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Abstract
Radiation enteritis (RE) is a common complication in cancer patients receiving radiotherapy. Although studies have shown the changes of this disease at clinical, pathological and other levels, the dynamic characteristics of local microbiome and metabolomics are hitherto unknown. We aimed to examine the multi-omics features of the gut microecosystem, determining the functional correlation between microbiome and lipid metabolites during RE activity. By delivering single high-dose irradiation, a RE mouse model was established. High-throughput 16S rDNA sequencing and global lipidomics analysis were performed to examine microbial and lipidomic profile changes in the gut microecosystem. Spearman correlation analysis was used to determine the functional correlation between bacteria and metabolites. Clinical samples were collected to validate the above observations. During RE activity, the intestinal inflammation of the mice was confirmed by typical signs, symptoms, imaging findings and pathological evidences. 16S datasets revealed that localized irradiation dramatically altered the gut microbial composition, resulting in a decrease ratio of Bacteroidetes to Firmicutes. Lipidomics analysis indicated the remarkable lipidomic profile changes in enteric epithelial barrier, determining that glycerophospholipids metabolism was correlated to RE progression with the highest relevance. Spearman correlation analysis identified that five bacteria-metabolite pairs showed the most significant functional correlation in RE, including Alistipes-PC(36:0e), Bacteroides-DG(18:0/20:4), Dubosiella-PC(35:2), Eggerthellaceae-PC(35:6), and Escherichia-Shigella-TG(18:2/18:2/20:4). These observations were partly confirmed in human specimens. Our study provided a comprehensive description of microbiota dysbiosis and lipid metabolic disorders in RE, suggesting strategies to change local microecosystem to relieve radiation injury and maintain homeostasis.
Highlights
Radiation enteritis (RE) is a major health concern in recipients of radiation therapy (Andreyev, 2007)
Mice were irradiated with the doses of 6Gy, 12Gy or 18Gy, 18Gy was defined as the optimal dose to induce acute RE based on typical histopathologic changes and radiation injury score (Table 1) after 1 week of irradiation (Figures 1A, F), without leading to lethal acute gastrointestinal syndrome
It has been reported that pathological features of chronic RE usually occur after 6 weeks of irradiation (Gerassy-Vainberg et al, 2017; Sokol and Adolph, 2018), so we chose this time point to observe radiation-induced chronic intestinal injury
Summary
Radiation enteritis (RE) is a major health concern in recipients of radiation therapy (Andreyev, 2007). Pelvic and rectal cancer patients, approximately 90% of them develop a permanent change in bowel habits after radiotherapy, and 50% have an associated reduction in quality of life (Pfaendler et al, 2015). Known as gut flora or gut microbiome, is the microorganisms that live in the digestive tracts of humans Its role in both health and disease has been the subject of extensive research (Gong et al, 2018; Lee et al, 2019; Pryor et al, 2019), establishing its involvement in human metabolism, nutrition, physiology, and immune function (McKenzie et al, 2017). Elucidating the interaction mechanisms between microbiome and host may offer potential therapeutic benefits
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