,如尿液中的甜菜碱、4-甲酚硫酸、肌氨酸、肌氨酸酐、马尿酸、壬二酸和酰基甘氨酸,以及血液中的葡萄糖、脂蛋白、甜菜碱、缬氨酸、亮氨酸和异亮氨酸等。这些代谢物的变化说明,在运输实验中,羊的肠道和能量代谢发生改变,肌肉发生了分解代谢,并且肾脏代谢可能也发生了变化。在运输过程中和恢复期间,一些酰基甘氨酸和二羧酸的分泌增加了,因而我们认为运输相关压力引起了羊的过氧化物酶体的脂肪酸代谢发生变化。
而本文的第二部分论述了代谢组学研究中一些基本研究,包括：
1.以巴豆酰甘氨酸的鉴定为例,说明如何使用核磁共振、质谱和色谱等分析技术来鉴定未知化合物。尿液作为最重要的生物样品之一,已经被广泛应用于代谢组学的研究。生物体把数以千计的化合物分泌到尿液中,这造成了尿液样品的核磁共振一维氢谱中的信号重叠严重。目前的公共数据库中仅仅包括大约有一千个左右的代谢物的信息,所以在代谢组学的研究中,仍然有大量的重要的代谢物需要被鉴定。在实验中,我们发现有一个未知代谢物是区分不同运输时间作用的关键性的代谢物。为了鉴定这个化合物,我们使用反相高效液相色谱来分离尿液样品,以减轻核磁共振一维氢谱的复杂度。我们成功地将未知化合物分离到单一的组分中。结合该组分的核磁共振和电喷雾飞行时间质谱数据,我们认为此化合物是巴豆酰甘氨酸。我们用合成的巴豆酰甘氨酸的标准物来标记尿液样品,确认了此鉴定的正确性。我们的研究表明多种分析技术的结合在发现和鉴定潜在的生物标志物的中有着重要的作用。
2.优化羊的尿液和血清样品的缓冲液。NMR样品的pH值和盐离子浓度都会对样品中的代谢物的化学位移产生影响,为了消除化学位移变化对多变量统计分析的影响,我们对尿液和血清样品的缓冲液进行了优化。我们比较了生理盐水、0.075M、0.1M、0.25M和0.5M磷酸盐缓冲液等几种缓冲液对羊血清样品pH值和代谢物化学位移的影响,并最终将血清样品的缓冲液定为0.25M的磷酸盐缓冲液。在尿液样品缓冲液的优化过程中,我们也选择了同样浓度的磷酸盐缓冲液。
综上所述,本文的研究说明了基于核磁共振的代谢组学方法在家畜的相关研究中有着广阔的应用前景。
The physical, endocrine and metabolic responses of livestock to road transport have been evaluated by conventional haematological and biochemistry parameters for more than twenty years. However, these measures are relatively insensitive to subtle metabolic adaptations. In this thesis, we applied NMR-based metabonomics to assess system-wide metabolic responses as expressed in urine and serum of a large cohort of animals (n=80) subjected to 12 hour and 48 hour road transport (without food and water), with two replicates. Sera and urine samples were taken at pre-transport, and at 0 h,24 h,48 h, and 72 h post-transport. Our results revealed clear metabolic responses to road transport. The amplification of the response and recovery trajectory in the cohort subjected to the longer duration transport could be observed in both blood serum and urine samples using Multivariate Statistical Analysis (MVSA), which demonstrated the animals transported for 48 hours exhibited a deeper metabolic response to the transport event, and a complex and expanded metabolic trajectory over the 72 h recovery period. Betaine, phenylacetylglycine, creatine/creatinine, hippurate, azelate, and a number of acyl glycines were characterized as key metabolites in urine study. For blood serum study, glucose, lipoprotein, betaine, valine, isoleucine and leucine are responsible for the metabolic changes. Therefore, the profiling of 1H NMR spectra revealed that the transported animals experienced altered gut and energy metabolism, muscle catabolism and possibly a renal response. Intriguingly, the excretion of acyl glycines and a dicarboxylic acid was observed after transport and during recovery, implicating peroxisomal fatty acid oxidation as a metabolic response to transport-induced stress.
We also report the identification of crotonyl glycine, a key metabolite in the metabolic response to long duration road transport. Urine, one of the most important biological samples, has been widely investigated in NMR-based metabonomics studies. Thousands of metabolites are excreted into urine, causing extensive overlap of signals in NMR spectra. Currently, less than one thousand metabolites can be identified through data in publicly available sources, whereas numerous chemical compounds which are potential biomarkers for the clinical application still need to be identified. We found an unknown constituent was important in separating the urine from animals undergoing different treatments. To identify this metabolite, a pool of urine was separated by reversed phase HPLC. The complexity of 1H NMR spectra of the collected fractions was reduced, greatly improving the resolution, and revealing that the unknown metabolite had separated into a single fraction. This fraction was spiked by synthesized crotonyl glycine which proved the identification. Mass determination of parent ion and its fragments by nano ESI-TOF-MS also helped to confirm the identity of crotonyl glycine. Our results demonstrated the combination of analytical methods has a great application in the discovery of potential biomarkers.
To eliminate the influences of pH and ionic strength on chemical shifts variations, we optimized buffers for sheep urine and serum samples. Ten healthy sheep were involved in the analysis. After comparing the effects of saline,0.075 M,0.1 M, 0.25 M, and 0.5 M phosphate buffer on minimizing variations of chemical shifts, we determined the 0.25 M phosphate buffer as the buffer for sheep serum with the consideration of matching and tunning issue of probe. The same buffer was also selected for urine samples.
In conclusion, NMR-based metabonomics combined with statistical analysis can offer fresh insights into livestock research.
引文
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