Sexual Dimorphism of Gut Microbiota Dictates Therapeutics Efficacy of Radiation Injuries

Accidental or iatrogenic ionizing radiation exposure precipitates acute and chronic radiation injuries. The traditional paradigm of mitigating radiotherapy‐associated adverse side effects has ignored the gender‐specific dimorphism of patients' divergent responses. Here, the effects of sexual dimorphism on curative efficiencies of therapeutic agents is examined in murine models of irradiation injury. Oral gavage of simvastatin ameliorates radiation‐induced hematopoietic injury and gastrointestinal tract dysfunction in male mice, but adversely deteriorates these radiation syndromes in female animals. In a sharp contrast, feeding animals with high‐fat diet (HFD) elicites explicitly contrary results. High‐throughput sequencing of microbial 16S rRNA, host miRNA, and mRNA shows that simvastatin or HFD administration preventes radiation‐altered enteric bacterial taxonomic structure, preserves miRNA expression profile, and reprogrammes the spectrum of mRNA expression in small intestines of male or female mice, respectively. Notably, faecal microbiota transplantation of gut microbes from opposite sexual donors abrogates the curative effects of simvastatin or HFD in respective genders of animals. Together, these findings demonstrate that curative efficiencies of therapeutic strategies mitigating radiation toxicity might be dependent on the gender of patients, thus simvastatin or HFD might be specifically useful for fighting against radiation toxicity in a sex‐dependent fashion partly based on sex‐distinct gut microbiota composition in preclinical settings.