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This Article Full Text Full Text (PDF) Supplemental Tables All Versions of this Article: 296/1/E182    most recent 90459.2008v2 90459.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Boukhettala, N. Articles by Coëffier, M. Search for Related Content PubMed PubMed Citation Articles by Boukhettala, N. Articles by Coëffier, M.

Methotrexate induces intestinal mucositis and alters gut protein metabolism independently of reduced food intake

¹ADEN-EA4311, Institute for Biomedical Research and European Institute for Peptide Research (IFRMP 23); ²Laboratory of Medical Biochemistry, Rouen University Hospital, Rouen, France; ³Nestlé Research Center, Nutrition and Health Department, Lausanne, Switzerland; and ⁴Laboratory of Anatomo-Pathology, Rouen University Hospital, Rouen, France

Submitted 22 May 2008 ; accepted in final form 31 October 2008

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. At the same time, food intake is decreased, which 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 3 days (D0-D2). Methotrexate-treated rats were compared with ad libitum and pair-fed controls. Histological examinations and specific markers of the immune and nonimmune gut barrier function were assessed at D4 or D7. Compared with 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. At 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 the duodenum and plasma. At D7, these alterations were partially or completely normalized. In addition to the 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.

chemotherapy; intestine; nutrition; mucin; protein turnover