Abstract
Intestinal microbes promote the injurious effects of radiation on those tissues. However, the molecular factors mediating this effect are largely unknown. In this work, we explored the effects of orally administered antibiotics and MyD88, a key adapter molecule in toll-like receptor signaling, on molecular and cellular responses of mouse colon to radiation. Results show that oral antibiotics lowered radiation-induced colonic damage by protecting epithelial cells against radiation-induced apoptosis, leading to increased survival of crypts. MyD88 deficiency partially phenocopied the effects of oral antibiotics on apoptosis and crypt survival, suggesting that colonic microbes exert their injurious effects in part via that molecule. Analysis of DNA double-strand breaks, the primary genotoxic lesions induced by radiation, showed that their early induction in mouse colon was unaffected by MyD88. However, MyD88 deficiency resulted in the later disappearance of DNA double-strand breaks. Loss of DNA double-strand breaks was accompanied by the evidence of increased activation of both the non-homologous end-joining and homologous recombination pathways of DNA repair in MyD88-deficient mice. These results show that colonic microbes and MyD88 regulate DNA double-strand break repair in irradiated mouse colon, effects which exert significant control over radiation-induced apoptosis and crypt survival.
Highlights
During the radiotherapy of abdominal or pelvic malignancies, ionizing radiation can damage the mucosal surface of the gastrointestinal tract, leading to symptoms that may necessitate a reduction in radiation dose or the cessation of therapy
We first treated mice with broad spectrum mice (Figure 1c). These results suggested that oral antibiotics orally administered antibiotics, according to established protocols might mitigate radiation-induced gastrointestinal (GI) syndrome
Our results show that exposure of mice to a regime of oral antibiotics that significantly alters the intestinal microbial flora[13,14] affects the sensitivity of the colon epithelial cells to radiationinduced apoptosis, crypt loss and GI syndrome
Summary
During the radiotherapy of abdominal or pelvic malignancies, ionizing radiation can damage the mucosal surface of the gastrointestinal tract, leading to symptoms that may necessitate a reduction in radiation dose or the cessation of therapy. If double-strand breaks are few, the p53 response may halt cell cycle progression and following DNA double-strand break repair, allow the cell to survive.[2] In the intestinal epithelium, the rapidly dividing crypt transit cells are the most sensitive to radiation-induced apoptosis, which can be detected at doses of o1 Gy, within minutes of radiation. At radiation doses of 8–12 Gy, the relatively more radioresistant stem cells of the crypts undergo apoptosis.[3] The death of these cells is assessed by using the crypt microcolony assay that measures the survival and repopulation of damaged crypts several days after radiation.[4] The early induction of intestinal epithelial cell apoptosis by radiation, followed by later mucosal damage due to progressive loss of crypts leads to the mucositis that follows several days after the beginning of abdominal or pelvic radiotherapy. The sensitivity of intestinal crypt epithelial stem cells to undergo apoptosis following radiation determines the severity of injury
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