Caloric Restriction Alleviates Radiation Injuries In A Sex-Dependent Fashion

Abstract

Background: There remain unmet clinical needs for safe and effective regimen to fight against radiation injuries from medical irradiation or accidental exposure. Intestinal microbes play important roles in radiation damage. Diet is an efficacious mediator to educate the gut microbiota directly. Methods: In this case, we investigated whether 30% reduced calorie might ameliorate radiation enteritis and hematopoietic toxicity. Male and female C57BL/6J mice were either fed ad libitum (AL) or caloric restriction (CR) preconditioning for 10-day and then exposed to total body radiation (TBI) or total abdominal radiation (TAI). Findings: Gross examinations showed that short-term CR pretreatment restored hematogenic organs and improved intestinal architecture in both sexes of mice. Intriguingly, CR mitigated radiation-induced systemic and enteric inflammations in females, while the gut barrier function improved in irradiated male mice. 16S rRNA high-throughput sequencing was performed and showed that after 10-day of CR preconditioning, proinflammatory microbes including Helicobacter and Desulfovibrionaceae were lessened in female mice, while an enrichment of short-chain fatty acids (SCFAs)-producing bacteria such as Faecalibaculum, Clostridiales and Lactobacillus was observed in males. Gut flora shifts by fecal microbiota transplantation (FMT) or antibiotic administration counteracted CR-elicited radiation tolerance of both male and female mice, further demonstrated that the radioprotection of CR depends on the CR-restructured sex-specific gut microbiota configuration. Interpretation: Together, our findings provide new insights into CR in clinical applications, and indicate that short-term CR diet prior to radiation modulates the gut microbiota in a sex-dependent fashion, protecting male and female patients against the side effects caused by accidental or iatrogenic radiation challenge. Funding: Natural Science Foundation of China [81730086, 81872555, 82003399]; Science Foundation for Distinguished Young Scholars of Tianjin [20JCJQJC00100]; Drug Innovation Major Project of China [2018ZX09711001-007-008]. Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: The animal use protocol has been reviewed and approved by the Animal Ethical and Welfare Committee (AEWC)