Submitted on May 22, 2008
Revised on October 15, 2008
Accepted on October 31, 2008
Methotrexate induces intestinal mucositis and alters gut protein metabolism independently of reduced food intake
Nabile Boukhettala1, Jonathan LEBLOND1, Sophie Claeyssens2, Magali Faure3, Florence Le Pessot4, Christine Bôle-Feysot1, Aktham Hassan1, Christine Mettraux3, Jacques Vuichoud3, Alain Lavoinne2, Denis Breuillé3, Pierre Déchelotte1, and Moïse Coeffier1*
1 ADEN - EA4311, Institute for Biomedical Research and European Institute for Peptide Research (IFRMP23), Rouen University and Rouen University Hospital, Rouen, France
2 Laboratory of Medical Biochemistry, Rouen University Hospital, Rouen, France
3 Nestlé Research Center, Nutrition & Health Department, Lausanne, Switzerland
4 Laboratory of Anatomo-Pathology, Rouen University Hospital, Rouen, France
* To whom correspondence should be addressed. E-mail: moise.coeffier{at}univ-rouen.fr.
One of the main secondary toxic side effects of antimitotic agents used to treat cancer patients is intestinal mucositis. This one is characterized by compromised digestive and absorptive functions, barrier integrity and immune competence. In the same time, food intake is decreased and may induce intestinal damages per se. The aim of the study was to characterize which alterations are specific to methotrexate, independently of the anorexic effect of the drug. Male Sprague-Dawley rats received subcutaneously saline solution as control group or 2.5 mg/kg of methotrexate during three days (D0-D2). Methotrexate-treated rats were compared to ad libitum and pair-fed controls. Histological examinations and specific markers of the immune and non-immune gut barrier function were assessed at D4 or D7. As compared to ad libitum and pair fed controls, methotrexate induced at D4 villus atrophy associated with epithelial necrosis. Mucosal protein synthesis rate and mucin contents of methotrexate treated rats were reduced. In the same time, cathepsin D proteolytic activity was increased compared with ad libitum and pair fed controls whereas calpain activity was increased when compared with the only pair fed controls. These intestinal lesions were associated with various metabolic disturbances such as increased TNF
level and inflammation score in the jejunum but also disturbances of amino acid concentrations in duodenum and plasma. At D7, these alterations were partially or completely normalised. In addition to consequences of a low food intake, methotrexate further impairs different biological processes leading to a dramatic loss of gut homeostasis. Targeted nutritional management of chemotherapy receiving patients should be set up to prevent or limit such alterations.
