{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T05:25:38Z","timestamp":1763702738523,"version":"3.45.0"},"reference-count":39,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T00:00:00Z","timestamp":1763510400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Science Centre, Poland","award":["Sonatina 5 2021\/40\/C\/NZ7\/00231"],"award-info":[{"award-number":["Sonatina 5 2021\/40\/C\/NZ7\/00231"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The tormentil rhizome (Potentilla erecta L.) is traditionally used to treat gastrointestinal and inflammatory disorders, yet the mechanisms underlying its immunomodulatory activity remain unclear. No studies have examined the metabolism of tormentil constituents by the human gut microbiota and their effects on innate immune cells. This study evaluated the effects of the ethanolic extract of tormentil rhizome (EtTR) and its gut microbiota-derived metabolites (TRGMs) on innate immune function using human neutrophils and THP-1-derived macrophages. The chemical composition of EtTR and TRGMs was characterized by LC-MS, revealing fractions enriched in catechins and procyanidins (30% MeOH) or ellagic acid derivatives and triterpenes (100% MeOH). EtTR and all TRGM fractions significantly reduced ROS production, while the extract and selected metabolites decreased IL-1\u03b2 and TNF-\u03b1 secretion in neutrophils, whereas IL-8 showed marked induction. In macrophages, EtTR and selected fractions suppressed TNF-\u03b1 and MCP-1 release but variably affected IL-6, reflecting donor-dependent modulation. The strongest inhibition was observed for fractions rich in catechins and triterpenoid conjugates, indicating synergistic activity between these compound classes. Overall, EtTR and its microbiota-derived metabolites exerted complementary antioxidant and immunomodulatory effects, providing mechanistic evidence that microbial transformation of tormentil polyphenols yields bioactive postbiotic metabolites capable of modulating inflammatory signaling.<\/jats:p>","DOI":"10.3390\/ijms262211164","type":"journal-article","created":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T10:02:13Z","timestamp":1763546533000},"page":"11164","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["In Vitro Evaluation of Antioxidant and Cytokine-Modulating Activity of Tormentil Rhizome Extract and Its Microbial Metabolites in Human Immune Cells"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5323-7093","authenticated-orcid":false,"given":"Aleksandra","family":"Kruk","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Biology, Faculty of Pharmacy, Medical University of Warsaw, Banacha 1 Street, 02-097 Warsaw, Poland"},{"name":"Microbiota Lab, Department of Pharmaceutical Microbiology and Bioanalysis, Faculty of Pharmacy, Medical University of Warsaw, Banacha 1b Street, 02-097 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Dawson, S.L., Todd, E., and Ward, A.C. (2025). The Interplay of Nutrition, the Gut Microbiota and Immunity and Its Contribution to Human Disease. Biomedicines, 13.","DOI":"10.3390\/biomedicines13020329"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Mahdi, L., Graziani, A., Baffy, G., Mitten, E.K., Portincasa, P., and Khalil, M. (2025). Unlocking Polyphenol Efficacy: The Role of Gut Microbiota in Modulating Bioavailability and Health Effects. Nutrients, 17.","DOI":"10.3390\/nu17172793"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Campbell, C., Kandalgaonkar, M.R., Golonka, R.M., Yeoh, S., Vijay-Kumar, M., and Saha, P. (2023). Crosstalk between Gut Microbiota and Host Immunity: Impact on Inflammation and Immunotherapy. Biomedicines, 11.","DOI":"10.3390\/biomedicines11020294"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1050","DOI":"10.1055\/a-1129-7214","article-title":"Tormentillae Rhizoma\u2014Review for an Underestimated European Herbal Drug # Authors Phytochemistry of the Underground Parts","volume":"86","author":"Melzig","year":"2020","journal-title":"Planta Medica"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1016\/j.jep.2008.12.022","article-title":"Potentilla-A Review of Its Phytochemical and Pharmacological Profile","volume":"122","author":"Tomczyk","year":"2009","journal-title":"J. Ethnopharmacol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"114326","DOI":"10.1016\/j.foodres.2024.114326","article-title":"Heterogeneity of Transport and Metabolism of Tormentillae Rhizoma Constituents across Human Intestinal Epithelium Cellular Model","volume":"188","author":"Kruk","year":"2024","journal-title":"Food Res. Int."},{"key":"ref_7","first-page":"86","article-title":"Anti-Inflammatory and Vasoconstrictive Properties of Potentilla Erecta\u2014A Traditional Medicinal Plant from the Northern Hemisphere","volume":"23","author":"Ho","year":"2017","journal-title":"J. Ethnopharmacol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1002\/pca.2570","article-title":"Quantification of Tannins and Related Polyphenols in Commercial Products of Tormentil (Potentilla tormentilla)","volume":"26","author":"Fecka","year":"2015","journal-title":"Phytochem. Anal."},{"key":"ref_9","first-page":"113412","article-title":"Recent Phytochemical and Pharmacological Advances in the Genus Potentilla L. Sensu Lato\u2014An Update Covering the Period from 2009 to 2020","volume":"226","author":"Augustynowicz","year":"2020","journal-title":"J. Ethnopharmacol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Olech, M., Ziemich, W., and Nowacka-Jechalke, N. (2021). The Occurrence and Biological Activity of Tormentic Acid\u2014A Review. Molecules, 26.","DOI":"10.3390\/molecules26133797"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Mantiniotou, M., Athanasiadis, V., Kalompatsios, D., Bozinou, E., and Lalas, S.I. (2025). Therapeutic Capabilities of Triterpenes and Triterpenoids in Immune and Inflammatory Processes: A Review. Compoundsompounds, 5.","DOI":"10.3390\/compounds5010002"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Hoffmann, J., Casetti, F., Bullerkotte, U., Haarhaus, B., Vagedes, J., Schempp, C.M., and W\u00f6lfle, U. (2016). Anti-Inflammatory Effects of Agrimoniin-Enriched Fractions of Potentilla Erecta. Molecules, 21.","DOI":"10.3390\/molecules21060792"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1002\/ptr.5773","article-title":"Ethanol Extract of Potentilla Supina Linne Suppresses LPS-Induced Inflammatory Responses through NF- \u03ba B and AP-1 Inactivation in Macrophages and in Endotoxic Mice","volume":"31","author":"Lee","year":"2017","journal-title":"Phytother. Res."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Kim, J.W., Kwon, K.W., Kim, M., and Cho, J.Y. (2022). Potentilla Paradoxa Nutt. Ethanol Extract Exhibits Anti-Inflammatory Effects by Suppression of the Src\/NF- \u03ba B Signaling Pathway. Plants, 11.","DOI":"10.3390\/plants11131750"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Zhang, X., Kang, Y., Li, X., Huang, Y., Qi, R., and Han, Y. (2021). Biomedicine & Pharmacotherapy Potentilla Discolor Ameliorates LPS-Induced Inflammatory Responses through Suppressing NF- \u03ba B and AP-1 Pathways. Biomed. Pharmacother., 144.","DOI":"10.1016\/j.biopha.2021.112345"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1957","DOI":"10.1007\/s00394-020-02386-y","article-title":"Comparative Studies of Urolithins and Their Phase II Metabolites on Macrophage and Neutrophil Functions","volume":"60","author":"Bobowska","year":"2021","journal-title":"Eur. J. Nutr."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Huang, W., Liou, C., Shen, S., Hu, S., and Chao, J.C. (2022). Urolithin A Inactivation of TLR3\/TRIF Signaling to Block the NF-\u03baB\/STAT1 Axis Reduces Inflammation and Enhances Antioxidant Defense in Poly (I:C)-Induced RAW264.7 Cells. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23094697"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Abdelazeem, K.N.M., Kalo, M.Z., Hammer, S.B., and Lang, F. (2021). The Gut Microbiota Metabolite Urolithin A Inhibits NF-\u03baB Activation in LPS Stimulated BMDMs. Sci. Rep., 11.","DOI":"10.1038\/s41598-021-86514-6"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1017\/S0007114510000826","article-title":"NF- k B-Dependent Anti-Inflammatory Activity of Urolithins, Gut Microbiota Ellagic Acid-Derived Metabolites, in Human Colonic Fibroblasts","volume":"104","author":"Larrosa","year":"2010","journal-title":"Br. J. Nutr."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Tow, W., Chee, P., and Sundralingam, U. (2022). The Therapeutic Relevance of Urolithins, Intestinal Metabolites of Ellagitannin-Rich Food: A Systematic Review of In Vivo Studies. Nutrients, 25.","DOI":"10.3390\/nu14173494"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1038\/s41423-022-00902-0","article-title":"Redox Regulation of the Immune Response","volume":"19","author":"Morris","year":"2022","journal-title":"Cell. Mol. Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1038\/s41392-024-01933-x","article-title":"Neutrophil Extracellular Traps in Homeostasis and Disease","volume":"9","author":"Wang","year":"2024","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1038\/nri1785","article-title":"Neutrophils and Immunity: Challenges and Opportunities","volume":"6","author":"Nathan","year":"2006","journal-title":"Nat. Rev. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Salvador, P. (2022). Macrophage Polarization and Reprogramming in Acute Inflammation: A Redox Perspective. Antioxidants, 11.","DOI":"10.3390\/antiox11071394"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1089\/ars.2012.4785","article-title":"Redox Control of Inflammation in Macrophages","volume":"19","author":"Bru","year":"2013","journal-title":"Antioxid. Redox Signal."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1002\/path.4133","article-title":"Macrophage Plasticity and Polarization in Tissue Repair and Remodelling","volume":"229","author":"Mantovani","year":"2013","journal-title":"J. Pathol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Macrophages, M., Daigneault, M., Preston, J.A., Marriott, H.M., Whyte, M.K.B., and Dockrell, D.H. (2010). The Identification of Markers of Macrophage Differentiation in PMA-Stimulated THP-1 Cells And. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0008668"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"143674","DOI":"10.1016\/j.foodchem.2025.143674","article-title":"Selective Metabolism of Tormentil Rhizome Constituents by Human Gut Microbiota and Its Impact on Biodiversity Ex Vivo","volume":"478","author":"Kruk","year":"2025","journal-title":"Food Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"100460","DOI":"10.1016\/j.hermed.2021.100460","article-title":"A Holistic Overview of Different Species of Potentilla a Medicinally Important Plant along with Their Pharmaceutical Significance: A Review","volume":"29","author":"Kumari","year":"2021","journal-title":"J. Herb. Med."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Kruk, A., Piwowarski, J.P., Paw\u0142owska, K.A., Popowski, D., and Granica, S. (2021). High Molecular Pyrogens Present in Plant Extracts Interfere with Examinations of Their Immunomodulatory Properties in vitro. Sci. Rep., 11.","DOI":"10.1038\/s41598-020-79579-2"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/j.taap.2011.06.007","article-title":"De Plant Polyphenols Differentially Modulate Inflammatory Responses of Human Keratinocytes by Interfering with Activation of Transcription Factors NF \u03ba B and AhR and EGFR\u2013ERK Pathway","volume":"255","author":"Potapovich","year":"2011","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_32","first-page":"104","article-title":"Differential Modulation of Stress-Inflammation Responses by Plant Polyphenols in Cultured Normal Human Keratinocytes and Immortalized HaCaT Cells","volume":"63","author":"Pastore","year":"2011","journal-title":"J. Dermatol. Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1172\/JCI114265","article-title":"Neutrophil-Activating Peptide-1\/Lnterleukin 8, a Novel Cytokine That Activates Neutrophils","volume":"84","author":"Baggiolini","year":"1989","journal-title":"J. Clin. Investig."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3424","DOI":"10.4049\/jimmunol.0900305","article-title":"Differential Activation and Regulation of CXCR1 and CXCR2 by CXCL8 Monomer and Dimer","volume":"183","author":"Nasser","year":"2009","journal-title":"J. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Verhelst, R.E., and Kruk, A. (2025). Integrated Molecular and Functional Analysis of Hop Ethanolic Extract in Caco-2 Cells: Insights into Inflammation, Barrier Function, and Transport. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms262110608"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"120433","DOI":"10.1016\/j.jep.2025.120433","article-title":"Chemical Composition, Skin Microbiota Metabolism, Antimicrobial Potential and Anti-Inflammatory Properties of Witch Hazel Bark (Hamamelis virginiana L.)","volume":"353","author":"Piwowarski","year":"2025","journal-title":"J. Ethnopharmacol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"115355","DOI":"10.1016\/j.jep.2022.115355","article-title":"Tiliae Flos Metabolites and Their Beneficial Influence on Human Gut Microbiota Biodiversity Ex Vivo","volume":"294","author":"Kruk","year":"2022","journal-title":"J. Ethnopharmacol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"107706","DOI":"10.1016\/j.jfca.2025.107706","article-title":"Evaluation of Phytochemical Profiles and Anti- Inflammatory Potential of Dietary Supplements Containing Cistus spp","volume":"144","author":"Kiss","year":"2025","journal-title":"J. Food Compos. Anal."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Korczak, M., Roszkowski, P., Granica, S., and Piwowarski, J.P. (2022). Conjugates of Urolithin A with NSAIDs, Their Stability, Cytotoxicity, and Anti-Inflammatory Potential. Sci. Rep., 12, Correction in Sci. Rep. 2022, 12, 1. https:\/\/doi.org\/10.1038\/s41598-022-22926-2.","DOI":"10.1038\/s41598-022-22926-2"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/22\/11164\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T05:21:26Z","timestamp":1763702486000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/22\/11164"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,19]]},"references-count":39,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2025,11]]}},"alternative-id":["ijms262211164"],"URL":"https:\/\/doi.org\/10.3390\/ijms262211164","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2025,11,19]]}}}