E0703 Promotes Recovery from Acute Radiation-Induced Intestinal Damage by Akkermansia muciniphila Growth

The development of safe and reliable acute radiation protection drugs with minimal side effects, particularly for lethal doses, represents a significant global concern. The novel steroidal compound E0703, structurally derived from estradiol, has exhibited promising radioprotective properties with minimal estrogenic side effects in previous pharmacodynamic studies. In this investigation, we observed that E0703 effectively promotes an increase in the abundance of Akkermansia muciniphila (AKK) bacteria in the intestines of both irradiated and non-irradiated mice. AKK combined with E0703 intervention can effectively improve the survival rate of mice within one week after lethal dose (8.5Gy) irradiation. The administration of E0703 has been shown to induce advantageous alterations in the expression of the AKK gene, which is significantly enriched in pathways including amino acid biosynthesis, aminoacyl-tRNA biosynthesis, the citrate cycle (TCA cycle), and fatty acid biosynthesis. E0703 facilitates the production of glucosamine 6-phosphate (GlcN-6-P) by AKK, thereby supporting the growth of intestinal tissues post-irradiation. Furthermore, single-cell transcriptome analysis revealed that E0703 significantly enhances the proportion of stem cells and goblet cells in the intestinal epithelium of mice by the fifth day following irradiation. Mechanistically, E0703 primarily influences the biological functions of stem cells and goblet cells via the oxidative phosphorylation pathway, including the production of Muc2. Our research demonstrated that E0703 can enhance the abundance of AKK in the gut following irradiation, particularly when supplemented with mucin, thereby increasing the production of GlcN-6-P, a critical substrate for the repair of intestinal organoids. In summary, E0703 exerts a direct beneficial effect on goblet cells and AKK, fostering a positive interaction between intestinal cells and probiotics in irradiated mice, which significantly improves their survival rate.