Background <p>Chronic liver diseases (CLDs) are pervasive health issue worldwide, whereas radiation-induced intestinal injury is a frequent and consequential complication of abdominopelvic radiotherapy. Although these two pathological states often coexist clinically, the effects of CLDs on the development and severity of enteric radiation damage remain poorly understood. Therefore, the aim of this study was to investigate the effects of CLDs on radiation-induced intestinal injury and to elucidate the underlying mechanisms involved.</p> Methods <p>Mouse models of CCl₄-induced liver injury or alcoholic fatty liver disease were established. Single-cell RNA sequencing was conducted to understand the repertoire of small intestinal crypts. The gut microbiota was assessed using 16&#xa0;S rRNA gene sequencing. Untargeted metabolomics, along with experiments using cell lines, intestinal organoids and mouse models, was utilized to identify key effector molecules and explore their mechanism of action.</p> Results <p>CLDs reshaped the intestinal cellular landscape and exacerbated radiation-induced intestinal syndrome through bile acid-mediated hepatoenteric signalling. Liver injury shifted the gut microbiota, enriching <i>Lachnospiraceae</i> and other taxa, which led to abnormal elevation of taurocholic acid (TCA) in serum. Under radiation exposure, TCA overload disrupted intestinal homeostasis through three synergistic mechanisms. First, TCA compromised intestinal stem cell vitality, lowering the self-renewal and regenerative properties of the irradiated small intestine. Second, TCA activated Notch signalling in stem cells, impeding the differentiation of irradiated intestinal progenitors towards the secretory lineage to disrupt the differentiation trajectory. Third, TCA accumulated in irradiated absorptive enterocytes, destroying mitochondrial membrane integrity and hastening intrinsic apoptosis, contributing to radiation-induced cell death. Potential therapeutic strategies, including liver-protective agents, microbiota-targeted interventions, and mitochondrial protective compounds, have been proposed to mitigate the worsening intestinal toxicity associated with CLDs comorbidity during radiotherapy.</p> Conclusions <p>This study offers a detailed mechanistic understanding of how dysregulation of hepato-enteric crosstalk negatively affects the sensitivity of the intestines to ionizing radiation and proposes potential therapeutic approaches to reduce intestinal complications in patients with concurrent chronic liver diseases who are undergoing irradiation.</p>