The Journal of Practical Medicine >

2026 , Vol. 42 >Issue 7: 1149 - 1157

DOI: https://doi.org/10.3969/j.issn.1006-5725.2026.07.005

Feature Reports：Tuberculosis

Untargeted metabolomics-based discovery of potential biomarkersfor active pulmonary tuberculosis

  • Yuan WANG ,
  • Zijie CHEN ,
  • Jieqing ZHONG ,
  • Yujie MO ,
  • Xiaoling QIN ,
  • Dongxu LIANG ,
  • Xiaojing GUO ,
  • Shiyi CHEN ,
  • Dan LUO
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  • School of Public Health and Management，Guangxi University of Chinese Medicine，Nanning 530299，Guangxi，China

Received date: 2025-08-07

  Revised date: 2025-09-25

  Accepted date: 2025-09-30

  Online published: 2026-04-13

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Abstract

Objective To analyze the fecal metabolic profile of active tuberculosis（ATB） patients in order to explore novel non-invasive diagnostic biomarkers. Methods A total of 33 treatment-naive ATB patients（TB group） and 30 healthy controls（HC group） were recruited. Fresh fecal specimens from both groups were examined using UHPLC-MS-based untargeted metabolomics. Differential metabolites were selected by partial least squares discriminant analysis（PLS-DA） with the thresholds of variable importance in projection（VIP） ≥ 1.0， |log? FC| ≥ 0.585 （1.5-fold change）， and P ≤ 0.05. Potential biomarkers were recognized through KEGG pathway enrichment and clustering analyses， and their diagnostic effectiveness was assessed via receiver operating characteristic（ROC） curves. Results A total of 515 differential metabolites were identified （312 in ESI-； 203 in ESI+）， which were primarily enriched in purine metabolism， bile secretion， and nicotinate/nicotinamide metabolism. In the ESI- mode， 16 out of the top 20 metabolites were significantly down-regulated in the TB group， whereas PGE?， N-｛3-［（3，5-difluorophenyl）oxy］pyridin-2-yl｝-4-pentylbenzenesulfonamide， N'-2-acetylpyridine-2-carbohydrazone， and 5-hydroxyindole-2-carboxylic acid were up-regulated. In the ESI+ mode， 18 out of the top 20 metabolites were up-regulated， while 3-acetyl-2，5-dimethylfuran and fumaric acid were down-regulated. Metabolic pathway analysis combined with functional prediction identified three potential biomarkers—prostaglandin E2（PGE2）， trans-2-Butene-1，4-dicarboxylic Acid， and 5-hydroxyindole-2-carboxylic acid， with areas under the curve（AUC） of 0.911， 0.859， and 0.824， respectively. The logistic regression model integrating these three biomarkers achieved an AUC of 0.957 for combined diagnosis. Conclusions Differential metabolites in patients with active pulmonary tuberculosis were mainly enriched in purine metabolism， bile secretion， and nicotinate and nicotinamide metabolism pathways. Both PGE2， trans-2-Butene-1，4-dicarboxylic acid， 5-hydroxyindole-2-carboxylic acid， and their combined diagnostic model showed good diagnostic efficacy for pulmonary tuberculosis.

Key words： active tuberculosis; untargeted metabolomics; feces; biomarkers

Cite this article

Yuan WANG , Zijie CHEN , Jieqing ZHONG , Yujie MO , Xiaoling QIN , Dongxu LIANG , Xiaojing GUO , Shiyi CHEN , Dan LUO . Untargeted metabolomics-based discovery of potential biomarkersfor active pulmonary tuberculosis[J]. The Journal of Practical Medicine, 2026 , 42(7) : 1149 -1157 . DOI: 10.3969/j.issn.1006-5725.2026.07.005

References

[1] 李媛媛， 谢晶晶， 李树涛， 等. 2024年WHO全球结核病报告：全球与中国关键数据分析［J］. 新发传染病电子杂志， 2024， 9（6）： 92-98. doi： 10.19871/j.cnki.xfcrbzz.2024.06.016 .
[2] 孙微， 麻斌喜， 郑甜， 等. 结核病诊断技术的研究进展［J］. 新疆医学， 2025， 55（3）： 349-353. doi:10.3760/cma.j.issn.1001-5183.2025.03.120
[3] DU PREEZ I， LOOTS D T. New sputum metabolite markers implicating adaptations of the host to Mycobacterium tuberculosis， and vice versa［J］. Tuberculosis， 2013， 93（3）： 330-337. doi： 10.1016/j.tube.2013.02.008 .
[4] CHEN Y， WU Y， LV J， et al. Overall and individual associations between per- and polyfluoroalkyl substances and liver function indices and the metabolic mechanism［J］. Environment Int， 2024， 183： 108405. doi： 10.1016/j.envint.2023.108405 .
[5] ISA F， COLLINS S， LEE M H， et al. Mass Spectrometric Identification of Urinary Biomarkers of Pulmonary Tuberculosis［J］. EBioMedicine， 2018， 31： 157-165. doi： 10.1016/j.ebiom.2018.04.014 .
[6] 中华人民共和国国家卫生健康委员会. 肺结核诊断： WS 288—2017［EB/OL］. 北京： 中华人民共和国国家卫生健康委员会， 2017（2017-11-09）［2025-06-26］. .
[7] HONG Y， CHEN B， ZHAI X， et al. Integrated analysis of the gut microbiome and metabolome in a mouse model of inflammation-induced colorectal tumors［J］. Front Microbiol， 2022， 13： 1082835. doi： 10.3389/fmicb.2022.1082835 .
[8] LUO D， YANG B， QIN K， et al. Untargeted Metabolomics of Feces Reveals Diagnostic and Prognostic Biomarkers for Active Tuberculosis and Latent Tuberculosis Infection： Potential Application for Precise and Non-Invasive Identification［J］. Infect Drug Resist， 2023， 16： 6121-6138. doi： 10.2147/IDR.S422363 .
[9] WANT E J， WILSON I D， GIKA H， et al. Global metabolic profiling procedures for urine using UPLC-MS［J］. Nat Protoc， 2010， 5（6）： 1005-1018. doi： 10.1038/nprot.2010.50 .
[10] WU X， LIU K， WU Q， et al. Biomarkers of Metabolomics in Inflammatory Bowel Disease and Damp-Heat Syndrome： A Preliminary Study［J］. Evid Based Complement Alternat Med， 2022， 2022： 3319646. doi： 10.1155/2022/3319646 .
[11] MURPHY R A， BUREYKO T F， MOURTZAKIS M， et al. Aberrations in plasma phospholipid fatty acids in lung cancer patients［J］. Lipids， 2012， 47（4）： 363-369. doi： 10.1007/s11745-011-3641-2 .
[12] KUHN T， FLOEGEL A， SOOKTHAI D， et al. Higher plasma levels of lysophosphatidylcholine 18：0 are related to a lower risk of common cancers in a prospective metabolomics study［J］. BMC Med， 2016， 14： 13. doi： 10.1186/s12916-016-0552-3 .
[13] FENG S， DU Y， ZHANG L， et al. Analysis of serum metabolic profile by ultra-performance liquid chromatography-mass spectrometry for biomarkers discovery： Application in a pilot study to discriminate patients with tuberculosis［J］. Chin Med J （Engl）， 2015， 128（2）： 159-168. doi： 10.4103/0366-6999.149188 .
[14] XIA Z， LI Y， YIN J， et al. Integrating Metabolomics and Gut Microbiota to Identify Key Biomarkers and Regulatory Pathways Underlying Metabolic Heterogeneity in Childhood Obesity［J］. Nutrients， 2025， 17（11）： 1876. doi： 10.3390/nu17111876 .
[15] LI C， FAN J， SUN G， et al. Nrf2 pathway activation promotes the expression of genes related to glutathione metabolism in alcohol-exposed astrocytes［J］. PeerJ， 2024， 12： e17541. doi： 10.7717/peerj.17541 .
[16] GUO Y， WAN S， HAN M， et al. Plasma Metabolomics Analysis Identifies Abnormal Energy， Lipid， and Amino Acid Metabolism in Abdominal Aortic Aneurysms［J］. Med Sci Monit， 2020， 26： e926766. doi： 10.12659/MSM.926766 .
[17] AGRAWAL S， JASWAL K， SHIVER A L， et al. A genome-wide screen in Escherichia coli reveals that ubiquinone is a key antioxidant for metabolism of long-chain fatty acids［J］. J Biol Chem， 2017， 292（49）： 20086-20099. doi： 10.1074/jbc.M117.806240 .
[18] 蒋彩虹， 高子蕊， 郭丽凯， 等. 前列腺素E2在癌症发生发展中的研究进展［J］. 生理科学进展， 2018， 49（1）： 53-57. doi： 10.3969/j.issn.0559-7765.2018.01.010 .
[19] 刘彪. 血清微小RNA-27a、微小RNA-147、前列腺素E2水平与肺结核患者病情严重程度的关系研究［J］. 陕西医学杂志， 2025， 54（4）： 510-514. doi： 10.3969/j.issn.1000-7377.2025.04.015 .
[20] 吴显劲， 黄海勇， 萧乐瑶， 等. 巨噬细胞极化与结核分枝杆菌感染的研究进展［J］. 中国防痨杂志， 2023， 45（12）： 1198-1204. doi： 10.19982/j.issn.1000-6621.20230265 .
[21] PEURA A， TURPIN R， LIU R， et al. Soft matrix promotes immunosuppression in tumor-resident immune cells via COX-FGF2 signaling［J］. Nat Commun， 2025， 16（1）： 4908. doi： 10.1038/s41467-025-60092-x .
[22] RUECKER N， JANSEN R， TRUJILLO C， et al. Fumarase Deficiency Causes Protein and Metabolite Succination and Intoxicates Mycobacterium tuberculosis［J］. Cell Chem Biol， 2017， 24（3）： 306-315. doi： 10.1016/j.chembiol.2017.01.005 .
[23] CAI X， JIN J， YE H， et al. Altered serum metabolome is associated with disease activity and immune responses in rheumatoid arthritis［J］. Clin Rheumatol， 2024， 43（12）： 3669-3678. doi： 10.1007/s10067-024-07201-1 .
[24] VELAGAPUDI V R， HEZAVEH R， REIGSTAD C S， et al. The gut microbiota modulates host energy and lipid metabolism in mice［J］. J Lipid Res， 2010， 51（5）： 1101-1112. doi： 10.1194/jlr.M002774 .
[25] ZHAO L， TANG S， CHEN F， et al. Regulation of macrophage polarization by targeted metabolic reprogramming for the treatment of lupus nephritis［J］. Mol Med， 2024， 30（1）： 96. doi： 10.1186/s10020-024-00866-z .
[26] COLLINS J M， SIDDIQA A， JONES D P， et al. Tryptophan catabolism reflects disease activity in human tuberculosis［J］. JCI Insight， 2020， 5（10）： e137131. doi： 10.1172/jci.insight.137131 .
[27] ZHANG K， MISHRA A， JAGANNATH C. New insight into arginine and tryptophan metabolism in macrophage activation during tuberculosis［J］. Front Immunol， 2024， 15： 1363938. doi： 10.3389/fimmu.2024.1363938 .
[28] XUE C， LI G， ZHENG Q， et al. Tryptophan metabolism in health and disease［J］. Cell Metab， 2023， 35（8）： 1304-1326. doi： 10.1016/j.cmet.2023.06.004 .
[29] LU Z， ZHANG C， ZHANG J， et al. The Kynurenine Pathway and Indole Pathway in Tryptophan Metabolism Influence Tumor Progression［J］. Cancer Med， 2025， 14（6）： e70703. doi： 10.1002/cam4.70703 .
[30] BARAL T， JOHNSON A S， UNNIKRISHNAN M K， et al. Potential role of indole-3-propionic acid in tuberculosis： Current perspectives and future prospects［J］. Expert Opin Ther Targets，2025， 29（3）： 171-178. doi： 10.1080/14728222.2025.2482548 .
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