Dietary Factors Modulate Gastrointestinal Adverse Effects of Methotrexate

  • Higuchi Takashi
    Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, Japan
  • Yoshimura Mika
    Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, Japan
  • Oka Shomi
    Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, Japan Clinical Research Center for Allergy and Rheumatology, National Hospital Organization Sagamihara National Hospital, Japan
  • Kawasaki Aya
    Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, Japan
  • Warabi Eiji
    Environmental Molecular Biology Laboratory, Faculty of Medicine, University of Tsukuba, Japan
  • Mizuno Seiya
    Laborarory Animal Resource Center, University of Tsukuba, Japan
  • Ono Masao
    Department of Clinical Laboratory, National Hospital Organization Mito Medical Center, Japan
  • Takahashi Satoru
    Department of Anatomy and Embryology, Faculty of Medicine, University of Tsukuba, Japan
  • Tohma Shigeto
    Clinical Research Center for Allergy and Rheumatology, National Hospital Organization Sagamihara National Hospital, Japan
  • Tsuchiya Naoyuki
    Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, Japan
  • Furukawa Hiroshi
    Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, Japan Clinical Research Center for Allergy and Rheumatology, National Hospital Organization Sagamihara National Hospital, Japan

Abstract

<p>Background: Methotrexate (MTX) is the most commonly used disease modifying anti-rheumatic drug. Gastrointestinal adverse effects are often observed during the treatment of rheumatoid arthritis; MTX is discontinued due to these adverse effects. It has been suspected that dietary factors may modulate gastrointestinal adverse effects of MTX, but it remains unresolved. In the present study, we tried to reveal the effects of the dietary factors on the gastrointestinal toxicity of MTX. </p><p>Methods: C57BL/6J male mice were fed normal chow (NC) or high fat high sucrose diet (HFHSD) for 14 days before the gavage administration of MTX (3mg/kg/day) and survival rate and body weight were observed. Effects of high fat diet, high sucrose diet, high fat high sucrose soybean diet (casein was replaced by soybean derived protein), folinic acid (2.6mg/kg/day), and omega-3 fatty acid (1500mg/kg/day) were evaluated. HFHSD was changed to NC 24h before starting administration of MTX. Mice were given vancomycin (0.5g/L) in their drinking water. </p><p>Results: The administration of MTX significantly decreased survival rates of mice fed HFHSD compared with mice fed NC (p=0.0002, log-rank test). The body weight of MTX treated HFHSD fed mice were significantly decreased (p<0.05, U test). The intestinal epithelial damage was detected in MTX treated HFHSD fed mice (Figure). Plasma concentrations of MTX were comparable between these groups, but the amounts of excreted MTX in feces were reduced in mice fed HFHSD. High sucrose diet improved the survival rates compared with mice fed HFHSD, but high fat diet did not. Feeding diet that replaced casein of HFHSD with soybean derived protein increased the survival rates. Intraperitoneal administration of folinic acid rescued the MTX treated mice fed HFHSD. Oral administration of omega-3 fatty acid was tended to improve the survival of mice fed HFHSD. When HFHSD was changed to NC, mice were rescued in spite of obesity. Vancomycin treatment reduced the survival rates of mice fed NC. </p><p>Conclusion: It was suggested that HFHSD could modify the toxicity of MTX on intestinal epithelia due to the altered distribution of MTX and was probably mediated by the changed intestinal microbiota or their metabolites. </p>

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