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

ABSTRACT The gut microbiome (GM) plays an essential role in health, and its dysbiosis can increase the risk of colon cancer. While the detrimental effects of high-dose ionizing radiation on GM have been documented, little is known about the effects of low doses, including from internal exposure to tritium, which is produced by nuclear power generation and emits beta radiation, making it a public concern. We examined the effects of chronic irradiation with internal tritium beta radiation or external 60 Co gamma radiation on GM and intestinal tumorigenesis in the Apc Min/+ mouse model of colorectal cancer. Mice were exposed to tritiated drinking water (HTO) or gamma radiation at cumulative doses of 0, 10, 100, and 2,000 mGy, followed by intestine, blood plasma, and fecal sample collections at 12, 16, and 20 weeks of age. HTO- and gamma-exposed cohorts had distinct tumor size and multiplicity patterns, with non-monotonous dose-responses. Complex patterns of blood cytokine changes with age, dose, and type of irradiation were recorded. GM analyses using 16S rRNA amplicon sequencing revealed significant changes in alpha and beta diversity in irradiated mice compared to controls, indicating altered microbial dynamics. HTO and gamma radiation induced distinct microbiome changes that 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 GM in a radiation type and dose-dependent non-linear manner. Our results provide novel insight into the effects of low-dose gamma- and tritium beta radiation on GM and a possible association with tumorigenesis. IMPORTANCE Low-dose ionizing radiation is one of the few environmental stressors that simultaneously reshapes host physiology and the structure-function landscape of resident microbiomes, yet mechanistic insight at ecologically relevant doses has been scarce. By integrating longitudinal 16S rRNA profiling, multiplex cytokine analyses, and quantitative tumor phenotyping in the Apc Min/+ mouse model, our study demonstrates that continuous exposure to either external 60 Co γ-photons or tritium beta particles perturbs gut microbial community structure in radiation-quality-specific ways and that these shifts track with, and sometimes precede, complex, non-monotonic changes in intestinal tumor burden. The work expands the traditional radiobiology focus from host-centric DNA damage to a systems-level view in which microbe-host-radiation interactions form a dynamic network influencing early colorectal carcinogenesis.