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Role of gut microbiota in the pathogenesis of castration-resistant prostate cancer: a comprehensive study using sequencing and animal models

Oncogene volume 43, pages 2373–2388 (2024)Cite this article

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Abstract

CRPC remains a significant challenge in prostate cancer research. We aimed to elucidate the role of gut microbiota and its specific mechanisms in CRPC using a multidisciplinary approach. We analyzed 16S rRNA sequencing data from mouse fecal samples, revealing substantial differences in gut microbiota composition between CRPC and castration-sensitive prostate cancer mice, particularly in Firmicutes and Bacteroidetes. Functional analysis suggested different bacteria may influence CRPC via the α-linolenic acid metabolism pathway. In vivo, experiments utilizing mouse models and fecal microbiota transplantation (FMT) demonstrated that FMT from healthy control mice could decelerate tumor growth in CRPC mice, reduce TNF-α levels, and inhibit the activation of the TLR4/MyD88/NF-κB signaling pathway. Transcriptome sequencing identified crucial genes and pathways, with rescue experiments confirming the gut microbiota’s role in modulating CRPC progression through the TLR4/MyD88/NF-κB pathway. The activation of this pathway by TNF-α has been corroborated by in vitro cell experiments, indicating its role in promoting prostate cancer cell proliferation, migration, and invasion while inhibiting apoptosis. Gut microbiota dysbiosis may promote CRPC development through TNF-α activation of the TLR4/MyD88/NF-κB signaling pathway, potentially linked to α-linolenic acid metabolism.

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Fig. 1: Comparison of gut microbiota species diversity in the CR group and Sham group.
Fig. 2: Differential analysis of the species composition of the intestinal microbiota between CR group and Sham group mice at different levels.
Fig. 3: Differential composition of gut microbiota at the genus level between CR and Sham groups as analyzed by LEfSe.
Fig. 4: Functional enrichment analysis of differential gut microbiota between the CR and Sham groups.
Fig. 5: Effect of broad-spectrum antibiotics (ABX) treatment on tumor growth in prostate cancer mice.
Fig. 6: Effects of fecal microbiota transplantation (FMT) on tumor growth and α-linolenic acid metabolism in castration-resistant prostate cancer mice.
Fig. 7: Selection of critical genes and pathways between the FMT (from ABX) group and the FMT (from NC) group.
Fig. 8: Effects of FMT on TNF-α and TLR4/MyD88/NF-κB signaling in mouse tumors and colon tissues.
Fig. 9: Effects of TNF-α on proliferation, migration, invasion, and apoptosis of DU-145 cells through the regulation of TLR4 expression.
Fig. 10: Effects of TNF-α gene knockout and FMT treatment on tumor growth and α-linolenic acid metabolism in castration-resistant prostate cancer mice.
Fig. 11: Gut Microbiota Activates TNF-α/TLR4/MyD88/NF-κB in Prostate Cancer Progression.

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Data availability

The datasets generated and/or analyzed during the current study are available in the manuscript and supplementary materials.

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Funding

This study was supported by Shanghai Medical Innovation Research Special Foundation (No.23Y11908800); Shanghai Natural Science Foundation (No.21ZR1414500); National Natural Science Foundation of China (No.82303856) and China Anti-cancer Association Foundation (No.YJQN202201).

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  1. These authors contributed equally: Guowen Lin, Feng Zhang, Xiaoling Weng.

Authors and Affiliations

  1. Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China

    Guowen Lin, Zhe Hong & Dingwei Ye

  2. Shanghai Genitourinary Cancer Institute, Shanghai, 200032, China

    Guowen Lin, Zhe Hong & Dingwei Ye

  3. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China

    Guowen Lin, Zhe Hong & Dingwei Ye

  4. Department Of Urology, Shanghai Eighth People’s Hospital, Shanghai, 200235, China

    Feng Zhang

  5. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China

    Xiaoling Weng

  6. Department of Urology, Huashan Hospital, Fudan University, Shanghai, 200040, China

    Gangmin Wang

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Contributions

Guowen Lin was involved in conceptualization, methodology, data curation, and the initial draft of the manuscript. Feng Zhang contributed to conceptualization, methodology, investigation, and reviewing and editing of the manuscript. Xiaoling Weng participated in methodology, data curation, and manuscript reviewing and editing. Zhe Hong was involved in methodology, investigation, and manuscript reviewing and editing. Dingwei Ye played a role in conceptualization, manuscript reviewing, editing, and funding support, and supervision of the project. Gangmin Wang contributed to conceptualization, manuscript reviewing and editing, and project supervision.

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Correspondence to Guowen Lin, Zhe Hong, Dingwei Ye or Gangmin Wang.

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All experiments involving mice were approved by the Animal Ethics Committee of Fudan University Shanghai Cancer Center (No. FUSCC-IACUC-S2023-0427).

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Lin, G., Zhang, F., Weng, X. et al. Role of gut microbiota in the pathogenesis of castration-resistant prostate cancer: a comprehensive study using sequencing and animal models. Oncogene 43, 2373–2388 (2024). https://doi.org/10.1038/s41388-024-03073-6

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