Kynurenine mediates the chemotherapy-induced intestinal toxicity through modulation of gut microbiota
- Hongyu Xie
- Jingyi Yang
- Jinjie Wu
- Wenhao Ma
- Haoyang Xu
- Shuang Guo
- Yanchun Xie
- Zhanhao Luo
- Dayi Liang
- Mujia Cao
- Danling Liu
- Sanqing Jin
- Ping Lan
- Zhen He
2026-01-27
Chemotherapy-induced intestinal toxicity is a major dose-limiting complication, but the underlying mechanisms linking systemic metabolism to localized gut damage are poorly understood. Here we show that serum L-kynurenine, a tryptophan metabolite, is elevated in patients with severe oxaliplatin-induced intestinal toxicity. Accumulation of L-kynurenine is driven by IFNγ-mediated induction of indoleamine 2,3-dioxygenase 1 (IDO1) in myeloid cells. Using scRNA-seq and myeloid cell-specific knockout models, we confirm that myeloid cell-derived L-kynurenine exacerbates toxicity. Critically, L-kynurenine accumulation drives gut dysbiosis, characterized by the loss of Lactobacillus johnsonii , and subsequently activates the TNFα/JNK pathway, leading to intestinal epithelial apoptosis. Pharmacological inhibition or engineered reduction of L-kynurenine mitigates chemotherapy-induced intestinal injury. Our findings reveal an important role of L-kynurenine from myeloid cells in chemotherapy tolerance and propose its targeting as a potential therapeutic strategy.