The DOI matches its Crossref record; 44 of the 44 references it cites were found in a registry or an index.
Lactobacillus gallinarum-derived metabolites boost anti-PD1 efficacy in colorectal cancer by inhibiting regulatory T cells through modulating IDO1/Kyn/AHR axis
Open accessAbstract
Objective: Gut microbiota is a key player in dictating immunotherapy response. We aimed to explore the immunomodulatory effect of probiotic Lactobacillus gallinarum and its role in improving anti-programmed cell death protein 1 (PD1) efficacy against colorectal cancer (CRC). Design: The effects of L. gallinarum in anti-PD1 response were assessed in syngeneic mouse models and azoxymethane/dextran sulfate sodium-induced CRC model. The change of immune landscape was identified by multicolour flow cytometry and validated by immunohistochemistry staining and in vitro functional assays. Liquid chromatography-mass spectrometry was performed to identify the functional metabolites. Results: L. gallinarum significantly improved anti-PD1 efficacy in two syngeneic mouse models with different microsatellite instability (MSI) statuses (MSI-high for MC38, MSI-low for CT26). Such effect was confirmed in CRC tumourigenesis model. L. gallinarum synergised with anti-PD1 therapy by reducing Foxp3+ CD25+ regulatory T cell (Treg) intratumoural infiltration, and enhancing effector function of CD8+ T cells. L. gallinarum-derived indole-3-carboxylic acid (ICA) was identified as the functional metabolite. Mechanistically, ICA inhibited indoleamine 2,3-dioxygenase (IDO1) expression, therefore suppressing kynurenine (Kyn) production in tumours. ICA also competed with Kyn for binding site on aryl hydrocarbon receptor (AHR) and antagonised Kyn binding on CD4+ T cells, thereby inhibiting Treg differentiation in vitro. ICA phenocopied L. gallinarum effect and significantly improved anti-PD1 efficacy in vivo, which could be reversed by Kyn supplementation. Conclusion: L. gallinarum-derived ICA improved anti-PD1 efficacy in CRC through suppressing CD4+Treg differentiation and enhancing CD8+T cell function by modulating the IDO1/Kyn/AHR axis. L. gallinarum is a potential adjuvant to augment anti-PD1 efficacy against CRC.
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Cites
Cancer immunotherapy using checkpoint blockade
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Self-citation
Cited by
Gao, Z., Jiang, A., Li, Z., Zhu, L., Mou, W., Shen, W., Luo, P., Tang, B., Zhang, J., & Lin, A. (2025) · Med Research · doi:10.1002/mdr2.70006 · Cited by 51
Gut microbial metabolites in cancer therapy
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Zhang, Z., Zheng, K., Zhang, Z., Cao, L., Lin, L., Sun, W., & Qiu, F. (2025) · Microbial Cell Factories · doi:10.1186/s12934-025-02662-8 · Cited by 22
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Metadata
- Authors
- Fong, W., Li, Q., Ji, F., Liang, W., Lau, H. C. H., Kang, X., Liu, W., To, K. K.-W., Zuo, Z., Li, X., Zhang, X., Sung, J. J., & Yu, J.
- Venue
- Gut
- Publisher
- BMJ
- Published
- 2023-09-28
- Volume
- 72
- Issue
- 12
- Pages
- 2272-2285
- ISSN
- 0017-5749 (ISSN-L)
- 1468-3288
- OpenAlex
- W4387141604
- Cited by
- 312
- References
- 44
- FWCI
- 32.30
- Type
- journal article
- Language
- en
- Open access
- hybrid
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- Fong, W., Li, Q., Ji, F., Liang, W., Lau, H. C. H., Kang, X., Liu, W., To, K. K.-W., Zuo, Z., Li, X., Zhang, X., Sung, J. J., & Yu, J. (2023). Lactobacillus gallinarum-derived metabolites boost anti-PD1 efficacy in colorectal cancer by inhibiting regulatory T cells through modulating IDO1/Kyn/AHR axis. Gut. https://doi.org/10.1136/gutjnl-2023-329543
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