2. Academic Validation
  3. Neutrophil elastase inhibitor (MPH-966) improves intestinal mucosal damage and gut microbiota in a mouse model of 5-fluorouracil-induced intestinal mucositis

Neutrophil elastase inhibitor (MPH-966) improves intestinal mucosal damage and gut microbiota in a mouse model of 5-fluorouracil-induced intestinal mucositis

  • Biomed Pharmacother. 2021 Feb;134:111152. doi: 10.1016/j.biopha.2020.111152.
Kung-Ju Chen 1,  Yu-Li Chen 2,  Shir-Hwa Ueng 3,  Tsong-Long Hwang 4,  Liang-Mou Kuo 5,  Pei-Wen Hsieh 6
Affiliations

Affiliations

  • 1 Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Graduate Institute of Natural Products, School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
  • 2 Graduate Institute of Natural Products, School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
  • 3 Department of Pathology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan.
  • 4 Graduate Institute of Natural Products, School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Department of Anesthesiology, Chang Gung Memorial Hospital, Linkou, Taiwan; Research Center for Chinese Herbal Medicine, Chang Gung University of Science and Technology, Taoyuan, Taiwan; Chinese Herbal Medicine Research Team, Healthy Aging Research Center, Chang Gung University, Taoyuan, Taiwan; Department of Chemical Engineering, Ming Chi University of Technology, New Taipei City, Taiwan.
  • 5 Department of General Surgery, Chang Gung Memorial Hospital, Chiayi, 613, Taiwan. Electronic address: abcd2438@adm.cgmh.org.tw.
  • 6 Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Graduate Institute of Natural Products, School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Department of Anesthesiology, Chang Gung Memorial Hospital, Linkou, Taiwan; Research Center for Chinese Herbal Medicine, Chang Gung University of Science and Technology, Taoyuan, Taiwan. Electronic address: pewehs@mail.cgu.edu.tw.
PMID: 33373916 DOI: 10.1016/j.biopha.2020.111152
Abstract

Background: 5-Fluorouracil (5-FU)-based chemotherapy is first-line chemotherapy for colorectal Cancer. However, 5-FU-induced intestinal mucositis (FUIIM) is a common adverse effect that severely impairs drug tolerance and results in poor patient health.

Methods: Male C57BL/6 mice were given 5-FU (50 mg/kg/day, i.p.) and treated with MPH-966 (5 and 7.5 mg/kg/day, p.o.) for five days. The body weight loss and the amount of food intake, and histopathological findings were recorded and analyzed. In addition, the neutrophil infiltration, levels of neutrophil serine proteases and pro-inflammatory cytokines, and tight junction proteins expression in intestinal tissues were determined. The ecology of gut microbiota was performed through next-generation Sequencing technologies.

Results: Neutrophil Elastase (NE) overexpression is a key feature in FUIIM. This study showed that treatment with the specific NE inhibitor MPH-966 (7.5 mg/kg/day, p.o.) significantly reversed 5-FU-induced loss in body weight and food intake; reversed villous atrophy; significantly suppressed myeloperoxidase, NE, and proteinase 3 activity; and reduced pro-inflammatory cytokine expression in an FUIIM mouse model. In addition, MPH-966 prevented 5-FU-induced intestinal barrier dysfunction, as indicated by the modulated expression of the tight junction proteins zonula occludin-1 and occludin. MPH-966 also reversed 5-FU-induced changes in gut microbiota diversity and abundances, specifically the Firmicutes-to-Bacteroidetes ratio; Muribaculaceae, Ruminococcaceae, and Eggerthellaceae abundances at the family level; and Candidatus Arthromitus abundance at the genus level.

Conclusion: These data indicate that NE inhibitor is a key treatment candidate to alleviate FUIIM by regulating abnormal inflammatory responses, intestinal barrier dysfunction, and gut microbiota imbalance.

Keywords

5-Fluorouracil; Gut microbiota; Intestinal mucositis; MPH-966; Neutrophil elastase.

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