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  • Clinical Research
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Gut environment changes due to androgen deprivation therapy in patients with prostate cancer

Prostate Cancer and Prostatic Diseases volume 26, pages 323–330 (2023)Cite this article

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Abstract

Background

It is estimated that by 2040 there will be 1,017,712 new cases of prostate cancer worldwide. Androgen deprivation therapy (ADT) is widely used as a treatment option for all disease stages. ADT, and the resulting decline in androgen levels, may indirectly affect gut microbiota. Factors affecting gut microbiota are wide-ranging; however, literature is scarce on the effects of ADT on gut microbiota and metabolome profiles in patients with prostate cancer.

Methods

To study the changes of gut microbiome by ADT, this 24-week observational study investigated the relationship between testosterone levels and changes in gut microbiota in Japanese patients with prostate cancer undergoing ADT. Sequential faecal samples were collected 1 and 2 weeks before ADT, and 1, 4, 12, and 24 weeks after ADT. Blood samples were collected at almost the same times. Bacterial 16 S rRNA gene-based microbiome analyses and capillary electrophoresis-time-of-flight mass spectrometry-based metabolome analyses were performed.

Results

In total, 23 patients completed the study. The α- and ß-diversity of gut microbiota decreased significantly at 24 weeks after ADT (p = 0.017, p < 0.001, respectively). Relative abundances of Proteobacteria, Gammaproteobacteria, Pseudomonadales, Pseudomonas, and concentrations of urea, lactate, butyrate, 2-hydroxyisobutyrate and S-adenosylmethionine changed significantly after ADT (p < 0.05). There was a significant positive correlation between the abundance of Proteobacteria, a known indicator of dysbiosis, and the concentration of lactate (R = 0.49, p < 0.01).

Conclusions

The decline in testosterone levels resulted in detrimental changes in gut microbiota. This dysbiosis may contribute to an increase in frailty and an increased risk of adverse outcomes in patients with prostate cancer.

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Fig. 1: Study design and overview.
Fig. 2: Variations in the gut microbiome before and after ADT.
Fig. 3: Changes in the relative abundance of Proteobacteria, Gammaproteobacteria, Pseudomonadales, Pseudomonas and Turicibacter for each prostate cancer patient with data for all time points pre- and post-ADT at each sample time point (n = 10).
Fig. 4: Variations in the faecal metabolome for each prostate cancer patient with data at all time points before and after ADT at each sample time point (n = 10): urea, S-adenosylmethionine, 2-hydroxyisobutyrate, lactate and butyrate.
Fig. 5: Correlation analysis between microbes and metabolites from faecal samples of 10 prostate cancer patients with data at all time points pre- and post-ADT.

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Data availability

The data collected for this study are available on request. Please note that the data for participant number 1 was collected during the study after deidentification; these data included gut microbiota genome analyses and clinical information, but no end of study data are available for this participant. The 16 S rRNA gut microbiota gene sequences have been deposited in the DDBJ database (http://getentry.ddbj.nig.ac.jp/) under accession number DRA009707. The clinical data are available on permission of the corresponding authors (sfukuda@sfc.keio.ac.jp and shorie@juntendo.ac.jp).

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Acknowledgements

We are grateful to the study participants. We would like to thank Yuka Ohara, Mitsuko Komatsu, Noriko Kagata, Noriko Fukuda, and Naoki Tanigawa for their technical support. Medical writing support, in accordance with GPP guidelines, was provided by Mediwrite Asia Inc Pte Ltd and included proofreading and editing services. This work was supported in part by JSPS KAKENHI (18H04805 to SF), AMED-CREST (JP20gm1010009 to SF), JST ERATO (JPMJER1902 to SF), the Takeda Science Foundation (to SF), the Food Science Institute Foundation (to SF), and the Programme for the Advancement of Research in Core Projects under Keio University’s Longevity Initiative (to SF).

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Authors and Affiliations

  1. Department of Urology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan

    Akimasa Kure, Haruna Kawano, Toshiyuki China, Fumitaka Shimizu, Masayoshi Nagata, Shinji Isotani, Satoru Muto & Shigeo Horie

  2. Institute for Advanced Biosciences, Keio University, 246-2 Mizukami, Kakuganji, Tsuruoka, Yamagata, 997-0052, Japan

    Akimasa Kure, Tomoya Tsukimi, Chiharu Ishii, Wanping Aw, Akiyoshi Hirayama & Shinji Fukuda

  3. Transborder Medical Research Centre, Faculty of Medicine, University of Tsukuba, 1–1–1 Tennodai, Tsukuba, Ibaraki, 305–8575, Japan

    Akimasa Kure, Nozomu Obana & Shinji Fukuda

  4. Systems Biology Programme, Graduate School of Media and Governance, Keio University, 5322 Endo, Fujisawa, Kanagawa, 252-0882, Japan

    Tomoya Tsukimi, Chiharu Ishii, Wanping Aw, Akiyoshi Hirayama & Shinji Fukuda

  5. Kanagawa Institute of Industrial Science and Technology, Life Science & Environment Research Centre (LiSE) 4th floor Room 4C-6, 3-25-13 Tonomachi, Kawasaki-ku, Kawasaki-shi, Kanagawa, 210-0821, Japan

    Gaku Nakato & Shinji Fukuda

  6. Department of Advanced Informatics for Genetic Diseases, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan

    Satoru Muto & Shigeo Horie

Authors
  1. Akimasa Kure
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Contributions

SF and SH designed the project. AK, TT, and CI performed the main part of microbiome and metabolome analysis. AK, TT, CI, and WA wrote the draft of manuscript. SF supervised the project and wrote the paper. NO, GN, AH, HK, TC, FS, MN, SI, and SM contributed to experimental design and data analysis. All authors reviewed and edited the manuscript.

Corresponding authors

Correspondence to Shigeo Horie or Shinji Fukuda.

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The authors declare no competing interests.

Ethics approval and consent to participate

This study was conducted in accordance with the ethical principles of Declaration of Helsinki. The samples and clinical information used in this study were obtained by written informed consent and with the approval of the institutional review boards of Juntendo University school of Medicine (Approval number: 14-117). This study was also registered in the UMIN clinical registry (UMIN000021161).

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Kure, A., Tsukimi, T., Ishii, C. et al. Gut environment changes due to androgen deprivation therapy in patients with prostate cancer. Prostate Cancer Prostatic Dis 26, 323–330 (2023). https://doi.org/10.1038/s41391-022-00536-3

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