{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T06:47:57Z","timestamp":1785739677431,"version":"3.56.0"},"reference-count":36,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004731","name":"Zhejiang Provincial Natural Science Foundation of China","doi-asserted-by":"publisher","award":["LQ23C020001"],"award-info":[{"award-number":["LQ23C020001"]}],"id":[{"id":"10.13039\/501100004731","id-type":"DOI","asserted-by":"publisher"}]},{"award":["LQ23C020001"],"award-info":[{"award-number":["LQ23C020001"]}],"id":[{"id":"https:\/\/ror.org\/04aqat463","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Wenzhou Basic Scientific Research Project","award":["Y2023201"],"award-info":[{"award-number":["Y2023201"]}]},{"name":"General Project of Zhejiang Provincial Department of Education","award":["Y202250066"],"award-info":[{"award-number":["Y202250066"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background: Chemotherapy-induced intestinal mucositis (CIM) is a common gastrointestinal complication of anticancer therapy, and 5-fluorouracil (5-FU) is among the agents most frequently implicated. Betulin (BE), a lupane-type pentacyclic triterpenoid with anti-inflammatory and cytoprotective activities, has not been systematically evaluated in 5-FU-induced CIM. Purpose: This study evaluated the therapeutic effects of BE in a mouse model of 5-FU-induced CIM and examined associated histopathological, apoptotic, inflammatory, and gut microbiota changes. Methods: BALB\/c mice received intraperitoneal 5-FU (30 mg\/kg\/day) for four consecutive days, followed by oral BE at 0, 50, 100, 200, or 400 mg\/kg\/day for another four days. Clinical manifestations, colon morphometry, blinded descriptive histopathological assessment, apoptosis- and inflammation-related markers, and gut microbiota were assessed. Results: BE treatment alleviated body weight loss, diarrhea, and reduced food intake and was associated with improved colon morphometry and less severe histological injury. At 200 mg\/kg, BE treatment was associated with lower Tnf and Nos2 mRNA expression, lower Bax and total caspase-3 protein abundance, higher Bcl-2 protein abundance, and lower iNOS protein abundance. Microbiota analysis of the 200 mg\/kg group showed treatment-associated differences in microbial diversity and community composition; these findings were considered exploratory because of the small sample size. Conclusions: BE showed therapeutic potential in 5-FU-induced intestinal mucositis. The molecular and microbiota findings obtained at 200 mg\/kg support associations with apoptosis-, inflammation-, and microbiota-related changes but do not establish a definitive mechanism.<\/jats:p>","DOI":"10.3390\/nu18152487","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T06:17:40Z","timestamp":1785737860000},"page":"2487","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Betulin Alleviates 5-Fluorouracil-Induced Intestinal Mucositis in Mice"],"prefix":"10.3390","volume":"18","author":[{"given":"Shiyi","family":"Sun","sequence":"first","affiliation":[{"name":"National and Local Joint Engineering Research Center of Ecological Treatment Technology for Urban Water Pollution, Zhejiang Provincial Key Laboratory for Water Environment and Marine Biological Resources Protection, College of Life and Environmental Science, Wenzhou University, Wenzhou 325035, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziming","family":"Wang","sequence":"additional","affiliation":[{"name":"National and Local Joint Engineering Research Center of Ecological Treatment Technology for Urban Water Pollution, Zhejiang Provincial Key Laboratory for Water Environment and Marine Biological Resources Protection, College of Life and Environmental Science, Wenzhou University, Wenzhou 325035, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haoyue","family":"Xu","sequence":"additional","affiliation":[{"name":"National and Local Joint Engineering Research Center of Ecological Treatment Technology for Urban Water Pollution, Zhejiang Provincial Key Laboratory for Water Environment and Marine Biological Resources Protection, College of Life and Environmental Science, Wenzhou University, Wenzhou 325035, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengheng","family":"Dai","sequence":"additional","affiliation":[{"name":"National and Local Joint Engineering Research Center of Ecological Treatment Technology for Urban Water Pollution, Zhejiang Provincial Key Laboratory for Water Environment and Marine Biological Resources Protection, College of Life and Environmental Science, Wenzhou University, Wenzhou 325035, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenhannian","family":"Li","sequence":"additional","affiliation":[{"name":"National and Local Joint Engineering Research Center of Ecological Treatment Technology for Urban Water Pollution, Zhejiang Provincial Key Laboratory for Water Environment and Marine Biological Resources Protection, College of Life and Environmental Science, Wenzhou University, Wenzhou 325035, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengcheng","family":"Ying","sequence":"additional","affiliation":[{"name":"National and Local Joint Engineering Research Center of Ecological Treatment Technology for Urban Water Pollution, Zhejiang Provincial Key Laboratory for Water Environment and Marine Biological Resources Protection, College of Life and Environmental Science, Wenzhou University, Wenzhou 325035, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayimnisa","family":"Ayitniyaz","sequence":"additional","affiliation":[{"name":"National and Local Joint Engineering Research Center of Ecological Treatment Technology for Urban Water Pollution, Zhejiang Provincial Key Laboratory for Water Environment and Marine Biological Resources Protection, College of Life and Environmental Science, Wenzhou University, Wenzhou 325035, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changmin","family":"Shao","sequence":"additional","affiliation":[{"name":"Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou 325001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiwei","family":"Hu","sequence":"additional","affiliation":[{"name":"National and Local Joint Engineering Research Center of Ecological Treatment Technology for Urban Water Pollution, Zhejiang Provincial Key Laboratory for Water Environment and Marine Biological Resources Protection, College of Life and Environmental Science, Wenzhou University, Wenzhou 325035, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"108689","DOI":"10.1016\/j.pharmthera.2024.108689","article-title":"Vitamins and fatty acids against chemotherapy-induced intestinal mucositis","volume":"261","author":"Alcorta","year":"2024","journal-title":"Pharmacol. Ther."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1778","DOI":"10.1056\/NEJMoa2309863","article-title":"Nivolumab plus gemcitabine-cisplatin in advanced urothelial carcinoma","volume":"389","author":"Sonpavde","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1056\/NEJMoa2503119","article-title":"Trastuzumab deruxtecan or ramucirumab plus paclitaxel in gastric cancer","volume":"393","author":"Shitara","year":"2025","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1677","DOI":"10.1016\/j.apsb.2023.12.015","article-title":"Eubacterium coprostanoligenes alleviates chemotherapy-induced intestinal mucositis by enhancing intestinal mucus barrier","volume":"14","author":"Bai","year":"2024","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"114644","DOI":"10.1016\/j.biopha.2023.114644","article-title":"Review on the effect of chemotherapy on the intestinal barrier: Epithelial permeability, mucus and bacterial translocation","volume":"162","author":"Dahlgren","year":"2023","journal-title":"Biomed. Pharmacother."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"117545","DOI":"10.1016\/j.carbpol.2020.117545","article-title":"Oyster polysaccharides ameliorate intestinal mucositis and improve metabolism in 5-fluorouracil-treated S180 tumour-bearing mice","volume":"256","author":"Cai","year":"2021","journal-title":"Carbohydr. Polym."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Lin, J.G., Sun, Y.W., Wu, W.L., Jiang, W.-P., Zhung, F.-Y., and Huang, G.-J. (2025). Multi-target protective effects of sanghuangporus sanghuang against 5-fluorouracil-induced intestinal injury through suppression of inflammation, oxidative stress, epithelial-mesenchymal transition, and tight junction. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26073444"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"112519","DOI":"10.1016\/j.jep.2019.112519","article-title":"Patchouli oil ameliorates 5-fluorouracil-induced intestinal mucositis in rats via protecting intestinal barrier and regulating water transport","volume":"250","author":"Gan","year":"2020","journal-title":"J. Ethnopharmacol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"155492","DOI":"10.1016\/j.phymed.2024.155492","article-title":"Astragalus polysaccharides attenuate chemotherapy-induced immune injury by modulating gut microbiota and polyunsaturated fatty acid metabolism","volume":"128","author":"Wang","year":"2024","journal-title":"Phytomedicine"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1038\/s41565-023-01346-x","article-title":"Artificial-enzymes-armed Bifidobacterium longum probiotics for alleviating intestinal inflammation and microbiota dysbiosis","volume":"18","author":"Cao","year":"2023","journal-title":"Nat. Nanotechnol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e2411939","DOI":"10.1002\/advs.202411939","article-title":"Orally administered functional polyphenol-nanozyme-armored probiotics for enhanced amelioration of intestinal inflammation and microbiota dysbiosis","volume":"12","author":"Zhu","year":"2025","journal-title":"Adv. Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.bbi.2019.02.020","article-title":"Impact of 5 fluorouracil chemotherapy on gut inflammation, functional parameters, and gut microbiota","volume":"80","author":"Sougiannis","year":"2019","journal-title":"Brain Behav. Immun."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Qu, L., Tan, W., Yang, J., Lai, L., Liu, S., Wu, J., and Zou, W. (2020). Combination compositions composed of l-glutamine and si-jun-zi-tang might be a preferable choice for 5-fluorouracil-induced intestinal mucositis: An exploration in a mouse model. Front. Pharmacol., 11.","DOI":"10.3389\/fphar.2020.00918"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"117612","DOI":"10.1016\/j.lfs.2020.117612","article-title":"Protective effect of Andrographolide on 5-Fu induced intestinal mucositis by regulating p38 MAPK signaling pathway","volume":"252","author":"Xiang","year":"2020","journal-title":"Life Sci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"107409","DOI":"10.1016\/j.biotechadv.2019.06.008","article-title":"Betulin and its derivatives as novel compounds with different pharmacological effects","volume":"38","author":"Amiri","year":"2020","journal-title":"Biotechnol. Adv."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Adepoju, F.O., Duru, K.C., Li, E., Kovaleva, E.G., and Tsurkan, M.V. (2023). Pharmacological potential of betulin as a multitarget compound. Biomolecules, 13.","DOI":"10.3390\/biom13071105"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Ning, S.Y., Zang, J., Zhang, B.Y., Feng, X., and Qiu, F. (2022). Botanical drugs in traditional chinese medicine with wound healing properties. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.885484"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Kruszniewska-Rajs, C., Strza\u0142ka-Mrozik, B., Kimsa-Dudek, M., Synowiec-Wojtarowicz, A., Chrobak, E., B\u0119benek, E., Boryczka, S., G\u0142uszek, S., and Gola, J.M. (2022). The influence of betulin and its derivatives EB5 and ECH147 on the antioxidant status of human renal proximal tubule epithelial cells. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23052524"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Madej, M., Gola, J., and Chrobak, E. (2023). Synthesis, Pharmacological properties, and potential molecular mechanisms of antitumor activity of betulin and its derivatives in gastrointestinal cancers. Pharmaceutics, 15.","DOI":"10.3390\/pharmaceutics15122768"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"540","DOI":"10.4062\/biomolther.2022.093","article-title":"Betulin, an anti-inflammatory triterpenoid compound, regulates MUC5AC mucin gene expression through NF-kB signaling in human airway epithelial cells","volume":"30","author":"Hossain","year":"2022","journal-title":"Biomol. Ther."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"112539","DOI":"10.1016\/j.fct.2021.112539","article-title":"Anti-inflammatory action of betulin and its potential as a dissociated glucocorticoid receptor modulator","volume":"157","author":"Ren","year":"2021","journal-title":"Food Chem. Toxicol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"10059","DOI":"10.1002\/fsn3.4639","article-title":"Chemopreventive and chemotherapeutic potential of betulin and betulinic acid: Mechanistic insights from in vitro, in vivo and clinical studies","volume":"12","author":"Nemli","year":"2024","journal-title":"Food Sci. Nutr."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"103750","DOI":"10.1016\/j.etap.2021.103750","article-title":"Anti-inflammatory\/anti-apoptotic impact of betulin attenuates experimentally induced ulcerative colitis: An insight into TLR4\/NF-kB\/caspase signalling modulation","volume":"88","author":"Eisa","year":"2021","journal-title":"Environ. Toxicol. Pharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Chen, H.Y., Han, X., and Pang, J.W. (2020). Parameter optimization and potential bioactivity evaluation of a betulin extract from white birch bark. Plants, 9.","DOI":"10.3390\/plants9030392"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1038\/s41538-025-00473-0","article-title":"Improved gut microbiota by selenium-enriched Bifidobacterium longum DD98 alleviates chemotherapy-induced intestinal mucositis via inhibiting the STING pathway","volume":"9","author":"Qiu","year":"2025","journal-title":"NPJ Sci. Food"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"6551","DOI":"10.1038\/s41598-022-10564-7","article-title":"Baicalin regulates autophagy to interfere with small intestinal acute graft-versus-host disease","volume":"12","author":"Sun","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"852","DOI":"10.1038\/s41587-019-0209-9","article-title":"Reproducible, interactive, scalable and extensible microbiome data science using QIIME 2","volume":"37","author":"Bolyen","year":"2019","journal-title":"Nat. Biotechnol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1016\/j.tem.2023.05.006","article-title":"Gut microbiota controlling radiation-induced enteritis and intestinal regeneration","volume":"34","author":"Moraitis","year":"2023","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1016\/j.ejphar.2018.12.014","article-title":"Diadzein ameliorates 5-fluorouracil-induced intestinal mucositis by suppressing oxidative stress and inflammatory mediators in rodents","volume":"843","author":"Atiq","year":"2019","journal-title":"Eur. J. Pharmacol."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Machado, G.F., Pereira, Q.C., Fagundes, F.L., Em\u00edlio-Silva, M.T., Rodrigues, V.P., Pati\u00f1o, M.d.A., Jorge, G.I., Pereira, J.A., Martinez, C.A.R., and Hiruma-Lima, C.A. (2025). The anthocyanidins malvidin and cyanidin alleviate irinotecan-triggered intestinal mucositis by modulating oxidative stress and cytokine release. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms262110747"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Chang, C.W., Lee, H.C., Li, L.H., Chiau, J.-S.C., Wang, T.-E., Chuang, W.-H., Chen, M.-J., Wang, H.-Y., Shih, S.-C., and Liu, C.-Y. (2020). Fecal microbiota transplantation prevents intestinal injury, upregulation of toll-like receptors, and 5-fluorouracil\/oxaliplatin-induced toxicity in colorectal cancer. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21020386"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Wr\u00f3blewska-\u0141uczka, P., Cabaj, J., B\u0105k, W., Bargie\u0142, J., Grabarska, A., G\u00f3ralczyk, A., and \u0141uszczki, J.J. (2022). Additive Interactions between Betulinic Acid and Two Taxanes in In Vitro Tests against Four Human Malignant Melanoma Cell Lines. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23179641"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"114150","DOI":"10.1016\/j.ecoenv.2022.114150","article-title":"Inhibition of the NF-\u03baB pathway and ERK-mediated mitochondrial apoptotic pathway takes part in the mitigative effect of betulinic acid on inflammation and oxidative stress in cyclophosphamide-triggered renal damage of mice","volume":"246","author":"Zhu","year":"2022","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1186\/s12974-020-02042-6","article-title":"Oleanolic acid ameliorates intestinal alterations associated with EAE","volume":"17","author":"Gutierrez","year":"2020","journal-title":"J. Neuroinflammation"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"126","DOI":"10.3892\/mmr.2026.13836","article-title":"Mechanisms and therapeutic potential of glycyrrhizic acid: Insights into key signaling pathways and disease modulation (Review)","volume":"33","author":"Yu","year":"2026","journal-title":"Mol. Med. Rep."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Alam, M., Ali, S., Ahmed, S., Elasbali, A.M., Adnan, M., Islam, A., Hassan, I., and Yadav, D.K. (2021). Therapeutic Potential of Ursolic Acid in Cancer and Diabetic Neuropathy Diseases. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222212162"}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/18\/15\/2487\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T06:28:02Z","timestamp":1785738482000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/18\/15\/2487"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,1]]},"references-count":36,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["nu18152487"],"URL":"https:\/\/doi.org\/10.3390\/nu18152487","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,1]]}}}