S2567
Radiobiology – Normal tissue radiobiology
ESTRO 2026
Proffered Paper 1994 Targeting the Microbiota-Derived Metabolite Kynurenic Acid–GPR35 Axis to Mitigate Radiation- Induced Intestinal Injury Liwei Xie 1,2 , Chengzhi Liu 1 , Shang Cai 1,2 , Ye Tian 1,2 1 Department of Radiotherapy and Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, China. 2 Institute of Radiotherapy and Oncology, Soochow University, Suzhou, China Purpose/Objective: Radiation-induced enteropathy (RIE) remains a serious complication of radiotherapy for abdominopelvic cancers, with limited effective treatment options. The gut microbiota and its metabolites play crucial roles in intestinal homeostasis, yet their potential in modulating radiation toxicity is not fully understood. This study investigates whether kynurenic acid (KYNA), a microbiota-derived tryptophan metabolite, protects against RIE via activation of its cognate receptor, GPR35. Material/Methods: Male C57BL/6J mice (6–8 weeks old) were exposed to 13 Gy total abdominal irradiation (TAI) to model RIE. Mice received KYNA (200 mg/kg) or vehicle by oral gavage before and after irradiation. Gut microbiota depletion was achieved using broad-spectrum antibiotics, and GPR35 was inhibited using the selective antagonist CID2745687. Intestinal injury and repair were evaluated via histopathology (H&E, PAS), immunohistochemistry (Lgr5, tight junctions), TUNEL assay, and ELISA. Gut microbiota composition was assessed by 16S rRNA sequencing, and KYNA levels were quantified via HPLC. Organoid culture and molecular analyses (qRT ‒ PCR, Western blot) were used to explore mechanisms. Results: KYNA treatment significantly improved mouse survival, reduced weight loss, and preserved intestinal morphology after TAI. It enhanced the regeneration of Lgr5 ⁺ intestinal stem cells (ISCs), increased epithelial proliferation, and strengthened mucosal barrier integrity. KYNA also modulated the gut microbiota by enriching beneficial bacteria and reducing pathogenic species. In vitro, KYNA enhanced organoid recovery post-irradiation. These protective effects were dependent on GPR35 activation, as its pharmacological inhibition abrogated KYNA-mediated benefits. Conclusion: Our findings reveal a novel role for microbiota-derived KYNA in protecting against radiation-induced intestinal injury through dual mechanisms: remodeling the gut microbiome and activating host GPR35 signaling to promote ISC regeneration and epithelial repair. These results highlight the therapeutic potential of targeting
irradiated mice treated with PAE or vehicle were transplanted into antibiotic-pretreated recipient mice by fecal microbiota transplantation (FMT). Results: Oral administration of PAE significantly attenuated the clinical manifestations of radiation-induced enteritis, as reflected by reduced body weight loss, improved diarrhea scores and increased survival. Histological analysis showed that PAE treatment preserved villus architecture better, manifestingas increased villus height and crypt depth, reduced epithelial cell apoptosis, and increased crypt cell proliferation. Following PAE treatment, the expression of tight junction proteins was restored and intestinal permeability was reduced, indicating improved intestinal mucosal barrier function. Additionally, the pro-inflammatory cytokines levels in intestinal tissues and serum were also markedly decreased in the PAE group, suggesting the suppression of the inflammatory response. 16S rRNA sequencing revealed that irradiation induced pronounced gut dysbiosis, characterized by reduced microbial diversity, depletion of short-chain fatty acid (SCFA)- producing commensals and expansion of potentially pathogenic taxa. PAE partially reversed these alterations by increasing microbial diversity, enriching beneficial SCFA-producing bacteria and shifting predicted microbial functions toward anti- inflammatory and barrier-supporting pathways. Notably, FMT from PAE-treated donor mice significantly alleviated radiation-induced intestinal injury in recipient mice, whereas FMT from vehicle- treated donors had no such effect, suggesting that the protective action of PAE is at least partially mediated by gut microbiota remodeling. Conclusion: Our findings suggest that PAE may serve as an effective oral radioprotective agent and highlight gut microbiota–targeted modulation as a feasible therapeutic strategy for preventing or attenuating radiation-induced intestinal injury. References: 1.Gandle C, Dhingra S, Agarwal S. Radiation-Induced Enteritis [J]. Clin Gastroenterol Hepatol. 2020,18(3):A39-A40.2.Moraitis I, Taelman J, Arozamena B,et al. Mucosal Macrophages Govern Intestinal Regeneration in Response to Injury [J]. Gastroenterology. 2025,169(1):119-135.e26.3.Ni L, Lu Q, Tang M, Tao L, et al. Periplaneta americana extract ameliorates dextran sulfate sodium-induced ulcerative colitis via immunoregulatory and PI3K/AKT/NF- κ B signaling pathways [J]. Inflammopharmacology. 2022,30(3):907-918.4.Li W, Chen Y, Li K, et al. Periplaneta americana extract improves recurrent oral ulcers through regulation of TLR4/NF- κ B and Nrf2/HO- 1 pathways [J]. Sci Rep. 2025,15(1):8578. Keywords: enteritis, intestinal mucosal barrier, PAE
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