Vitamin A deficiency exacerbates methotrexate-induced jejunal injury in rats

Two studies were conducted to investigate whether vitamin A-deficient rats were more susceptible to intestinal injury caused by methotrexate (MTX), since vitamin A deficiency alone causes only mild changes to jejunal structure and function. Weanling male rats were fed a vitamin A-deficient diet (-VA) for 40-42 d and compared to rats either pair-fed (PF) or with free access (+VA) to the same diet. Drinking water of PF and +VA rats was supplemented with 37.5 micrograms (Study 1) or 75 micrograms (Study 2) vitamin A (Rovimix A 500W)/d. Rats in each group received MTX (-VAMTX, PFMTX, +VAMTX) or vehicle. MTX administration reduced intestinal mucosal wet weight, protein and DNA concentrations, and sucrase and maltase activities in -VA and PF rats (P 0.02). In Study 1, -VAMTX rats developed a severe jejunal enteropathy and had a higher incidence of diarrhea (P 0.005), greater weight loss (P 0.005), more disruption of villus architecture (P 0.0001) and lower disaccharidase activity (P 0.007) than PFMTX rats. Similar results were observed in Study 2. Liver retinol concentration (but no other variable) was greater in rats receiving 75 micrograms vitamin A/d (P 0.001) than in those receiving 37.5 micrograms/d. The interaction of vitamin A deficiency and small intestinal injury may explain the efficacy of vitamin A supplementation in preventing childhood diarrheal disease mortality in developing countries, and highlights the need for ensuring adequate vitamin A status in people worldwide with diseases and/or treatments which may injure the gastrointestinal tract