{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T06:10:32Z","timestamp":1779257432014,"version":"3.51.4"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T00:00:00Z","timestamp":1779235200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Polygalae Radix a widely used tranquilizing traditional Chinese medicine, is limited by gastrointestinal adverse effects. The Polygala total saponins are identified as its major toxic constituents.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>To clarify the toxicity of PTS and elucidate its underlying toxic mechanism, this study performed five key experiments: First, we observed the toxic manifestations of PTS in male ICR mice and collected serum and intestinal tissue samples after administration. Second, we obtained toxicological evidence through histopathological examination and serum biochemical analysis. Third, we detected the protein and mRNA expression levels of tight junctions (TJs) in intestinal tissues, as well as the content of short-chain fatty acids (SCFAs) in feces. Fourth, we analyzed fecal microbial community structure using 16S rRNA gene sequencing after PTS exposure. Fifth, we explored the potential toxic mechanisms using metabolomics and transcriptomic analysis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Three days after PTS administration (i.g., 120 and 240\u00a0mg\/kg\/d), mice exhibited obvious intestinal damage. The main mechanisms underlying PTS-induced intestinal toxicity involved disrupted digestive and absorptive functions, enhanced intestinal inflammation, impaired intestinal barrier integrity (including compromised tight junctions), and severe intestinal microbiota dysbiosis. Notably, intestinal microbiota dysbiosis was closely correlated with body weight loss and intestinal barrier injury in PTS-treated mice. Further analysis revealed that PTS significantly reduced the abundance of multiple genera within the Lachnospiraceae family and tended to decrease short-chain fatty acid (SCFA) levels. Mechanistically, PTS promoted intestinal inflammation at least partially by upregulating arachidonic acid metabolism.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study interprets the mechanism of intestinal toxicity of PTS from the perspectives of metabolites, DEGs, and microbiota. This helps us refine the toxicological evidence chain (TEC) of PTS and further understand its toxicity mechanism.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1782000","type":"journal-article","created":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T05:39:47Z","timestamp":1779255587000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Intestinal toxicity evaluation of polygala total saponins in mice according to toxicological evidence chain (TEC) concept"],"prefix":"10.3389","volume":"17","author":[{"given":"Yulu","family":"Liang","sequence":"first","affiliation":[{"name":"School of Chinese Materia Medica, Beijing University of Chinese Medicine","place":["Beijing, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yihong","family":"Li","sequence":"additional","affiliation":[{"name":"School of Chinese Materia Medica, Beijing University of Chinese Medicine","place":["Beijing, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiaqi","family":"Xie","sequence":"additional","affiliation":[{"name":"School of Chinese Materia Medica, Beijing University of Chinese Medicine","place":["Beijing, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuhan","family":"Sun","sequence":"additional","affiliation":[{"name":"School of Chinese Materia Medica, Beijing University of Chinese Medicine","place":["Beijing, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kaikai","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Chinese Materia Medica, Beijing University of Chinese Medicine","place":["Beijing, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junbo","family":"Cui","sequence":"additional","affiliation":[{"name":"School of Chinese Materia Medica, Beijing University of Chinese Medicine","place":["Beijing, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xingyu","family":"Gao","sequence":"additional","affiliation":[{"name":"School of Chinese Materia Medica, Beijing University of Chinese Medicine","place":["Beijing, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chuanxin","family":"Liu","sequence":"additional","affiliation":[{"name":"Henan Key Laboratory of Rare Diseases, Endocrinology and Metabolism Center, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology","place":["Luoyang, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianmei","family":"Huang","sequence":"additional","affiliation":[{"name":"School of Chinese Materia Medica, Beijing University of Chinese Medicine","place":["Beijing, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1002\/biof.1766","article-title":"Rapid and simultaneous determination of histidine metabolism intermediates in human and mouse microbiota and biomatrices","volume":"48","author":"Acu\u00f1a","year":"2022","journal-title":"Biofactors"},{"key":"B2","doi-asserted-by":"publisher","first-page":"004805","DOI":"10.1099\/ijsem.0.004805","article-title":"Cellvibrio polysaccharolyticus sp. Nov., a cellulolytic bacterium isolated from agricultural soil","volume":"71","author":"\u00c1kos","year":"2021","journal-title":"Int. J. Syst. Evol. Microbiol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2021\/8855536","article-title":"Comparative study on the chemical components and gastrointestinal function on rats of the raw product and licorice-simmered product of Polygala tenuifolia","volume":"14","author":"Cui","year":"2021","journal-title":"Evidence-based Complementary Altern. Med."},{"key":"B4","doi-asserted-by":"publisher","first-page":"11731","DOI":"10.1038\/s41598-020-68616-9","article-title":"Loss of chymotrypsin-like protease (CTRL) alters intrapancreatic protease activation but not pancreatitis severity in mice","volume":"10","author":"D\u00f3ra","year":"2020","journal-title":"Sci. Rep."},{"key":"B5","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/B978-0-12-804024-9.00031-8","article-title":"Chapter 31 - the influence of microbiota on mechanisms of bariatric surgery","volume-title":"The microbiota in gastrointestinal pathophysiology","author":"Floch","year":"2017"},{"key":"B6","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1016\/j.plefa.2008.09.019","article-title":"Too much linoleic acid promotes inflammation-doesn't it?","volume":"79","author":"Fritsche","year":"2008","journal-title":"Prostagl. Leukot. Essent. Fat. Acids"},{"key":"B7","doi-asserted-by":"publisher","first-page":"619","DOI":"10.1186\/s40168-024-01966-y","article-title":"The compromised intestinal barrier induced by mycotoxins","volume":"12","author":"Gao","year":"2020","journal-title":"Toxins"},{"key":"B8","doi-asserted-by":"publisher","first-page":"974","DOI":"10.1161\/HYPERTENSIONAHA.116.07910","article-title":"Increased systolic and diastolic blood pressure is associated with altered gut microbiota composition and butyrate production in early pregnancy","volume":"68","author":"Gomez-Arango Luisa","year":"2016","journal-title":"Hypertens. Dallas, Tex"},{"key":"B9","doi-asserted-by":"publisher","first-page":"e008831","DOI":"10.1136\/jitc-2024-008831","article-title":"Inhibition of the NF-\u03baB\/HIF-1\u03b1 signaling pathway in colorectal cancer by tyrosol: a gut microbiota-derived metabolite","volume":"12","author":"Guo","year":"2024","journal-title":"J. For Immunother. Cancer"},{"key":"B10","doi-asserted-by":"publisher","first-page":"50","DOI":"10.13412\/j.cnki.zyyl.2005.04.027","article-title":"Study on acute toxicity of total saponins, alkaloids, ketones and fatty oils in shengyuanzhi","volume":"21","author":"Hui","year":"2005","journal-title":"Pharmacol. Clin. Chin. Materia Medica"},{"key":"B11","doi-asserted-by":"publisher","first-page":"3086","DOI":"10.1002\/ijc.32037","article-title":"Colitis-induced colorectal cancer and intestinal epithelial estrogen receptor beta impact gut microbiota diversity","volume":"144","author":"Ibrahim","year":"2019","journal-title":"Int. J. Cancer"},{"key":"B13","doi-asserted-by":"publisher","first-page":"116895","DOI":"10.1016\/j.jep.2023.116895","article-title":"Dissection of scientific compatibility of Chinese medicinal formula realgar-indigo naturalis as an effective treatment for promyelocytic leukemia from the perspective of toxicology","volume":"317","author":"Jiang","year":"2023","journal-title":"J. Ethnopharmacol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1186\/s13059-019-1831-z","article-title":"Gut microbiome composition in the Hispanic community health study\/study of latinos is shaped by geographic relocation, environmental factors, and obesity","volume":"20","author":"Kaplan","year":"2019","journal-title":"Genome Biol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"113157","DOI":"10.1016\/j.ecoenv.2021.113157","article-title":"Multi modular toxicity assessment of nephrotoxicity in podophyllotoxin exposure rats on account of toxicological evidence chain (TEC) concept","volume":"231","author":"Kong","year":"2022","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"B16","doi-asserted-by":"publisher","first-page":"823","DOI":"10.7539\/j.issn.1672-2981.2022.04.016","article-title":"Chemical constituents from different parts of wild sour jujube at helan Mountains in Ningxia based on LC-MS","volume":"20","author":"Liang","year":"2022","journal-title":"Cent. South Pharm."},{"key":"B17","doi-asserted-by":"publisher","first-page":"110073","DOI":"10.1016\/j.ecoenv.2019.110073","article-title":"Study on potential toxic material base and mechanisms of hepatotoxicity induced by Dysosma versipellis based on toxicological evidence chain (TEC) concept","volume":"190","author":"Liu","year":"2020","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"B18","doi-asserted-by":"publisher","first-page":"925","DOI":"10.1038\/cdd.2010.160","article-title":"Interferon-stimulated gene ISG12b2 is localized to the inner mitochondrial membrane and mediates virus-induced cell death","volume":"18","author":"Lu","year":"2011","journal-title":"Cell Death Differ."},{"key":"B19","first-page":"1","article-title":"Medicinal natural products\u2014An introduction","volume-title":"Annual reports in medicinal chemistry","author":"Lutfun","year":"2020"},{"key":"B20","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1080\/19490976.2020.1832857","article-title":"Spermidine improves gut barrier integrity and gut microbiota function in diet-induced obese mice","volume":"12","author":"Ma","year":"2020","journal-title":"Gut Microbes"},{"key":"B21","doi-asserted-by":"publisher","first-page":"2367","DOI":"10.1016\/j.cmet.2024.08.007","article-title":"Dietary-timing-induced gut microbiota diurnal oscillations modulate inflammatory rhythms in rheumatoid arthritis","volume":"36","author":"Ma","year":"2024","journal-title":"Cell Metab."},{"key":"B22","doi-asserted-by":"publisher","first-page":"703","DOI":"10.1093\/gbe\/evu050","article-title":"A phylogenomic view of ecological specialization in the lachnospiraceae, a family of digestive tract-associated bacteria","volume":"6","author":"Meehan","year":"2014","journal-title":"Genome Biol. Evol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"757718","DOI":"10.3389\/fcimb.2021.757718","article-title":"Roseburia intestinalis: a beneficial gut organism from the discoveries in genus and species","volume":"11","author":"Nie","year":"2021","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"1444","DOI":"10.1016\/j.cell.2015.10.072","article-title":"Epithelial IL-18 equilibrium controls barrier function in colitis","volume":"163","author":"Roni","year":"2015","journal-title":"Cell"},{"key":"B25","doi-asserted-by":"publisher","first-page":"D10","DOI":"10.1093\/nar\/gkaa892","article-title":"Database resources of the national center for biotechnology information","volume":"49","author":"Sayers","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"B26","doi-asserted-by":"publisher","first-page":"1221849","DOI":"10.3389\/fphar.2023.1221849","article-title":"Mechanism of qingchang suppository on repairing the intestinal mucosal barrier in ulcerative colitis","volume":"14","author":"Shan","year":"2023","journal-title":"Front. Pharmacol."},{"key":"B27","first-page":"2592","volume-title":"Handbook of proteolytic enzymes","author":"Shigemi","year":"2013"},{"key":"B28","doi-asserted-by":"publisher","first-page":"124842","DOI":"10.1016\/j.jchromb.2025.124842","article-title":"Biotransformation and its effects on anxiolytic activity and toxicity of polygalae radix saponins","volume":"1268","author":"Sun","year":"2026","journal-title":"J. Chromatogr. B Anal. Technol. Biomed. Life Sci."},{"key":"B29","doi-asserted-by":"publisher","first-page":"847","DOI":"10.13463\/j.cnki.cczyy.2022.08.006","article-title":"Clinical application and dose-effect relationship of milkwort root","volume":"38","author":"Tongyue","year":"2022","journal-title":"J. Changchun Univ. Chin. Med."},{"key":"B30","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1016\/j.bbi.2021.07.004","article-title":"Kefir ameliorates specific microbiota-gut-brain axis impairments in a mouse model relevant to autism spectrum disorder","volume":"97","author":"van de Wouw","year":"2021","journal-title":"Brain, Behav. Immun."},{"key":"B31","doi-asserted-by":"publisher","first-page":"fuaf005","DOI":"10.1093\/femsre\/fuaf005","article-title":"Bile acids as germinants for Clostridioides difficile spores, evidence of adaptation to the gut?","volume":"49","author":"Vinay","year":"2025","journal-title":"FEMS Microbiol. Rev."},{"key":"B32","doi-asserted-by":"publisher","first-page":"483","DOI":"10.13220\/j.cnki.jipr.2020.07.001","article-title":"Research advances in the chemical constituents and pharmacological effects of polygalae radix (PR), a traditional Chinese medicine, and a predictive analysis of potential PR quality-makers","volume":"47","author":"Wang","year":"2020","journal-title":"J. Int. Pharm. Res."},{"key":"B33","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1038\/s41392-020-00443-w","article-title":"Metabolism pathways of arachidonic acids: mechanisms and potential therapeutic targets","volume":"6","author":"Wang","year":"2021","journal-title":"Signal Transduct. Target Ther."},{"key":"B34","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1016\/j.fshw.2021.12.003","article-title":"Metabolic fate of tea polyphenols and their crosstalk with gut microbiota","volume":"11","author":"Wang","year":"2022","journal-title":"Food Sci. Hum. Wellness"},{"key":"B35","doi-asserted-by":"publisher","first-page":"6745","DOI":"10.1007\/s12010-024-04871-0","article-title":"High-level expression and biochemical characterization of a maltotetraose amylase in Pichia pastoris X-33 for maltotetraose production","volume":"196","author":"Wang","year":"2024","journal-title":"Appl. Biochem. Biotechnol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"918048","DOI":"10.1155\/2015\/918048","article-title":"The gastrointestinal irritation of polygala saponins and its potential mechanism in vitro and in vivo","volume":"2015","author":"Wen","year":"2015","journal-title":"BioMed Res. Int."},{"key":"B38","doi-asserted-by":"publisher","first-page":"28","DOI":"10.13412\/j.cnki.zyyl.2010.03.012","article-title":"The effects of electrical slow waves in the gastrointestinal tract of crude Radix polygalae and its saponins and honey-stir-baked Radix polygalae in rats","volume":"26","author":"Yang","year":"2010","journal-title":"Pharmacol. Clin. Chin. Materia Medica"},{"key":"B39","first-page":"33","article-title":"Study of cajal interstitial cells in stomach and small intestine of rats with crude, honey-stir-baked Radix polygalae and its saponins","volume":"34","author":"Yang","year":"2011","journal-title":"J. Chin. Med. Mater."},{"key":"B40","doi-asserted-by":"publisher","first-page":"132338","DOI":"10.1016\/j.chemosphere.2021.132338","article-title":"The potential role of fertilizer-derived exogenous bacteria on soil bacterial community assemblage and network formation","volume":"287","author":"Yang","year":"2022","journal-title":"Chemosphere"},{"key":"B41","doi-asserted-by":"publisher","first-page":"801","DOI":"10.3109\/13880200903280042","article-title":"Anxiolytic and sedative-hypnotic activities of polygalasaponins from Polygala tenuifolia in mice","volume":"48","author":"Yi","year":"2010","journal-title":"Pharm. Biol."},{"key":"B42","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1007\/978-3-642-30138-4_281","volume-title":"The family iamiaceae. The prokaryotes: actinobacteria","author":"Yokota","year":"2014"},{"key":"B43","doi-asserted-by":"publisher","first-page":"159382","DOI":"10.1016\/j.bbalip.2023.159382","article-title":"Integration of systematic review, lipidomics with experiment verification reveals abnormal sphingolipids facilitate diabetic retinopathy by inducing oxidative stress on RMECs","volume":"1868","author":"Yuan","year":"2023","journal-title":"Biochimica Biophysica Acta (BBA)"},{"key":"B44","doi-asserted-by":"publisher","first-page":"738796","DOI":"10.3389\/fmicb.2021.738796","article-title":"Altered fecal microbiome and metabolome in a mouse model of choroidal neovascularization","volume":"12","author":"Yun","year":"2021","journal-title":"Front. Microbiol."},{"key":"B45","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/j.pnpbp.2014.02.013","article-title":"The discovery of Yuanzhi-1, a triterpenoid saponin derived from the traditional Chinese medicine, has antidepressant-like activity","volume":"53","author":"Zeng-liang","year":"2014","journal-title":"Prog. Neuro-psychopharmacology & Biol. Psychiatry"},{"key":"B46","doi-asserted-by":"publisher","first-page":"154483","DOI":"10.1016\/j.phymed.2022.154483","article-title":"Therapeutic potential of polygala saponins in neurological diseases","volume":"108","author":"Zhang","year":"2023","journal-title":"Phytomedicine Int. J. Phytotherapy Phytopharm."},{"key":"B66","doi-asserted-by":"publisher","first-page":"104759","DOI":"10.1177\/1747493018778713","article-title":"Polygalae radix: a review of its traditional uses, phytochemistry, pharmacology, toxicology, and pharmacokinetics","volume":"147","author":"Zhao","year":"2020","journal-title":"Fitoterapia"},{"key":"B47","doi-asserted-by":"publisher","first-page":"157","DOI":"10.2217\/fmb-2016-0130","article-title":"Roseburia spp.: a marker of health?","volume":"12","author":"Zohreh","year":"2017","journal-title":"Future Microbiol."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1782000\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T05:39:53Z","timestamp":1779255593000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1782000\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,20]]},"references-count":46,"alternative-id":["10.3389\/fphar.2026.1782000"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2026.1782000","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,20]]},"article-number":"1782000"}}