Impact of chronic low-dose external gamma- and internal tritium beta-irradiation on gut microbiome in the context of intestinal tumorigenesis in ApcMin/+ mice

The gut microbiome plays an essential role in health, and its dysbiosis can increase the risk of cancer in general and colon cancer in particular. Whereas detrimental effects of high dose ionizing radiation on gut microbiome have been documented, little is known about the effects of low doses and low dose rates, including from internal exposure to tritium. Due to its release into the environment as a result of nuclear power generation and accidents, this beta-emitting radionuclide causes substantial public concerns. In this study, we examined the effects of chronic irradiation with internal tritium beta-particles or external 60Co gamma-photons on the microbiome and intestinal tumorigenesis in the ApcMin/+ mouse model of human colorectal cancer. Mice were exposed to tritiated drinking water (HTO) or matching gamma-irradiation from the age of 4 weeks continuously for 8 weeks at cumulative doses of 0, 10, 100, and 2000 mGy followed by intestine, blood plasma and fecal sample collections at 12, 16 and 20 weeks of age. Tumor size and counts changed differentially between HTO- and gamma-exposed cohorts, with complex non-monotonous dose-responses that depended on age. Similarly, complex patterns of 23 blood cytokines changes with age, dose and type of irradiation were recorded. Gut microbiome analyses using 16S rRNA amplicon sequencing revealed significant changes in alpha and beta diversity in irradiated mice compared to control, indicating altered microbial dynamics. Notably, HTO and gamma-radiation induced distinct microbiome changes that were opposite in directionality andthat did not correlate with tumor and blood cytokine readouts. Our results suggest that chronic exposure to low-dose gamma- or internal HTO beta-radiation can affect the gut microbiome. Observed alterations depended on radiation type and dose, with no evidence of linearity. Our results provide novel insight into the effects of low-dose gamma- and tritium beta-radiation on the gut microbiome and possible association to tumorigenesis.