基于1H NMR代谢组学的针刺治疗功能性消化不良的经穴效应特异性研究
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摘要
目的
采用基于1H NMR(1H Nuclear Magnetic Resonance,NMR)代谢组学的技术和方法研究本经特定穴、本经非特定穴、他经取穴、非经非穴四种不同针刺取穴方式对功能性消化不良(Functional Dyspepsia, FD)患者血浆代谢物的影响,探讨不同取穴方式对效应物质基础的调控作用差异及其规律,为揭示足阳明经穴效应特异性提供新的生物信息学依据和线索。
方法
1.功能性消化不良患者的血浆代谢组学研究：采用尼平消化不良指数(Nepean Dyspepsia Index, NDI)量表评价功能性消化不良患者的症状和生活质量；采用1H-NMR代谢组学方法获得FD关键代谢物,通过关键代谢物与NDI量表积分的相关性分析,找出FD的潜在生物标志物,利用KEGG数据库分析潜在生物标志物的代谢途径。
2.足阳明经穴治疗FD的代谢组学研究：分别采用本经特定穴、本经非特定穴、他经取穴、非经非穴四种方法针刺治疗FD,运用基于1H NMR的代谢组学方法比较不同治疗时间各组对FD血浆代谢物的影响及组间差异,着重观察足阳明经穴对潜在生物标志物和关键代谢物的调控效应及其规律。
3.足阳明经穴治疗FD的代谢组学特征提取：采用相关系数算法对两两比较后特征值的载荷图进行相似度计算,探索不同取穴方式对FD关键代谢物作用的规律,分析本经特定穴与本经非特定穴的相似度,判断二者是否具有循经趋同性。
结果
1.与健康对照组相比,FD患者血浆中磷脂酰胆碱含量明显升高,与NDI症状积分正相关(P<0.01)；亮氨酸/异亮氨酸含量明显下降,与FD患者的NDI症状积分负相关(P<0.05),两者是FD的潜在生物标志物；此外,FD患者血浆中的丙氨酸、谷氨酰胺、脯氨酸、HDL、β-葡萄糖、α-葡萄糖、LDL/VLDL等一系列代谢物的含量也出现了显著变化,是FD的关键代谢产物。
2.针刺治疗FD 2个疗程后,四种针刺方式均能降低血浆磷脂酰胆碱的含量,但非经非穴组的调整作用与治疗前相比没有统计学差异；四种针刺方式均能升高亮氨酸/异亮氨酸的含量,但均不具有统计学意义。四组之间比较,本经特定穴组中磷脂酰胆碱含量最低(与其它组相比P值均<0.05),亮氨酸/异亮氨酸含量最高(与本经非特定穴组相比P>0.05,与他经取穴组和非经非穴组相比P值均<0.05)。针刺治疗4个疗程后,各组磷脂酰胆碱含量均继续降低,亮氨酸/异亮氨酸含量继续增高,其中本经特定穴组的亮氨酸/异亮氨酸含量升高最为明显(P<0.05)。
3.针刺治疗FD2个疗程后,本经特定穴组对FD血浆中偏离常态的谷氨酰胺、HDL、β-葡萄糖、LDL/VLDL也具有明显的良性调整作用(P<0.05)；本经非特定穴组能明显升高FD降低的苏氨酸含量,但却继续升高FD中原本就升高的α-葡萄糖的含量；他经取穴组也明显升高α-葡萄糖的含量；非经非穴组对大多数代谢物也是良性调整作用,但调整效应较弱(P<0.05)。针刺治疗4个疗程后,本经特定穴组的上述效应继续得到加强,但对丙氨酸、赖氨酸的影响与第2疗程相反,本经非特定穴仍然主要影响苏氨酸的含量。他经取穴组这一时期影响的物质较多,包括乙酰乙酸盐,α-葡萄糖、β-葡萄糖、UFA、丙氨酸和乳酸,其中对α-葡萄糖、β-葡萄糖和乳酸的影响与第2疗程的作用正好相反。非经非穴组除了对Nac的影响稍强于其它组外,对其它代谢物的影响基本与第2疗程相似。
4.相似度计算表明,针刺治疗FD 2个疗程后,本经非特定穴组与本经特定穴组的LED特征值载荷图相似；治疗4个疗程后,本经非特定穴组与本经特定穴组的CPMG、LED特征值载荷图均相似。
结论
1.一系列代谢物偏离常态是FD患者血浆代谢的共同特点,其中,血浆磷脂酰胆碱和亮氨酸/异亮氨酸与FD患者的NDI症状积分相关,是潜在的生物标志物。
2.四种针刺方式对FD潜在生物标志物都有一定的良性调整作用,但作用强度不同,随治疗时间的延续效应不同；四种针刺方法对FD其它关键代谢物均有调整作用,但针对性不同,调整强度不一,随治疗时间的延续效应也不同,对FD代谢系列组合的调整存在差异,为经穴效应特异性的存在提供了部分代谢组学依据。
3.阳明经特定穴对FD潜在生物标志物和一系列偏离常态的关键代谢物均有调整作用,且调整效应最大,针对性最强,系列组合优势更明显；非经非穴对FD潜在生物标志物也有调整效应,但作用强度最弱；对其它关键代谢物的调整范围较窄,延续效应较弱；阳明经特定穴与阳明经非特定穴在代谢组学特征上有一定的循经趋同性,为经穴效应特异性的内涵和规律提供了新的代谢组学线索。
OBJECTIVE
To investigate whether metabolic difference exists between acupuncture on specific acupoints of disease-relate meridian, on non-specific acupoints of disease-relate meridian, on acupoints of other meridian or on non-acupoints,1H NMR-based metabonomic method was used to study the metabolism changes in FD after treated by different acupuncture method.
METHOD
1. FD patients were recruited in and Nepean Dyspepsia Index (NDI) scale rating was employed to evaluate the the symptoms of dyspepsia and the quality of life for the patients. 1H NMR--based metabonomic techniques were used to detect the plasma metabolic profiles. Pattern recognition was used to find the difference and the key metabolites between groups. By calculating the correlation between the key metabolites and the NDI score, potential biomarkers were founded. KEGG database was mainly referenced to analyze the metabolic pathways of the potential biomarkers.
2. Four kinds of methods were chosen to treat FD:(1) specific acupoints of Stomach Meridian of Foot-Yangming (group A); (2) non-specific acupoints of the stomach meridian (group B); (3) acupoints of the gallbladder meridian (group C) and (4) non-acupoints(group D). Similarly,1H NMR--based metabonomic techniques had been used to detect the metabolites over two periods and four periods of treatment.
3. Analyze the eigenvalue on the loading plots of pairwise comparison and calculated the plots similarity by correlation coefficient algorithm.
RESULTS
1. The plasma level of phosphatidycholine (PtdCho) in FD increased significantly, and was positively related to the score of Nepean Dyspepsia Symptom Index (NDSI) (P<0.01); the plasma level of Leucine/isoleucine decreased obviously and was negatively related to the score of NDSI (P< 0.05), both compounds are FD potential biomarkers. In addition, Levels of a series compounds including glutamine, alanine, proline, HDL,β-glucose、α-glucose and LDL/VLDL were significantly changed in FD, they were considered to be FD key metabolites.
2. After two periods of treatment, all groups except group D could significantly reduce the concentration of PtdCho; all groups could increase the concentration of Leu/Ile, but no group has statistical significance. Comparison between groups showed that level of Ptdcho in group A was the lowest after two periods of treatment, with all pairwise comparison P values lower than 0.05.The level of Leu/Ile in group A was significantly higher than group C and D (both P<0.05), but only slightly higher than that of group B. After four periods of treatment, PtdCho continued to decrease and Leu/Ile continued to increase in group A, B and C. However, only Leu/Ile in group A was significantly improved (P<0.05).
3. After 2 periods treatment, levels of glutamine, LDL/VLDL andβ-glucose were obvoiously improved in group A (P<0.05); Level of threonine in group B was significantly improved (P<0.05). a-glucose in group B and group C was significantly changed but both were not benign improving effect. In Group D, concentrations of key metabolites were only slightly improved. After 4 periods treatment, the effects mentioned above in group A was continuously improved, however, the effect on alanine and lysine were weakened at this time point. Concentration of threonine in group B was continuously significantly increased. In group C, many compounds including acetoacetate,β-glucose, a-glucose, UFA, alanine and lactate were significantly changed, but its effect on P-glucose, a-glucose and lactate were oppositely to the 2nd periods (in other words the change was with the same trend as FD). In group D, almost all compounds slightly changed but no obvious different between 2 periods and 4 periods treatment.
4. After two periods of treatment, LED eigenvalue plots showed that group B was similar to group A; after four periods of treatment, both CPMG and LED eigenvalue plots in group B was similar to that of group A.
CONCLUSION
1. Many plasma metabolites are deviating from normal condition in FD, among them, concentration of PtdCho and Leu/Ile are closely related to FD symptoms, they are potential biomarkers.
2. Four kinds of acupuncture methods has certain positive role to FD potential biomarkers, but the intensity of adjustment and the continuation effect along with treating periods are different. Four kinds of methods can improve the levels of other key metabolites, but the main target metobolites, the intensity, the continuation effect along with treating periods and the scopes of the effect are different, The results provide some metabonomic basis for the specific effects of Foot-Yangming meridian in treating FD.
3. Puncturing on specific acupoints of the stomach meridian has a more significant and intensive effect on the two kinds of potential biomarkers of FD, and this effect would be enlarged after four periods of treatment. For most of the other key metabolites, this method is more effective and has a more intensive targeted effect than other methods. Puncturing on non-acupoints could also influence the potential biomarkers and key metabolites of FD, but with lower intensity, narrow range and weaker continuous effect. Specific acupoints and non-specific acupoints in the stomach meridian have common metabolic features. Our study provides new clues for considering the connotation of the specific effects of Foot-Yangming meridian.
采用基于1H NMR(1H Nuclear Magnetic Resonance,NMR)代谢组学的技术和方法研究本经特定穴、本经非特定穴、他经取穴、非经非穴四种不同针刺取穴方式对功能性消化不良(Functional Dyspepsia, FD)患者血浆代谢物的影响,探讨不同取穴方式对效应物质基础的调控作用差异及其规律,为揭示足阳明经穴效应特异性提供新的生物信息学依据和线索。
方法
1.功能性消化不良患者的血浆代谢组学研究：采用尼平消化不良指数(Nepean Dyspepsia Index, NDI)量表评价功能性消化不良患者的症状和生活质量；采用1H-NMR代谢组学方法获得FD关键代谢物,通过关键代谢物与NDI量表积分的相关性分析,找出FD的潜在生物标志物,利用KEGG数据库分析潜在生物标志物的代谢途径。
2.足阳明经穴治疗FD的代谢组学研究：分别采用本经特定穴、本经非特定穴、他经取穴、非经非穴四种方法针刺治疗FD,运用基于1H NMR的代谢组学方法比较不同治疗时间各组对FD血浆代谢物的影响及组间差异,着重观察足阳明经穴对潜在生物标志物和关键代谢物的调控效应及其规律。
3.足阳明经穴治疗FD的代谢组学特征提取：采用相关系数算法对两两比较后特征值的载荷图进行相似度计算,探索不同取穴方式对FD关键代谢物作用的规律,分析本经特定穴与本经非特定穴的相似度,判断二者是否具有循经趋同性。
结果
1.与健康对照组相比,FD患者血浆中磷脂酰胆碱含量明显升高,与NDI症状积分正相关(P<0.01)；亮氨酸/异亮氨酸含量明显下降,与FD患者的NDI症状积分负相关(P<0.05),两者是FD的潜在生物标志物；此外,FD患者血浆中的丙氨酸、谷氨酰胺、脯氨酸、HDL、β-葡萄糖、α-葡萄糖、LDL/VLDL等一系列代谢物的含量也出现了显著变化,是FD的关键代谢产物。
2.针刺治疗FD 2个疗程后,四种针刺方式均能降低血浆磷脂酰胆碱的含量,但非经非穴组的调整作用与治疗前相比没有统计学差异；四种针刺方式均能升高亮氨酸/异亮氨酸的含量,但均不具有统计学意义。四组之间比较,本经特定穴组中磷脂酰胆碱含量最低(与其它组相比P值均<0.05),亮氨酸/异亮氨酸含量最高(与本经非特定穴组相比P>0.05,与他经取穴组和非经非穴组相比P值均<0.05)。针刺治疗4个疗程后,各组磷脂酰胆碱含量均继续降低,亮氨酸/异亮氨酸含量继续增高,其中本经特定穴组的亮氨酸/异亮氨酸含量升高最为明显(P<0.05)。
3.针刺治疗FD2个疗程后,本经特定穴组对FD血浆中偏离常态的谷氨酰胺、HDL、β-葡萄糖、LDL/VLDL也具有明显的良性调整作用(P<0.05)；本经非特定穴组能明显升高FD降低的苏氨酸含量,但却继续升高FD中原本就升高的α-葡萄糖的含量；他经取穴组也明显升高α-葡萄糖的含量；非经非穴组对大多数代谢物也是良性调整作用,但调整效应较弱(P<0.05)。针刺治疗4个疗程后,本经特定穴组的上述效应继续得到加强,但对丙氨酸、赖氨酸的影响与第2疗程相反,本经非特定穴仍然主要影响苏氨酸的含量。他经取穴组这一时期影响的物质较多,包括乙酰乙酸盐,α-葡萄糖、β-葡萄糖、UFA、丙氨酸和乳酸,其中对α-葡萄糖、β-葡萄糖和乳酸的影响与第2疗程的作用正好相反。非经非穴组除了对Nac的影响稍强于其它组外,对其它代谢物的影响基本与第2疗程相似。
4.相似度计算表明,针刺治疗FD 2个疗程后,本经非特定穴组与本经特定穴组的LED特征值载荷图相似；治疗4个疗程后,本经非特定穴组与本经特定穴组的CPMG、LED特征值载荷图均相似。
结论
1.一系列代谢物偏离常态是FD患者血浆代谢的共同特点,其中,血浆磷脂酰胆碱和亮氨酸/异亮氨酸与FD患者的NDI症状积分相关,是潜在的生物标志物。
2.四种针刺方式对FD潜在生物标志物都有一定的良性调整作用,但作用强度不同,随治疗时间的延续效应不同；四种针刺方法对FD其它关键代谢物均有调整作用,但针对性不同,调整强度不一,随治疗时间的延续效应也不同,对FD代谢系列组合的调整存在差异,为经穴效应特异性的存在提供了部分代谢组学依据。
3.阳明经特定穴对FD潜在生物标志物和一系列偏离常态的关键代谢物均有调整作用,且调整效应最大,针对性最强,系列组合优势更明显；非经非穴对FD潜在生物标志物也有调整效应,但作用强度最弱；对其它关键代谢物的调整范围较窄,延续效应较弱；阳明经特定穴与阳明经非特定穴在代谢组学特征上有一定的循经趋同性,为经穴效应特异性的内涵和规律提供了新的代谢组学线索。
OBJECTIVE
To investigate whether metabolic difference exists between acupuncture on specific acupoints of disease-relate meridian, on non-specific acupoints of disease-relate meridian, on acupoints of other meridian or on non-acupoints,1H NMR-based metabonomic method was used to study the metabolism changes in FD after treated by different acupuncture method.
METHOD
1. FD patients were recruited in and Nepean Dyspepsia Index (NDI) scale rating was employed to evaluate the the symptoms of dyspepsia and the quality of life for the patients. 1H NMR--based metabonomic techniques were used to detect the plasma metabolic profiles. Pattern recognition was used to find the difference and the key metabolites between groups. By calculating the correlation between the key metabolites and the NDI score, potential biomarkers were founded. KEGG database was mainly referenced to analyze the metabolic pathways of the potential biomarkers.
2. Four kinds of methods were chosen to treat FD:(1) specific acupoints of Stomach Meridian of Foot-Yangming (group A); (2) non-specific acupoints of the stomach meridian (group B); (3) acupoints of the gallbladder meridian (group C) and (4) non-acupoints(group D). Similarly,1H NMR--based metabonomic techniques had been used to detect the metabolites over two periods and four periods of treatment.
3. Analyze the eigenvalue on the loading plots of pairwise comparison and calculated the plots similarity by correlation coefficient algorithm.
RESULTS
1. The plasma level of phosphatidycholine (PtdCho) in FD increased significantly, and was positively related to the score of Nepean Dyspepsia Symptom Index (NDSI) (P<0.01); the plasma level of Leucine/isoleucine decreased obviously and was negatively related to the score of NDSI (P< 0.05), both compounds are FD potential biomarkers. In addition, Levels of a series compounds including glutamine, alanine, proline, HDL,β-glucose、α-glucose and LDL/VLDL were significantly changed in FD, they were considered to be FD key metabolites.
2. After two periods of treatment, all groups except group D could significantly reduce the concentration of PtdCho; all groups could increase the concentration of Leu/Ile, but no group has statistical significance. Comparison between groups showed that level of Ptdcho in group A was the lowest after two periods of treatment, with all pairwise comparison P values lower than 0.05.The level of Leu/Ile in group A was significantly higher than group C and D (both P<0.05), but only slightly higher than that of group B. After four periods of treatment, PtdCho continued to decrease and Leu/Ile continued to increase in group A, B and C. However, only Leu/Ile in group A was significantly improved (P<0.05).
3. After 2 periods treatment, levels of glutamine, LDL/VLDL andβ-glucose were obvoiously improved in group A (P<0.05); Level of threonine in group B was significantly improved (P<0.05). a-glucose in group B and group C was significantly changed but both were not benign improving effect. In Group D, concentrations of key metabolites were only slightly improved. After 4 periods treatment, the effects mentioned above in group A was continuously improved, however, the effect on alanine and lysine were weakened at this time point. Concentration of threonine in group B was continuously significantly increased. In group C, many compounds including acetoacetate,β-glucose, a-glucose, UFA, alanine and lactate were significantly changed, but its effect on P-glucose, a-glucose and lactate were oppositely to the 2nd periods (in other words the change was with the same trend as FD). In group D, almost all compounds slightly changed but no obvious different between 2 periods and 4 periods treatment.
4. After two periods of treatment, LED eigenvalue plots showed that group B was similar to group A; after four periods of treatment, both CPMG and LED eigenvalue plots in group B was similar to that of group A.
CONCLUSION
1. Many plasma metabolites are deviating from normal condition in FD, among them, concentration of PtdCho and Leu/Ile are closely related to FD symptoms, they are potential biomarkers.
2. Four kinds of acupuncture methods has certain positive role to FD potential biomarkers, but the intensity of adjustment and the continuation effect along with treating periods are different. Four kinds of methods can improve the levels of other key metabolites, but the main target metobolites, the intensity, the continuation effect along with treating periods and the scopes of the effect are different, The results provide some metabonomic basis for the specific effects of Foot-Yangming meridian in treating FD.
3. Puncturing on specific acupoints of the stomach meridian has a more significant and intensive effect on the two kinds of potential biomarkers of FD, and this effect would be enlarged after four periods of treatment. For most of the other key metabolites, this method is more effective and has a more intensive targeted effect than other methods. Puncturing on non-acupoints could also influence the potential biomarkers and key metabolites of FD, but with lower intensity, narrow range and weaker continuous effect. Specific acupoints and non-specific acupoints in the stomach meridian have common metabolic features. Our study provides new clues for considering the connotation of the specific effects of Foot-Yangming meridian.
引文
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