{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T05:08:45Z","timestamp":1775797725516,"version":"3.50.1"},"reference-count":47,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T00:00:00Z","timestamp":1775779200000},"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>Introduction<\/jats:title>\n                    <jats:p>Chemotherapy-induced thrombocytopenia (CIT) presents as a prevalent hematological toxicity, often complicating the clinical management of cancer patients. SI XIAN Formula (SXF), a prescription consisting of ten traditional Chinese medicine for treating chemotherapy-induced thrombocytopenia (CIT), has been widely used to treat CIT patients more than 10\u00a0years. The mechanism of SXF remains unclear. This study was designed to systematically evaluate the therapeutic efficacy and elucidate the underlying mechanisms of SXF in a CIT mouse model.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A CIT mice model was successfully established via the tail vein injection of carboplatin. The Mice were subsequently treated daily with SXF for 15\u00a0days and 24\u00a0days. Body weight and platelet count were recorded every 3\u00a0days. The bone marrow cells and fluid were collected for flow cytometry analysis and cytokine detection separately. Histological changes in the femurs bone marrow were observed using H&amp;amp;E staining. The diversity and composition of the intestinal microbiota were analyzed using 16S rDNA gene sequencing. The bone marrow metabolites were identified by HPLC-MS\/MS analysis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      SXF administration significantly accelerated the recovery of platelet counts to baseline levels following carboplatin -induced thrombocytopenia. Mechanistically, SXF demonstrated protective effects on multiple hematopoietic cells, including hematopoietic stem\/progenitor cells, megakaryocytic progenitor cells, and bone marrow megakaryocytes in CIT-induced mice. Furthermore, SXF effectively restored carboplatin-induced alterations in hematopoietic cytokine profiles. SXF treatment altered gut microbial diversity and community structure, particularly reducing the abundance of\n                      <jats:italic>Paraprevotella<\/jats:italic>\n                      and\n                      <jats:italic>Bacteroides<\/jats:italic>\n                      while increasing the abundance of\n                      <jats:italic>Lachnospiraceae_NK4A136<\/jats:italic>\n                      compared with the model group, which is positively correlated with all hematopoietic function indicators (P &amp;lt; 0.001). Metabolomic profiling further revealed that SXF ameliorated the bone marrow metabolic profile in CIT-induced mice. Spearman correlation analysis revealed significant positive associations between\n                      <jats:italic>Parabacteroides<\/jats:italic>\n                      ,\n                      <jats:italic>Prevotellaceae_UCG-001<\/jats:italic>\n                      ,\n                      <jats:italic>Bacillu<\/jats:italic>\n                      s, and unclassified\n                      <jats:italic>Muribaculaceae<\/jats:italic>\n                      with upregulated metabolites, while showing inverse correlations with downregulated metabolites in SXF(H) versus MDL group comparisons. Our findings demonstrate that SXF alleviates CIT in mice by orchestrating a novel gut-bone marrow regulatory axis, bridging gut microbiota and marrow metabolic remodeling.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>In CIT murine models, SXF administration was shown to alleviate carboplatin-induced bone marrow microenvironment injury and accelerate platelet recovery via bidirectional regulation of gut microbiota and marrow metabolic remodeling.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1689477","type":"journal-article","created":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T04:26:58Z","timestamp":1775795218000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Si xian formula (SXF) alleviates carboplatin-induced bone marrow microenvironment damage and promotes thrombocytopenia recovery by regulating gut microbiota and bone marrow metabolites: a correlative study"],"prefix":"10.3389","volume":"17","author":[{"given":"Fang","family":"Li","sequence":"first","affiliation":[{"name":"Sichuan Academy of Chinese Medicine Sciences, Fungal Medicine Institute","place":["Chengdu, Sichuan, China"]},{"name":"Quality Research and Drug Innovation of Traditional Chinese Medicine Key Laboratory of Sichuan Province","place":["Chengdu, Sichuan, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meng-yao","family":"Yu","sequence":"additional","affiliation":[{"name":"Sichuan Academy of Chinese Medicine Sciences, Fungal Medicine Institute","place":["Chengdu, Sichuan, China"]},{"name":"Quality Research and Drug Innovation of Traditional Chinese Medicine Key Laboratory of Sichuan Province","place":["Chengdu, Sichuan, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nan","family":"Jiang","sequence":"additional","affiliation":[{"name":"Sichuan Academy of Chinese Medicine Sciences, Fungal Medicine Institute","place":["Chengdu, Sichuan, China"]},{"name":"Quality Research and Drug Innovation of Traditional Chinese Medicine Key Laboratory of Sichuan Province","place":["Chengdu, Sichuan, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mei-yi","family":"Yao","sequence":"additional","affiliation":[{"name":"Sichuan Academy of Chinese Medicine Sciences, Fungal Medicine Institute","place":["Chengdu, Sichuan, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiao-yan","family":"Xu","sequence":"additional","affiliation":[{"name":"Sichuan Academy of Chinese Medicine Sciences, Fungal Medicine Institute","place":["Chengdu, Sichuan, China"]},{"name":"Quality Research and Drug Innovation of Traditional Chinese Medicine Key Laboratory of Sichuan Province","place":["Chengdu, Sichuan, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Li-ming","family":"He","sequence":"additional","affiliation":[{"name":"Sichuan Academy of Chinese Medicine Sciences, Fungal Medicine Institute","place":["Chengdu, Sichuan, China"]},{"name":"Quality Research and Drug Innovation of Traditional Chinese Medicine Key Laboratory of Sichuan Province","place":["Chengdu, Sichuan, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhou","family":"zhou","sequence":"additional","affiliation":[{"name":"Sichuan Academy of Chinese Medicine Sciences, Fungal Medicine Institute","place":["Chengdu, Sichuan, China"]},{"name":"Quality Research and Drug Innovation of Traditional Chinese Medicine Key Laboratory of Sichuan Province","place":["Chengdu, Sichuan, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xia","family":"Luo","sequence":"additional","affiliation":[{"name":"Sichuan Academy of Chinese Medicine Sciences, Fungal Medicine Institute","place":["Chengdu, Sichuan, China"]},{"name":"Quality Research and Drug Innovation of Traditional Chinese Medicine Key Laboratory of Sichuan Province","place":["Chengdu, Sichuan, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,10]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"2334","DOI":"10.47391\/JPMA.23-99","article-title":"Gut microbiota and myeloproliferative neoplasms","volume":"73","author":"Adeniyi","year":"2023","journal-title":"J. Pak. Med. Assoc."},{"key":"B2","doi-asserted-by":"publisher","first-page":"584","DOI":"10.1111\/j.1349-7006","article-title":"Protective effect of recombinant human leukemia inhibitory factor against thrombocytopenia in carboplatin\u2010treated mice","volume":"88","author":"Akiyama","year":"1997","journal-title":"Jpn. J. Cancer Res."},{"key":"B3","doi-asserted-by":"publisher","first-page":"925","DOI":"10.1007\/s00280-007-0675-5","article-title":"Oxaliplatin-induced immune mediated thrombocytopenia","volume":"62","author":"Beg","year":"2008","journal-title":"Cancer Chemother. Pharmacol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"113180","DOI":"10.1016\/j.biopha.2022.113180","article-title":"Anti-inflammatory and immunoregulatory effects of icariin and icaritin","volume":"151","author":"Bi","year":"2022","journal-title":"Biomed. Pharmacother."},{"key":"B5","doi-asserted-by":"publisher","first-page":"e222","DOI":"10.1002\/mco2.222","article-title":"Protopanaxadiol manipulates gut microbiota to promote bone marrow hematopoiesis and enhance immunity in cyclophosphamide\u2010induced immunosuppression mice","volume":"4","author":"Cao","year":"2023","journal-title":"MedComm"},{"key":"B6","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1007\/978-981-32-9421-9_4","article-title":"Protective effect of ganoderma (lingzhi) on radiation and chemotherapy","volume":"1182","author":"Chen","year":"2019","journal-title":"Adv. Exp. Med. Biol."},{"key":"B7","volume-title":"Pharmacopoeia of the people\u2019s Republic of China","year":"2020"},{"key":"B8","doi-asserted-by":"publisher","first-page":"730776","DOI":"10.3389\/fphar.2021.730776","article-title":"Chinese herbal medicine therapy reduces the risks of overall and anemia-related mortalities in patients with aplastic anemia: a nationwide retrospective study in Taiwan","volume":"12","author":"Chiu","year":"2021","journal-title":"Front. Pharmacol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"861","DOI":"10.1615\/IntJMedMushrooms.2017024537","article-title":"The efficacy and toxicity of using the lingzhi or reishi medicinal mushroom, Ganoderma lucidum (agaricomycetes), and its products in chemotherapy","volume":"19","author":"Cizmarikova","year":"2017","journal-title":"Int. J. Med. Mushrooms"},{"key":"B10","doi-asserted-by":"publisher","first-page":"1848","DOI":"10.1016\/j.devcel.2021.05.018","article-title":"Niches that regulate stem cells and hematopoiesis in adult bone marrow","volume":"56","author":"Comazzetto","year":"2021","journal-title":"Dev. Cell."},{"key":"B11","doi-asserted-by":"publisher","first-page":"264","DOI":"10.1055\/s-0039-1697930","article-title":"Drug-induced thrombocytopenia: mechanisms and laboratory diagnostics","volume":"46","author":"Danese","year":"2020","journal-title":"Semin. Thromb. Hemost."},{"key":"B12","doi-asserted-by":"publisher","first-page":"835","DOI":"10.1038\/s44161-023-00325-8","article-title":"Critical shifts in lipid metabolism promote megakaryocyte differentiation and proplatelet formation","volume":"2","author":"De Jonckheere","year":"2023","journal-title":"Nat. Cardiovasc. Res."},{"key":"B13","doi-asserted-by":"publisher","first-page":"885","DOI":"10.1080\/01635581.2024.2383336","article-title":"Cancer-related therapeutic potential of epimedium and its extracts","volume":"76","author":"Ding","year":"2024","journal-title":"Nutr. Cancer"},{"key":"B15","doi-asserted-by":"publisher","first-page":"450","DOI":"10.1021\/acs.jafc.4c06905","article-title":"Immunomodulatory acidic polysaccharide from jujube fruit (Zizyphus jujuba mill.): insight into their chemical characteristics and modes of action","volume":"73","author":"Feng","year":"2025","journal-title":"J. Agricultural Food Chemistry"},{"key":"B16","doi-asserted-by":"publisher","first-page":"1689","DOI":"10.1182\/blood.2023021174","article-title":"Blood and guts: how the intestinal microbiome shapes hematopoiesis and treatment of hematologic disease","volume":"143","author":"Fernandez","year":"2024","journal-title":"Blood"},{"key":"B17","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1097\/NAN.0000000000000204","article-title":"Thrombocytopenia: a destruction of platelets","volume":"40","author":"Greenberg","year":"2017","journal-title":"J. Infus. Nurs."},{"key":"B19","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1038\/s41421-024-00665-0","article-title":"Microplastics dampen the self-renewal of hematopoietic stem cells by disrupting the gut microbiota-hypoxanthine-wnt axis","volume":"10","author":"Jiang","year":"2024","journal-title":"Cell Discov."},{"key":"B20","first-page":"282","article-title":"Managing thrombocytopenia associated with cancer chemotherapy","volume":"29","author":"Kuter","year":"2015","journal-title":"Oncol. Willist. Park"},{"key":"B21","doi-asserted-by":"publisher","first-page":"1243","DOI":"10.3324\/haematol.2021.279512","article-title":"Treatment of chemotherapy-induced thrombocytopenia in patients with non-hematologic malignancies","volume":"107","author":"Kuter","year":"2022","journal-title":"Haematologica"},{"key":"B22","doi-asserted-by":"publisher","first-page":"6118","DOI":"10.3390\/molecules28166118","article-title":"Pharmacological effects of astragaloside IV: a review","volume":"28","author":"Liang","year":"2023","journal-title":"Molecules"},{"key":"B23","doi-asserted-by":"publisher","first-page":"1421","DOI":"10.1007\/s00253-015-7039-6","article-title":"Denitrifying sulfide removal process on high-salinity wastewaters in the presence of halomonassp","volume":"100","author":"Liu","year":"2016","journal-title":"Appl. Microbiology Biotechnology"},{"key":"B24","doi-asserted-by":"publisher","first-page":"2330","DOI":"10.1007\/s12094-022-02919-3","article-title":"Interaction between gut microbiota and tumour chemotherapy","volume":"24","author":"Liu","year":"2022","journal-title":"Clin. Transl. Oncol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"1338178","DOI":"10.3389\/fimmu.2024.1338178","article-title":"The impact of gut microbial signals on hematopoietic stem cells and the bone marrow microenvironment","volume":"15","author":"Liu","year":"2024","journal-title":"Front. Immunol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1097\/MOH.0000000000000621","article-title":"Structural organization of the bone marrow and its role in hematopoiesis","volume":"28","author":"Lucas","year":"2021","journal-title":"Curr. Opin. Hematol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"216621","DOI":"10.1016\/j.canlet.2024.216621","article-title":"Icaritin with autophagy\/mitophagy inhibitors synergistically enhances anticancer efficacy and apoptotic effects through PINK1\/Parkin-mediated mitophagy in hepatocellular carcinoma","volume":"587","author":"Luo","year":"2024","journal-title":"Cancer Lett."},{"key":"B28","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1111\/bjh.12758","article-title":"Interpreting the developmental dance of the megakaryocyte: a review of the cellular and molecular processes mediating platelet formation","volume":"165","author":"Machlus","year":"2014","journal-title":"Br. J. Haematol."},{"key":"B29","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1007\/978-3-030-20315-3_9","article-title":"Management of thrombocytopenia in cancer patients","volume-title":"Thrombosis and hemostasis in cancer, cancer treatment and research","author":"Mones","year":"2019"},{"key":"B30","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1177\/1534735415607319","article-title":"Curculigo orchioides gaertn effectively ameliorates the Uro- and nephrotoxicities induced by cyclophosphamide administration in experimental animals","volume":"15","author":"Murali","year":"2016","journal-title":"Integr. Cancer Ther."},{"key":"B31","doi-asserted-by":"publisher","first-page":"303","DOI":"10.1038\/s41580-019-0103-9","article-title":"Haematopoietic stem cell activity and interactions with the niche","volume":"20","author":"Pinho","year":"2019","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"e214708","DOI":"10.1001\/jamanetworkopen.2021.4708","article-title":"Estimated projection of US cancer incidence and death to 2040","volume":"4","author":"Rahib","year":"2021","journal-title":"JAMA Netw. Open"},{"key":"B33","doi-asserted-by":"publisher","first-page":"598","DOI":"10.4103\/ijmr.ijmr_1821_22","article-title":"Cancer incidence estimates for 2022 and projection for 2025: result from national cancer registry programme, India","volume":"156","author":"Sathishkumar","year":"2022","journal-title":"Indian J. Med. Res."},{"key":"B34","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1200\/JCO.2017.76.1734","article-title":"Platelet transfusion for patients with cancer: american society of clinical oncology clinical practice guideline update","volume":"36","author":"Schiffer","year":"2018","journal-title":"J. Clin. Oncol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"662","DOI":"10.1111\/ejh.13595","article-title":"The incidence of thrombocytopenia in adult patients receiving chemotherapy for solid tumors or hematologic malignancies","volume":"106","author":"Shaw","year":"2021","journal-title":"Eur. J Haematol."},{"key":"B36","first-page":"1282","article-title":"Ganoderma lucidum enhances carboplatin chemotherapy effect by inhibiting the DNA damage response pathway and stemness","volume":"12","author":"Su\u00e1rez-Arroyo","year":"2022","journal-title":"Am. J. Cancer Res."},{"key":"B37","first-page":"153","article-title":"Efficacy of sixian granules in the treatment of thrombocytopenia after chemotherapy","volume":"42","author":"Tang","year":"2024","journal-title":"Sihcuanzhongyi"},{"key":"B38","doi-asserted-by":"publisher","first-page":"1151","DOI":"10.2165\/11594310-000000000-00000","article-title":"Thrombocytopenia in adult cancer patients receiving cytotoxic chemotherapy: results from a retrospective hospital-based cohort study","volume":"34","author":"Ten Berg","year":"2011","journal-title":"Drug Saf."},{"key":"B39","doi-asserted-by":"publisher","first-page":"e18024","DOI":"10.1016\/j.heliyon.2023.e18024","article-title":"Integration of gut microbiota and metabolomics for the hematopoiesis of siwu paste on anemia rats","volume":"9","author":"Wan","year":"2023","journal-title":"Heliyon"},{"key":"B40","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1186\/s40168-019-0721-7","article-title":"Longitudinal investigation of the swine gut microbiome from birth to market reveals stage and growth performance associated bacteria","volume":"7","author":"Wang","year":"2019","journal-title":"Microbiome"},{"key":"B41","doi-asserted-by":"publisher","first-page":"e32831","DOI":"10.1016\/j.heliyon.2024.e32831","article-title":"How aging influences the gut-bone marrow axis and alters hematopoietic stem cell regulation","volume":"10","author":"Wells","year":"2024","journal-title":"Heliyon"},{"key":"B42","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1186\/s12885-019-5354-5","article-title":"Risk and consequences of chemotherapy-induced thrombocytopenia in US clinical practice","volume":"19","author":"Weycker","year":"2019","journal-title":"BMC Cancer"},{"key":"B43","doi-asserted-by":"publisher","first-page":"6290","DOI":"10.3390\/ijms23116290","article-title":"Carboplatin-induced thrombocytopenia through JAK2 downregulation, S-phase cell cycle arrest and apoptosis in megakaryocytes","volume":"23","author":"Wu","year":"2022","journal-title":"Int. J. Mol. Sci."},{"key":"B44","doi-asserted-by":"publisher","first-page":"4718","DOI":"10.7150\/jca.26690","article-title":"A randomized controlled study of rhTPO and rhIL-11 for the prophylactic treatment of chemotherapy-induced thrombocytopenia in non-small cell lung cancer","volume":"9","author":"Xu","year":"2018","journal-title":"J. Cancer"},{"key":"B45","doi-asserted-by":"publisher","first-page":"132057","DOI":"10.1016\/j.jhazmat.2023.132057","article-title":"Adverse effect of oxidized cholesterol exposure on colitis is mediated by modulation of gut microbiota","volume":"459","author":"Yan","year":"2023","journal-title":"J. Hazard. Mater."},{"key":"B46","doi-asserted-by":"publisher","first-page":"2709","DOI":"10.21037\/apm-22-880","article-title":"Cost-effectiveness analysis of rhTPO and rhIL-11 in the treatment of chemotherapy-induced thrombocytopenia in hematological tumors based on real-world data","volume":"11","author":"Zhang","year":"2022","journal-title":"Ann. Palliat. Med."},{"key":"B47","doi-asserted-by":"publisher","first-page":"e112348","DOI":"10.15252\/embj.2022112348","article-title":"Bidirectional interplay between metabolism and epigenetics in hematopoietic stem cells and leukemia","volume":"42","author":"Zhang","year":"2023","journal-title":"EMBO J."},{"key":"B48","doi-asserted-by":"publisher","first-page":"2350784","DOI":"10.1080\/19490976.2024.2350784","article-title":"Ecological insights into hematopoiesis regulation: unraveling the influence of gut microbiota","volume":"16","author":"Zheng","year":"2024","journal-title":"Gut Microbes"},{"key":"B49","doi-asserted-by":"publisher","first-page":"274","DOI":"10.1002\/bjs.5719","article-title":"Chemotherapy-associated hepatotoxicity and surgery for colorectal liver metastases","volume":"94","author":"Zorzi","year":"2007","journal-title":"Br. J. Surg."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1689477\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T04:26:59Z","timestamp":1775795219000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1689477\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,10]]},"references-count":47,"alternative-id":["10.3389\/fphar.2026.1689477"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2026.1689477","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,10]]},"article-number":"1689477"}}