Crohn’s disease is a type of inflammatory bowel disease of unknown etiology. Administration of indomethacin (Indo) to rats induces acute mucosal lesions similar to those observed in Crohn’s disease patients, but the damage can be prevented by feeding the animals an elemental diet (ED). In this study, we examined changes in intestinal macroscopic appearance, permeability, and immunoglobulin production after administration of Indo to male Sprague-Dawley rats fed normal lab chow or an ED. Intestinal damage was induced by subcutaneous injection of Indo on two successive days. Mucosal permeability, as measured by urinary excretion of phenolsulfonphthalein, peaked on day 2 after Indo injection, whereas the most severe intestinal damage, as scored by macroscopic inflammatory changes, was observed on day 3. Flow cytometric analysis of mesenteric lymph node cells revealed that the proportion of CD45RA⁺ cells was increased after Indo treatment. Furthermore, in vitro-cultured mesenteric lymph node and spleen lymphocytes from Indo-treated rats produced higher levels of IgA and IgG than did cells from vehicle-treated rats. In contrast, IgG and albumin concentrations in plasma were significantly decreased by Indo administration. Notably, none of the Indo-induced changes was observed in ED-fed rats. These findings suggest that an ED may prevent the appearance of Indo-induced mucosal lesions, at least in part, by modulating intestinal permeability and antibody production.