ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Ethnopharmacology
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1623726
Daikenchuto improves methotrexate-induced chronic small intestinal mucositis by promoting angiogenesis
Provisionally accepted
Peilin Li1
Yusuke Inoue1
Daichi Sadatomi2
Sachiko Mogami2Daisuke Miyamoto1Toshiyuki Adachi1
Tomohiko Adachi1Akihiko Soyama1
Kengo Kanetaka1
Wei-Li Gu3
Susumu Eguchi1*- 1Department of Surgery, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
- 2Tsumura Kampo Research Laboratories, Tsumura ＆ Co., Ibaraki, Japan, ibaraki, Japan
- 32. Department of Surgery, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, China, Guangzhou, China
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Aim CIM is a severe gastrointestinal complication that has limited treatment options.This study investigated the potential therapeutic effects of DKT, a traditional medicine, on mitigating methotrexate (MTX)-induced CIM in rats.Methods Male Sprague-Dawley rats were assigned to four groups: control, MTX, DKT-MTX, and DKT. CIM was induced by intraperitoneal administration of MTX (10 mg/kg every 6 days), while DKT (2.7% wt/wt) was orally administered via feed. The surviving rats were euthanized on day 60. Rat intestinal epithelial cells (IEC-6) were used to examine DKT's cytoprotective effects in vitro.DKT treatment improved survival, reduced gastrointestinal symptoms, and alleviated histological damage, including villus atrophy and crypt hyperplasia. DKT restored mucosal integrity by enhancing the expression of tight junction proteins (CLDN-3) and nutrient transporters (B0,+AT, EAAT3), and by reducing oxidative stress and epithelial cell death. Furthermore, DKT promoted mucosal angiogenesis, as evidenced by increased expression of CD34, VEGFR2, and VEGFA in both tissues and cells. qRT-PCR confirmed upregulation of genes associated with angiogenesis, barrier repair, and mucosal regeneration. Conclusion DKT exerts protective effects against MTX-induced CIM by enhancing angiogenesis, promoting epithelial regeneration, and restoring mucosal barrier function. These findings suggest DKT as a promising adjunctive therapy for managing chronic intestinal toxicity induced by chemotherapy.
Keywords: chemotherapy, Methotrexate, intestinal mucositis, Daikenchuto, Angiogenesis
Received: 06 May 2025; Accepted: 08 Aug 2025.
Copyright: © 2025 Li, Inoue, Sadatomi, Mogami, Miyamoto, Adachi, Adachi, Soyama, Kanetaka, Gu and Eguchi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Susumu Eguchi, Department of Surgery, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
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