Cancer Hospital Chinese Academy of Medical Sciences Beijing, Beijing
X. Chen, X. Xu, R. Xu, and M. Deng; State Key Laboratory of Molecular Oncology and Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
Purpose/Objective(s): Radiation enteritis (RE) is one of the most common complications in radiotherapy of the pelvic areas, which seriously affects the clinical treatment effect and the quality of patients’ life. The pathogenesis of RE is closely related to oxidative damage caused by radiation. During the injury process of radiation enteritis, excessive accumulation of ROS can cause damage to intestinal epithelial cells and increase the permeability of the intestinal mucosa, thus inducing an inflammatory response. As one of the carotenoids,lycopene is a fat-soluble linear highly unsaturated polyolefin compound,composed of 11 hydrocarbon conjugated double bonds and 2 hydrocarbon non-conjugated double bonds. Studies have shown that lycopene can inhibit intracellular ROS production, double-stranded DNA breaks, ATM, and ATM-Rad3-related DNA damage responses. Therefore, it has potential benefits in treating oxidative stress-related damage. Materials/
Methods: Wild-type C57BL/6 mice were exposure to 12 Gy of abdominal irradiation before the gavage of lycopene for 7 days. After collecting the samples, the severity of radiation enteritis injury was evaluated by intestinal HE staining, and the degree of radioactive intestinal fibrosis was assessed by measuring rectal length, Masson staining, and Sirius red staining. We identified candidate proteins that mediate radiation protection through RNA-SEQ analysis. After 7 days of intragastric administration, fresh fecal samples were collected, and sterile fecal filtrate (SFF) was further processed. These fecal samples were tested by metagenomic sequencing to detect the changes in intestinal microbiome, and changes in metabolite abundance were further analyzed by untargeted metabolomic analysis. Results: Lycopene reduces the release of inflammatory factors such as IL17 by inhibiting the expression of the SAA3 gene, changes the intestinal microflora. Lycopene supplementation can effectively delay weight loss in mice, increase villus length and crypt number, and reduce radiation-induced damage. We observed a significant reduction in radioactive intestinal fibrosis using pathological staining techniques. Specifically, lycopene increase intestinal length, reduce the intensity of Masson and Sirius red staining, and a reduce the immunohistochemical alpha-SMA staining signal. At the same time, metagenomic sequencing showed that lycopene improved intestinal flora dysbiosis induced by ionizing radiation. Furthermore, metabolomic analysis revealed that intestinal flora modulates lycopene-induced metabolic reprogramming in intestinal tissues. Conclusion: This study demonstrates for the first time that oral lycopene can alleviate radiation-induced intestinal mucosal damage by regulating intestinal flora and related metabolites. Moreover, we explain the underlying molecular mechanisms of lycopene regulating intestinal microorganisms through IL17 which is mediated by SAA3.
