Commensal Viruses Promote Intestinal Stem Cell Regeneration Following Radiation Damage by Inhibiting Hyperactivation of RIG‐I and Notch Signals

Abstract Radiation‐induced intestinal injury is a common complication of abdominopelvic cancer radiotherapy, often associated with gut bacteriome dysbiosis. However, the involvement of gut virome in this process remains largely underexplored. Here, it was found that radiation disrupted the gut virome, altered the distribution of phages and their bacterial host. Fecal virome transplantation (FVT) from healthy donors ameliorated radiation‐induced intestinal damage and promoted stem cell proliferation by enriching phages targeting Salmonella . Conversely, decreased virome load exacerbated intestinal damage, reduced proliferating stem cells, and impaired secretory lineage differentiation. Mechanistically, exacerbated intestinal injury was associated with hyperactivation of RIG‐I and Notch signaling in intestinal stem cells, which was absent in RIG‐I‐deficient mice. Organoids from RIG‐I‐deficient mice displayed decreased Notch signals and increased regenerative capacity post radiation. These findings shed light on the intricate interplay between gut virome, intestinal injury, and stem cell responses, highlighting potential therapeutic interventions for targeting the virome to mitigate radiation‐induced intestinal damage.