{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T12:42:42Z","timestamp":1791549762349,"version":"4.3.4"},"reference-count":38,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2025,11,10]],"date-time":"2025-11-10T00:00:00Z","timestamp":1762732800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Key Research and Development Program of China","award":["2025YFC3408700"],"award-info":[{"award-number":["2025YFC3408700"]}]},{"name":"CAMS Innovation Fund for Medical Sciences","award":["2023-I2M-2-006"],"award-info":[{"award-number":["2023-I2M-2-006"]}]},{"name":"CAMS Innovation Fund for Medical Sciences","award":["2024-I2M-ZH-012"],"award-info":[{"award-number":["2024-I2M-ZH-012"]}]},{"name":"CAMS Innovation Fund for Medical Sciences","award":["2021-I2M-1-028"],"award-info":[{"award-number":["2021-I2M-1-028"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82530123"],"award-info":[{"award-number":["82530123"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Beijing Natural Science foundation","award":["F251033"],"award-info":[{"award-number":["F251033"]}]},{"name":"Beijing Key Laboratory of Key Technologies for Preclinical Research and Development of Innovative Drugs in Pharmacokinetics and Pharmacodynamics"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Polygala tenuifolia Willd., a widely used traditional Chinese medicine, has the function of coordinating heart and kidney and eliminating swelling. However, its renal-protective efficacy and possible material basis remain unknown. The aim of the study was to investigate the renal-protective effect of Polygala tenuifolia Willd. and identify the potential active substance and molecular mechanism. A gentamicin-induced kidney injury model was established to investigate efficacy. Secondly, potential active substances and molecular mechanisms were studied through integrated gut microbiota\u2013drug interaction analysis and network pharmacology at a cellular level. Finally, 16S rRNA sequencing and untargeted metabolomics were used to elucidate the gut microbiota composition and metabolic profile change. Polygala tenuifolia Willd. extracts (PWE), with tenuifoliside A (TFSA) as the key compound, significantly reversed gentamicin-induced acute kidney injury in mice. The gut microbiota-derived carboxylesterase metabolized TFSA into four characteristic metabolites (M1\u2013M4). Notably, both TFSA and M4 were detected in kidney and exerted protective effects via inhibiting TLR4\u2013NF-\u03baB pathway. Furthermore, metabolic pathways and gut microbiota composition change were identified. PWE treatment significantly increased the abundance of beneficial bacteria such as Akkermansia and Blautia, while reducing the abundance of harmful bacteria such as Oscillospira. Subsequently, PWE can reverse amino acid metabolic abnormalities by regulating the biosynthesis of phenylalanine, tyrosine, and tryptophan and ameliorating tryptophan metabolism disorder. This study was the first to verify the renal-protective effect of PWE and identify the effective substance basis (TFSA) and the molecular mechanism, providing a scientific foundation for the development of kidney drug treatment strategies targeting the intestinal flora.<\/jats:p>","DOI":"10.3390\/ijms262210889","type":"journal-article","created":{"date-parts":[[2025,11,10]],"date-time":"2025-11-10T10:35:31Z","timestamp":1762770931000},"page":"10889","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Integrated Gut Microbiota\u2013Drug Interaction Analysis and Network Pharmacology for the Investigation of Renal-Protective Effect of Polygala tenuifolia Willd"],"prefix":"10.3390","volume":"26","author":[{"given":"Jia-Chun","family":"Hu","sequence":"first","affiliation":[{"name":"State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical 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J. Ethnopharmacol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Sur, B., Lee, B., Yoon, Y., Lim, P., Hong, R., Yeom, M., Lee, H., Park, H., Shim, I., and Lee, H. (2017). Extract of Polygala Tenuifolia Alleviates Stress-Exacerbated Atopy-Like Skin Dermatitis through the Modulation of Protein Kinase A and P38 Mitogen-Activated Protein Kinase Signaling Pathway. IJMS, 18.","DOI":"10.3390\/ijms18010190"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1080\/13880209.2020.1758732","article-title":"Polygala Tenuifolia: A Source for Anti-Alzheimer\u2019s Disease Drugs","volume":"58","author":"Deng","year":"2020","journal-title":"Pharm. Biol."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Son, S.-R., Yoon, Y.-S., Hong, J.-P., Kim, J.-M., Lee, K.-T., and Jang, D.S. (2022). Chemical Constituents of the Roots of Polygala Tenuifolia and Their Anti-Inflammatory Effects. Plants, 11.","DOI":"10.3390\/plants11233307"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1178","DOI":"10.1016\/j.phymed.2014.04.022","article-title":"Effect of Tenuifoliside A Isolated from Polygala Tenuifolia on the ERK and PI3K Pathways in C6 Glioma Cells","volume":"21","author":"Dong","year":"2014","journal-title":"Phytomedicine"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"7637","DOI":"10.3892\/mmr.2015.4397","article-title":"Tenuifoliside A Promotes Neurite Outgrowth in PC12 Cells via the PI3K\/AKT and MEK\/ERK\/CREB Signaling Pathways","volume":"12","author":"Liu","year":"2015","journal-title":"Mol. Med. Rep."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/j.ejphar.2013.09.026","article-title":"The Inhibition of JNK MAPK and NF-\u03baB Signaling by Tenuifoliside A Isolated from Polygala Tenuifolia in Lipopolysaccharide-Induced Macrophages Is Associated with Its Anti-Inflammatory Effect","volume":"721","author":"Kim","year":"2013","journal-title":"Eur. J. Pharmacol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Chen, Z., Yang, Y., Han, Y., and Wang, X. (2022). Neuroprotective Effects and Mechanisms of Senegenin, an Effective Compound Originated From the Roots of Polygala Tenuifolia. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.937333"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1080\/13880209.2020.1818790","article-title":"UHPLC-MS\/MS Method for Pharmacokinetic and Bioavailability Determination of Five Bioactive Components in Raw and Various Processed Products of Polygala Tenuifolia in Rat Plasma","volume":"58","author":"Zhao","year":"2020","journal-title":"Pharm. Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1661","DOI":"10.1016\/j.cell.2020.05.001","article-title":"Personalized Mapping of Drug Metabolism by the Human Gut Microbiome","volume":"181","author":"Javdan","year":"2020","journal-title":"Cell"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1038\/535047a","article-title":"Intestinal Microbiota in Health and Disease","volume":"535","author":"Pariente","year":"2016","journal-title":"Nature"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1537","DOI":"10.1016\/j.apsb.2022.12.010","article-title":"Berberine Ameliorates Chronic Kidney Disease through Inhibiting the Production of Gut-Derived Uremic Toxins in the Gut Microbiota","volume":"13","author":"Pan","year":"2023","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"157477","DOI":"10.1016\/j.phymed.2025.157477","article-title":"Lycium Barbarum L. Polyphenols Improve HFD-Induced NAFLD through Liver and Colon Metabolism and Intestinal Microbiota:Potential Role of Methionine Cycle","volume":"148","author":"Liang","year":"2025","journal-title":"Phytomedicine"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/j.apsb.2024.11.009","article-title":"Gut Microbiota-Derived Tryptophan Metabolites Regulated by Wuji Wan to Attenuate Colitis through AhR Signaling Activation","volume":"15","author":"Jing","year":"2025","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.metabol.2017.02.003","article-title":"Berberine-Induced Bioactive Metabolites of the Gut Microbiota Improve Energy Metabolism","volume":"70","author":"Wang","year":"2017","journal-title":"Metabolism"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Zhang, H.-Y., Tian, J.-X., Lian, F.-M., Li, M., Liu, W.-K., Zhen, Z., Liao, J.-Q., and Tong, X.-L. (2021). Therapeutic Mechanisms of Traditional Chinese Medicine to Improve Metabolic Diseases via the Gut Microbiota. Biomed. Pharmacother., 133.","DOI":"10.1016\/j.biopha.2020.110857"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"eadh0215","DOI":"10.1126\/sciadv.adh0215","article-title":"Network Medicine Framework Reveals Generic Herb-Symptom Effectiveness of Traditional Chinese Medicine","volume":"9","author":"Gan","year":"2023","journal-title":"Sci. Adv."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Kamaraj, B. (2025). Exploring the Therapeutic Potential of Epigallocatechin-3-Gallate (Green Tea) in Periodontitis Using Network Pharmacology and Molecular Modeling Approach. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26189144"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"131755","DOI":"10.1016\/j.foodchem.2021.131755","article-title":"Integrated Network Pharmacology and Cellular Assay for the Investigation of an Anti-Obesity Effect of 6-Shogaol","volume":"374","author":"Jiao","year":"2022","journal-title":"Food Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"119359","DOI":"10.1016\/j.jep.2025.119359","article-title":"5\u03b2-Hydroxycostic Acid from Laggeraalata Ameliorates Sepsis-Associated Acute Kidney Injury through Its Anti-Inflammatory and Anti-Ferroptosis Effects via NF-\u03baB and MAPK Pathways.Pdf","volume":"341","author":"Li","year":"2025","journal-title":"J. Ethnopharmacol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1490","DOI":"10.1007\/s00134-025-08035-4","article-title":"State of the Art: Renal Recovery after AKI\u2014from Basic Science to Clinical Practice","volume":"51","author":"Ostermann","year":"2025","journal-title":"Intensive Care Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1344","DOI":"10.1038\/nm1135","article-title":"Berberine Is a Novel Cholesterol-Lowering Drug Working through a Unique Mechanism Distinct from Statins","volume":"10","author":"Kong","year":"2004","journal-title":"Nat. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1038\/s41392-020-00456-5","article-title":"Oral Berberine Improves Brain Dopa\/Dopamine Levels to Ameliorate Parkinson\u2019s Disease by Regulating Gut Microbiota","volume":"6","author":"Wang","year":"2021","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1016\/j.apsb.2024.12.024","article-title":"Integrated Evidence Chain-Based Effectiveness Evaluation of Traditional Chinese Medicines (Eff-iEC): A Demonstration Study","volume":"15","author":"Luo","year":"2025","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1024","DOI":"10.1016\/j.jpha.2023.06.012","article-title":"Gut Microbiota-Based Pharmacokinetic-Pharmacodynamic Study and Molecular Mechanism of Specnuezhenide in the Treatment of Colorectal Cancer Targeting Carboxylesterase","volume":"13","author":"Yu","year":"2023","journal-title":"J. Pharm. Anal."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"120368","DOI":"10.1016\/j.jep.2025.120368","article-title":"Atractylenolide III Attenuates Acute Kidney Injury through Phosphorylation of PIK3CA: Functional Activation and Molecular Interaction Analysis","volume":"353","author":"You","year":"2025","journal-title":"J. Ethnopharmacol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"120310","DOI":"10.1016\/j.jep.2025.120310","article-title":"Effects of and Mechanisms Underlying Qingwen Baidu Decoction in Sepsis-Associated Acute Kidney Injury","volume":"353","author":"Zhao","year":"2025","journal-title":"J. Ethnopharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Xu, R., Mao, F., Zhao, Y., Wang, W., Fan, L., Gao, X., Zhao, J., and Tian, H. (2017). UPLC Quantitative Analysis of Multi-Components by Single Marker and Quality Evaluation of Polygala Tenuifolia Wild. Extracts. Molecules, 22.","DOI":"10.3390\/molecules22122276"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1180","DOI":"10.1002\/fsn3.2098","article-title":"Involvement of 5-HT-BDNF Signaling Axis in Mediating Synergistic Antidepressant-like Effects after Combined Administration of Two Oligosaccharide Esters","volume":"9","author":"Yang","year":"2021","journal-title":"Food Sci. Nutr."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1385","DOI":"10.1002\/jssc.201601216","article-title":"Bioactivity Screening, Extraction, and Separation of Lactate Dehydrogenase Inhibitors from Polygala Tenuifolia Willd. Based on a Hyphenated Strategy","volume":"40","author":"Li","year":"2017","journal-title":"J. Sep. Sci."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Han, X., Li, M., Sun, L., Liu, X., Yin, Y., Hao, J., and Zhang, W. (2022). P-Hydroxybenzoic Acid Ameliorates Colitis by Improving the Mucosal Barrier in a Gut Microbiota-Dependent Manner. Nutrients, 14.","DOI":"10.3390\/nu14245383"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/j.ejmech.2019.04.009","article-title":"Research Progress in the Biological Activities of 3,4,5-Trimethoxycinnamic Acid (TMCA) Derivatives","volume":"173","author":"Zhao","year":"2019","journal-title":"Eur. J. Med. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"157060","DOI":"10.1016\/j.phymed.2025.157060","article-title":"Fucoidan Alleviates Renal Fibrosis in Mice via Akkermansia Muciniphila-Mediated Suppression of NEU1-TLR4\u2013NF\u03baB Signaling Axis","volume":"145","author":"Wang","year":"2025","journal-title":"Phytomedicine"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"155861","DOI":"10.1016\/j.phymed.2024.155861","article-title":"Hong Guo Ginseng Guo (HGGG) Protects against Kidney Injury in Diabetic Nephropathy by Inhibiting NLRP3 Inflammasome and Regulating Intestinal Flora","volume":"132","author":"Pan","year":"2024","journal-title":"Phytomedicine"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1016\/j.cell.2020.02.016","article-title":"A Cardiovascular Disease-Linked Gut Microbial Metabolite Acts via Adrenergic Receptors","volume":"180","author":"Nemet","year":"2020","journal-title":"Cell"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Chen, W., Zhang, K., Cui, H., Li, J., Yao, D., Wang, S., Tian, X., Kou, W., Huang, J., and Wang, H. (2024). Baicalin-2-Ethoxyethyl Ester Alleviates Gentamicin-Induced Acute Kidney Injury via NF-\u03baB Signaling Pathway. Biomed. Pharmacother., 172.","DOI":"10.1016\/j.biopha.2024.116276"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1869","DOI":"10.2147\/DDDT.S506545","article-title":"Gut-Brain Axis-Based Polygala Tenuifolia and Magnolia Officinalis Improve D-Gal-Induced Cognitive Impairment in Mice Through cAMP and NF-\u03baB Signaling Pathways","volume":"19","author":"Yang","year":"2025","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Qi, S., Liang, X., Wang, Z., Jin, H., Zou, L., and Yang, J. (2024). Potential Mechanism of Tibetan Medicine Liuwei Muxiang Pills against Colorectal Cancer: Network Pharmacology and Bioinformatics Analyses. Pharmaceuticals, 17.","DOI":"10.3390\/ph17040429"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/22\/10889\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,12]],"date-time":"2025-11-12T05:27:28Z","timestamp":1762925248000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/22\/10889"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,10]]},"references-count":38,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2025,11]]}},"alternative-id":["ijms262210889"],"URL":"https:\/\/doi.org\/10.3390\/ijms262210889","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,10]]}}}