Abstract

Emerging evidence suggests dietary interventions regulate inflammatory signaling through gut microbiome modulation, yet their therapeutic potential in radiation-induced intestinal injury (RIII) remains underexplored. This study demonstrates that ketogenic diet (KD), a high-fat and low-carbohydrate dietary regimen, exerts protective effects against RIII through dual mechanisms involving microbial regulation and inflammatory pathway inhibition. Using high-salt diet (HSD) as a dietary control, KD significantly attenuated intestinal inflammation by downregulating pro-inflammatory cytokines while enhancing barrier integrity through tight junction protein upregulation in radiation-exposed murine model. 16S rDNA sequencing showed KD enriched Akkermansia and reduced Enterobacteriaceae , whereas HSD exhibited inverse patterns. Mechanistically, RNA sequencing revealed that KD uniquely suppressed the JAK2/STAT3 pathway in RIII mice. In vitro studies demonstrated that β-hydroxybutyrate, a key ketone metabolite, effectively suppressed RORγt expression and subsequent downregulation of IL-17A gene transcription via the inhibition of JAK2/STAT3 pathway, thus mitigate inflammatory damage. Fecal microbiota transplantation validated that KD-modified microbiome directly inhibited JAK2/STAT3 signaling activation, as well as the downregulation of RORγt and IL-17A. These findings establish KD as a promising dietary strategy mitigate acute RIII through synergistic modulation of gut microbiota and inflammatory signaling, providing novel insights into nutritional approaches targeting microbial-host crosstalk in radiation injury.