Abstract
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.
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Data availability
The data that support the findings of this study are available in the main text, the Supplementary Information, and Source Data file. The RNA-Seq data generated have been deposited in the National Center for Biotechnology Information (NCBI) Sequence Read Archive (SRA) database under the accession code PRJNA1239919 and PRJNA1337323. The metabolomics data to the OMIX repository (accession number: OMIX013390 and OMIX013372). Any additional information required to reanalyze the data reported in this work is available from the lead contact upon request. Source data are provided with this paper.
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Acknowledgements
Guangdong S&T Program (Z.H., 2024B1111150001); Shenzhen Medical Research Special Fund Project Target disease (Z.H., B2302036); National Key R&D Program of China (P.L., 2022YFA1304000); the program of Guangdong Provincial Clinical Research Center for Digestive Diseases (P.L., 2020B1111170004), National Key Clinical Discipline; National Natural Science Foundation of China (P.L., U21A20344; Z.H., 82273346); Science and Technology Program of Guangdong Province, China (Z.H., 2021B1212040017, J.W., 2024A04J4086); Key laboratory start-up project (Sixth Affiliated Hospital of Sun Yat-sen University) (Z.H., 2023WST03); Guangdong Medical Development Foundation (H.X., B2025247). This project was also supported by Guang Dong Cheung Kong Philanthropy Foundation.
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Z.H., P.L. and S.Q.J. supervised the study and designed the experiments. H.Y.Xie, J.Y.Y., J.J.W., W.H.M., H.Y.Xu, S.G., Y.C.X., Z.H.L., D.Y.L., M.J.C. and D.L.L. performed the experiments. H.Y.Xie and J.J.W. collected, analyzed and interpreted the data. H.Y.Xie and J.Y.Y. wrote the manuscript. Z.H., P.L. and S.Q.J. revised the manuscript. All authors read and approved the final version of the manuscript.
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Xie, H., Yang, J., Wu, J. et al. Kynurenine mediates the chemotherapy-induced intestinal toxicity through modulation of gut microbiota. Nat Commun (2026). https://doi.org/10.1038/s41467-026-68741-5
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DOI: https://doi.org/10.1038/s41467-026-68741-5
