Proliferation, differentiation, and cell death were studied in small
intestinal and colonic epithelia of rats after treatment with
methotrexate. Days 1-2 after treatment were characterized by decreased
proliferation, increased apoptosis, and decreased numbers and depths of
small intestinal crypts in a proximal-to-distal decreasing gradient along
the small intestine. The remaining crypt epithelium appeared flattened,
except for Paneth cells, in which lysozyme protein and mRNA expression was
increased. Regeneration through increased proliferation during days 3-4
coincided with villus atrophy, showing decreased numbers of villus
enterocytes and decreased expression of the enterocyte-specific genes
sucrase-isomaltase and carbamoyl phosphate synthase I. Remarkably, goblet
cells were spared at villus tips and remained functional, displaying Muc2
and trefoil factor 3 expression. On days 8-10, all parameters had returned
to normal in the whole small intestine. No methotrexate-induced changes
were seen in epithelial morphology, proliferation, apoptosis, Muc2, and
TFF3 immunostaining in the colon. The observed small intestinal sparing of
Paneth cells and goblet cells following exposure to methotrexate is likely
to contribute to epithelial defense during increased vulnerability of the
intestinal epithelium