Gut Microbiota-Derived D-Tagatose from EGCG Attenuates Radiation-Induced Intestinal Injury.

PURPOSE/OBJECTIVE(S): As a rapidly self-renewing tissue, the small intestine is particularly sensitive to ionizing radiation, which limits the outcomes of radiotherapy against abdominal malignancies, resulting in poor prognosis. The polyphenol (-)-epigallocatechin-3-gallate (EGCG), a major bioactive constituent of green tea, is beneficial in radiation-induced intestinal injury (RIII) alleviation. However, the bioavailability of EGCG in vivo is very low, with only 0.1% to 1.6% being absorbed into the intestine of mice. It is unclear whether gut microbial metabolites mediated by EGCG exert an effect to protect against radiation-induced intestinal injury.

MATERIALS/METHODS: Male C57BL/6J mice were subjected to 13 Gy abdominal irradiation after EGCG gavage, and the severity of intestinal tissue damage was evaluated by HE staining, immunohistochemistry, and TUNEL assays. Fresh fecal samples were collected after the end of gavage, and then fecal sterile fecal filtrate (SFF) was obtained. Stool samples were collected 3 d after irradiation. The gut microbiome was detected by 16S rRNA sequencing, the metabolites were detected by GC‒MS analysis, and then the metabolites were applied to male C57BL/6J mice, observing and evaluating the severity of RIII.

RESULTS: We first explored the effect of oral EGCG delivery on radiation-induced intestinal injury. Our results revealed that EGCG pre-supplementation prolongs survival time, prevents weight loss in mice and mitigates radiation-induced intestinal injury in irradiated mice. Using 16S rRNA gene-based microbiota analysis, we first found that EGCG ameliorated ionizing radiation-induced gut microbiota dysbiosis and enriched short-chain fatty acid (SCFA)-producing bacteria such as Roseburia, Ruminococcus, and Clostridia_UCG-014. In addition, metabolomic profiling analysis showed that the gut microbiota modulated EGCG-induced metabolic reprogramming in colonic tissues, particularly by enhancing galactose metabolism. Notably, EGCG supplementation resulted in the enrichment of the microbiota-derived galactose metabolism metabolite D-tagatose. Furthermore, exogenous treatment with D-tagatose reproduced similar protective effects as EGCG to protect against radiation-induced intestinal injury (RIII). D-tagatose restored the length of villi and improved the number of goblet cells, Ki-67-positive cells and Lgr5+ ISCs, while the number of TUNEL-positive cells in the intestinal tissues decreased significantly. To validate these discoveries, we performed fecal sterile fecal filtrate (SFF) from EGCG-dosed mice to untreated mice before ionizing radiation. SFF from EGCG-dosed mice alleviated the RIII over SFF from control mice superiorly.

CONCLUSION: This study provides the first data indicating that oral EGCG ameliorated radiation-induced intestinal injury (RIII) by regulating the gut microbiota and metabolites. Our findings provide novel insights into D-tagatose derived by gut microbiota from EGCG-mediated remission of RIII.