Disruption of intestinal homeostasis occurs in the pathogenesis of chemotherapy-induced intestinal mucositis. Increasing enterocyte proliferation and the subsequent enhancement of tissue repair or inhibiting enterocyte apoptosis could attenuate gut inflammation [23]. Recent studies suggest that minocycline could suppress caspase activation and subsequently inhibit apoptotic cell death in mouse models of Fas-mediated fulminant hepatitis [24] and Huntington disease [15]. We therefore examined the effects of minocycline on cell proliferation and apoptosis in the small intestines of mice with 5-FU-induced intestinal mucositis, and the results revealed that 5-FU administration increased apoptosis in epithelial and crypt
BIBF1120 of the small intestine in mice (Fig. 3C and Supplementary Fig. 3A). Minocycline treatment restored the integrity of villi and decreased the apoptotic index of enterocytes in the villi of mice with 5-FU-induced mucositis (Fig. 3C and Supplementary Fig. 3A); moreover, we found that minocycline also blocked 5-FU-induced apoptosis in enterocyte IEC-6 cells (Supplementary Fig. 4). Administration of 5-FU suppressed cell proliferation in the crypts of the mouse small intestine (Fig. 3D and Supplementary Fig. 3B), and the proliferating
cells in injured small intestines of mice with 5-FU-induced mucositis were observed to be more scattered and in greater disarray than those of the control mice (Supplementary Fig. 3B). However, minocycline treatment did not alter the proliferation index of enterocytes in the small intestines of mice with 5-FU-induced mucositis (Fig. 3D and Supplementary Fig. 3B). Therefore, we conclude that, although it does not alter the proliferation status of crypt cells, minocycline does indeed decrease the number of apoptotic cells in the small intestines of mice treated with 5-FU. We have previously demonstrated the same phenomenon in a murine DSS-induced colitis model [18]. Thus, blocking the apoptotic process and subsequently maintaining gut homeostasis during intestinal mucositis may, at least in part, explain how minocycline attenuates experimental chemotherapy-induced intestinal mucositis.
