title: Methotrexate induces intestinal mucositis and alters gut protein metabolism independently of reduced food intake.
abstract: 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-alpha 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.
authors.affiliation: ADEN EA4311, Institute for Biomedical Research, IFRMP23, 22 Boulevard Gambetta 76183 Rouen Cedex 1, France.
authors.forename: Nabile
authors.initials: N
authors.lastname: Boukhettala
authors.forename: Jonathan
authors.initials: J
authors.lastname: Leblond
authors.forename: Sophie
authors.initials: S
authors.lastname: Claeyssens
authors.forename: Magali
authors.initials: M
authors.lastname: Faure
authors.forename: Florence
authors.initials: F
authors.lastname: Le Pessot
authors.forename: Christine
authors.initials: C
authors.lastname: Bôle-Feysot
authors.forename: Aktham
authors.initials: A
authors.lastname: Hassan
authors.forename: Christine
authors.initials: C
authors.lastname: Mettraux
authors.forename: Jacques
authors.initials: J
authors.lastname: Vuichoud
authors.forename: Alain
authors.initials: A
authors.lastname: Lavoinne
authors.forename: Denis
authors.initials: D
authors.lastname: Breuillé
authors.forename: Pierre
authors.initials: P
authors.lastname: Déchelotte
authors.forename: Moïse
authors.initials: M
authors.lastname: Coëffier
mesh_terms: D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D004435:Eating / Q000187:drug effects*; D005978:Glutathione / Q000378:metabolism; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism; D007583:Jejunum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008727:Methotrexate / Q000494:pharmacology*; D009077:Mucins / Q000235:genetics / Q000378:metabolism; D052016:Mucositis / Q000139:chemically induced* / Q000378:metabolism; D011506:Proteins / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000596:Amino Acids; D000964:Antimetabolites, Antineoplastic; D009077:Mucins; D011506:Proteins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D005978:Glutathione; D008727:Methotrexate