After birth, the epithelium that lines our gut transitions (or matures) so that it can deal with the transition from milk to solid foods. During this time more and more bacteria enter the gut to establish the microbiota, and so the epithelium also strengthens its barrier role by starting to secrete large amounts of antimicrobials that come from specialized epithelial Paneth cells. In this study, we identify the lysine demethylase LSD1 to be critical for the appearance of Paneth cells early in life. We further find that LSD1 accomplishes this by regulating specific histone marks to control persistent gene expression in gut epithelium. Altogether, this work establishes an important role for LSD1 in intestinal epithelial biology, both early in life and during challenges that damage the gut and require wound healing such as after ionizing radiation. Such damage is a common side effect in cancer patients receiving irradiation therapy, and thus we hope that in the future targeting LSD1 could be helpful for these patients.