Isolation-stress increases small intestinal sensitivity to chemotherapy in rats.

Severe gastrointestinal damage often complicates the use of chemotherapeutic agents such as methotrexate for anticancer treatment. Psychologic stress is known to be detrimental to normal intestinal physiology. We set out to determine if psychologic stress adds to the intestinal damage provoked by chemotherapy. Rats were treated with various doses of methotrexate and housed either alone, which induces mental stress, or maintained in groups of 3 animals. Treatment was evaluated by (immuno)histologic parameters. Epithelial crypt damage, increased lysozyme expression, decreased sucrase-isomaltase and sodium/glucose transporter 1 expression, and pathologic changes in mucin and trefoil factor protein expression could be prevented by avoiding isolation. Enhanced cytotoxicity of methotrexate through isolation was about 2-fold and involved an augmented inhibition of proliferation, increased epithelial apoptosis, increased villus damage, and delayed recovery. We could not identify a role for mucosal mast cells in the increased epithelial damage under isolated conditions. The clear beneficial effects of avoiding mental stress on the protection of the intestinal epithelium during cytostatic drug-treatment may be an important element for the treatment of cancer patients.