Single radiation exposure induces gut microbiota dysbiosis and decreases short-chain fatty acid metabolism and intestinal barrier integrity in mice.

Ionizing radiation causes biological damage, including DNA damage, inflammation, and tissue homeostasis disruption. The gastrointestinal tract, which harbors diverse gut microbiota, is particularly susceptible to radiation-induced injury and intestinal barrier dysfunction. We aimed to investigate the effects of single and fractionated radiation exposures on gut microbiota diversity and short-chain fatty acid (SCFA) metabolism. Mice were exposed to a single dose (1 Gy, one exposure; dose rate: 2.6 Gy/min) or fractionated doses (1 Gy accumulated over 75 fractions, 6.7 mGy/min for 2 min per session). In vitro, differentiated Caco-2 monolayers were used to assess radiation-induced tight junction disruption and reactive oxygen species (ROS) production. Single radiation exposure induced a stronger response than fractionated exposure, as evidenced by increased DNA damage foci, altered blood profiles, and elevated inflammatory cytokines. Gut dysbiosis was more pronounced in the single-radiation group, characterized by an increased Firmicutes/Bacteroidetes ratio and reduced microbial diversity. SCFA analysis revealed considerable reductions in acetic and propionic acid levels in the single-radiation group compared to those in the control and fractionated groups. The expression of the SCFA-sensing receptors GPR41 and GPR43 was markedly downregulated in the single-radiation group. Tight junction proteins (TJP1, CLDN1, CLDN3, and OCLN) were markedly decreased, indicating compromised intestinal barrier integrity and increased permeability both in vivo and in vitro. Single radiation exposure caused greater gut microbiota and metabolic disruptions than fractionated radiation exposure, emphasizing the distinct effects of each type and the critical roles of gut microbiota and SCFAs in radiation-induced intestinal damage.