Gut irradiation and microbiota status modulate the meningeal immune landscape

Abstract Introduction Radiotherapy (RT) is an important part of curative treatment in many common abdominal and pelvic cancers. However, the gastrointestinal toxicities can affect the quality of life and outcomes for many patients. The underlying local gut toxicity and systemic effects, including effects on mental health, are underexplored and poorly understood. Given emerging evidence of immunological communication across the gut-brain axis, we investigated whether abdominal RT could induce distal immune alterations in the dural meninges and explored potential behavioural outcomes. Methods and Results Using a preclinical model of image-guided abdominal RT treatment, we induced a local myeloid-driven inflammatory response in the small intestine and colon. We observed significant systemic immune modulations in the peripheral blood and dural meninges, affecting a diverse range of immune cells. Whilst circulating immune changes largely resolved alongside recovery of intestinal inflammation, dural immune alterations were prolonged and dynamically shifted across timepoints. Depletion of the gut microbiota partially attenuated both local and systemic immune responses, particularly affecting RT-induced increases in neutrophil and monocyte populations, implicating microbiota-dependent mechanisms in mediating these effects. After recovery from acute intestinal toxicity, RT-treated mice displayed increased anxiety-like phenotypes without evidence of cognitive impairment. Conclusion Collectively, these findings demonstrate that gut-targeted RT can drive systemic immunomodulatory effects that extend to the brain border tissues in a partially microbiota-dependent manner and can enhance anxiety-like behaviour in mice. This highlights the systemic immune consequences of RT beyond the targeted tissue site, and the potential importance of RT-mediated immune organ crosstalk in mediating therapy outcomes.