【目的】分析慢性再生障碍性贫血 （CAA） 患者与正常人粪便非靶向代谢组学改变及CAA不同中医证型间差异性粪便代谢物谱，以揭示CAA中医证型的物质基础。 【方法】纳入2018年7月至2021年6月南京中医药大学附属医院初治的CAA患者（CAA组） 21例及健康体检者 （正常人组） 24例，根据中医辨证分型标准，将21例CAA患者分为肾阳虚组4例、肾阴虚组12例、肾阴阳两虚组5例。通过粪便采集、气相色谱-质谱分析 （GC-MS） 、多元统计分析等筛选差异代谢物，进行代谢通路富集分析。 【结果】（1） 38种代谢物在 CAA 组与正常人组之间有明显差异，其中3-羟基苯乙酸、腺嘌呤、异柠檬酸、L-谷氨酰胺、尿酸、鸟嘌呤等27种代谢物相对含量在 CAA 中呈现上调，3’ -腺苷酸、花生酸、肌苷、N-乙酰鸟氨酸、去甲肾上腺素等11种代谢物则为下调。其差异代谢物富集的主要代谢通路包括：精氨酸生物合成、嘌呤代谢、癌症的中心碳代谢、乙醛酸和二羧酸代谢、GABA能突触、丙氨酸、天冬氨酸和谷氨酸代谢、D−谷氨酰胺和D−谷氨酸代谢等。 （2） 16种代谢物在CAA不同中医证型之间有显著性差异，包括5-甲氧基色胺、肾上腺素、熊果苷、β-丙氨酸、戊二胺、肌醇、丙酮酸、酪胺等，其差异代谢物富集的主要代谢通路包括：神经活性配体−受体相互作用、酪氨酸代谢、磷脂酰肌醇信号系统、泛酸和辅酶A生物合成、糖酵解/糖异生、初级胆汁酸生物合成、磷酸肌醇代谢、抗坏血酸和醛酸代谢、Ⅱ型糖尿病、心肌细胞中的肾上腺素能信号传导等。 【结论】CAA患者的粪便代谢组学与正常人相比存在明显异常，这可能反映CAA肠道菌群改变介导免疫失调、造血衰竭发生的代谢变化；该研究首次从粪便代谢组学水平揭示了CAA不同肾虚证型的物质基础，可为中医证型的现代化研究提供新思路。

Objective To reveal the material base of traditional Chinese medicine （TCM） syndrome types of chronic aplastic anemia （CAA） by investigating the differences of fecal non-targeted metabolomics changes in patients with CAA and normal people，and by analyzing the differential fecal metabolite profiles in CAA patients with various TCM syndrome types. Methods The analysis was performed on 21 CAA patients （CAA group） who were initially treated at Affiliated Hospital of Nanjing University of Chinese Medicine from July 2018 to June 2021 and on 24 volunteers who had healthy medical checkup （normal group） during the same period. The 21 cases of CAA patients were categorized into four cases of kidney yang deficiency group，12 cases of kidney yin deficiency group，and five cases of deficiency of kidney yin and yang group according to the criteria of TCM syndrome differentiation and classification. Differential metabolites were screened after stool collection， gas chromatography - mass spectrometry （GC-MS） analysis and multivariate statistical analysis，and then enrichment analysis of the metabolic pathway was conducted. Results （1） Obvious differences were presented in 38 kinds of metabolites between the CAA group and the normal group，of which there were 27 metabolites，including 3-hydroxyphenylacetic acid，adenine，isocitric acid，L-glutamine，uric acid and guanine，having the up-regulated relative contents in CAA group，while there were 11 metabolites，including 3’ -adenosine，eicosanoic acid，inosine，N-acetylornithine and norepinephrine，having the down-regulated relative contents in CAA group. The primary enriched metabolic pathways of the differential metabolites included arginine biosynthesis， purine metabolism， central carbon metabolism in cancer， glyoxylate and dicarboxylic acid metabolism， GABAergic synapses， metabolism of alanine，aspartate and glutamate，and D-glutamine and D-glutamate metabolism. （2） There were significant differences in 16 kinds of metabolites among the CAA patients with various TCM syndrome types，including 5-methoxytryptamine，epinephrine，arbutin，β-alanine，pentanediamine，inositol，pyruvate and tyramine，etc. The primary enriched metabolic pathways of the differential metabolites included neuroactive ligand-receptor interactions， tyrosine metabolism， phosphatidylinositol signaling system， pantothenic acid and coenzyme A biosynthesis， glycolysis/gluconeogenesis， primary bile acid biosynthesis， phosphoinositide metabolism，ascorbic acid and aldehyde acid metabolism，type Ⅱ diabetes mellitus，and adrenergic signal transduction in cardiomyocytes. Conclusion Significant differences exist in the fecal metabolomics between the CAA patients and the normal volunteers，which may reflect the metabolic changes of immune dysregulation and hematopoietic failure mediated by the altered intestinal flora in CAA patients. This study revealed the material base of CAA of various kidney deficiency syndromes for the first time at the level of fecal metabolomics，which provides a novel approach for the study of modernization of TCM syndrome.

R259.565

江苏省卫生健康委员会科研项目 （编号：Z2018004）；江苏省中医药管理局科研课题 （编号：YB201812，MS2023016）；第五批全国中医临床优秀人才研修项目 （国中医药人教函2022-1号）；江苏省中医院科研课题 （编号：Y22063）；2022年江苏省研究生实践创新项目 （编号：SJCX22-0761）