Amelioration of whole abdominal irradiation-induced intestinal injury in mice with 3,3'-Diindolylmethane (DIM)

Abstract

Ionizing radiation-induced intestinal injury is a catastrophic disease with limited effective therapies. 3,3'-Diindolylmethane (DIM), a potent antioxidant agent, has previously been shown to ameliorate hematopoietic injury in a murine model of total body radiation injury, but its effects on ionizing radiation-induced intestinal damage are not clear. Here, we demonstrate that administration of DIM not only protects mice against whole abdominal irradiation (WAI)-induced lethality and weight loss but also ameliorates crypt-villus structural and functional injury of the small intestine. In addition, treatment with DIM significant enhances WAI-induced reductions in Lgr5⁺ ISCs and their progeny cells, including lysozyme⁺ Paneth cells, Villin⁺ enterocytes and Ki67⁺ instantaneous amplifying cells, thus promoting small intestine repair following WAI exposure. Notably, the expression of Nrf2 increased, while the number of apoptotic cells and the expression of γH2AX decreased in the small intestines of DIM-treated mice compared to mice treated with vehicle following WAI. In vitro, we demonstrated that DIM protected human intestinal epithelial cell-6 (HIEC-6) against ionizing radiation, leading to increased cell vitality. Mechanistically, the radioprotective effect of DIM was likely attributable to its anti-DNA damage effects in irradiated HIEC-6 cells. Moreover, these changes were related to reduction in reactive oxygen species (ROS) levels and increased the activities of antioxidant enzymatic in irradiated HIEC-6 cells. Additionally, the DIM radioprotective effects on the intestine resulted in the restoration of the WAI-shifted gut bacteria composition in mice. Collectively, our findings demonstrate that the beneficial properties of DIM mitigate intestinal radiation injury, which provides a novel strategy for improving the therapeutic effects of irradiation-induced intestinal injury.

Keywords: Gastrointestinal tract; Intestinal flora; Ionizing radiation; NFE2L2/NRF2; Reactive oxygen species (ROS); Small intestine.