Dietary Spermidine Mitigates Radiation‐Induced Intestinal Injury by Reshaping the Microbiota‐Barrier‐Inflammation Axis

Radiation‐induced intestinal injury (RIII) is a major complication of radiotherapy, characterized by oxidative stress, intestinal barrier disruption, and gut microbiota dysbiosis. There is an urgent clinical need for highly effective and low‐toxicity radioprotective agents. Spermidine (SPD) is a natural polyamine widely found in various foods with well‐documented health‐promoting properties, yet its role in RIII remains elusive. Using a mouse model of whole‐abdominal irradiation, we demonstrated that SPD intervention significantly improved survival rates and mitigated intestinal pathological damage, including crypt loss and villus shortening. Mechanistically, SPD pretreatment activated the Nrf2 signaling pathway, thereby alleviating oxidative stress and reducing DNA double‐strand breaks in intestinal epithelial cells. Furthermore, SPD preserved intestinal barrier integrity by enhancing the expression of tight junction proteins (Occludin and ZO‐1) and reduced systemic inflammation (serum IL‐6). 16S rRNA sequencing revealed that SPD prevented radiation‐induced gut dysbiosis by significantly enriching beneficial butyrate‐producing bacteria (e.g. , Lachnospiraceae_NK4A136_group ) while suppressing potential pathogens (e.g. , Parabacteroides and Mucispirillum ). Our study reveals that SPD exerts multi‐targeted protection against RIII by coordinately regulating the “microbiota‐barrier‐inflammation” axis, positioning it as a promising candidate for preventing and treating RIII.