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Changes in the gut microbial profile during long-term androgen deprivation therapy for prostate cancer

Prostate Cancer and Prostatic Diseases (2023)Cite this article

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Abstract

Background

Recent studies have highlighted the association between androgen deprivation therapy (ADT) and the gut microbiota in prostate cancer. However, the impact of long-term ADT remains to be explored.

Methods

To examine changes in the gut microbial profile from short-term (a median of 7 months), and middle-term (a median of 18 months) to long-term ADT (>33 months), 16S rRNA data from 56 fecal samples were reanalyzed. Additionally, a two-sample Mendelian randomization was employed to investigate the relationships between particular microbial signatures and prostate cancer as well as testosterone levels.

Results

In contrast to the short- and middle-term ADT groups, the long-term ADT group had significant changes in alpha and beta diversity. In particular, the relative abundance of genera such as Catenibacterium and Holdemanella decreased in the long-term ADT group, whereas the opportunistic bacterium (Erysipelatoclostridium) and Ruminococcus gnavus showed increased abundance over ADT time. Moreover, a two-sample Mendelian randomization analysis revealed the negative associations between genetically predicated genera Coprobacter, Ruminococcaceae UCG002/011, and Defluviitaleacea-UCG-011, and testosterone levels.

Conclusions

In conclusion, long-term ADT use in prostate cancer patients was associated with detrimental changes in gut microbiota, including an increase in genera related to testosterone synthesis and opportunistic bacteria. These changes may be related to disease progression and side effects of long-term ADT while further longitudinal studies are required to prove this relationship.

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Fig. 1: Study workflow.
Fig. 2: The difference in gut microbiota profile of ADT groups.
Fig. 3: The taxonomic profiles in different ADT groups.
Fig. 4: Phylogenetic difference between groups.
Fig. 5: Microbial modules related to clinical features.
Fig. 6: Two-sample MR analysis between gut microbiota and prostate cancer and testosterone.

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Data availability

The 16S rRNA-seq was downloaded from the accession number PRJNA690135 [6]. The in-house R scripts used to perform microbial analysis by the “microeco” R package [37] and generate figures are available on GitHub (https://github.com/lynnLW/long-term-ADT).

References

  1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: Cancer J Clin. 2021;71:209–49.

    PubMed  Google Scholar 

  2. Zhu Y, Mo M, Wei Y, Wu J, Pan J, Freedland SJ, et al. Epidemiology and genomics of prostate cancer in Asian men. Nat Rev Urol. 2021;18:282–301.

    Article  CAS  PubMed  Google Scholar 

  3. Sharifi N, Gulley JL, Dahut WL. Androgen deprivation therapy for prostate cancer. JAMA. 2005;294:238–44.

    Article  CAS  PubMed  Google Scholar 

  4. Chandrasekar T, Yang JC, Gao AC, Evans CP. Mechanisms of resistance in castration-resistant prostate cancer (CRPC). Transl Androl Urol. 2015;4:365–80.

    PubMed  PubMed Central  Google Scholar 

  5. Karantanos T, Corn PG, Thompson TC. Prostate cancer progression after androgen deprivation therapy: mechanisms of castrate resistance and novel therapeutic approaches. Oncogene. 2013;32:5501–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Li JKM, Wang LL, Wong CYP, Chiu PKF, Teoh JYC, Kwok HSW, et al. A cross-sectional study on gut microbiota in prostate cancer patients with prostatectomy or androgen deprivation therapy. Prostate Cancer Prostatic Dis. 2021;24:1063–72.

    Article  CAS  PubMed  Google Scholar 

  7. Markowski MC, Sfanos KS. The interplay of microbiota and hormone regulation in men with prostate cancer. Prostate Cancer Prostatic Dis. 2021;24:935–6.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Sfanos KS, Markowski MC, Peiffer LB, Ernst SE, White JR, Pienta KJ, et al. Compositional differences in gastrointestinal microbiota in prostate cancer patients treated with androgen axis-targeted therapies. Prostate Cancer Prostatic Dis. 2018;21:539–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Routy B, Le Chatelier E, Derosa L, Duong CPM, Alou MT, Daillère R, et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science. 2018;359:91–7.

    Article  CAS  PubMed  Google Scholar 

  10. Terrisse S, Goubet AG, Ueda K, Thomas AM, Quiniou V, Thelemaque C, et al. Immune system and intestinal microbiota determine efficacy of androgen deprivation therapy against prostate cancer. J Immunother Cancer. 2022;10:e004191.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Pernigoni N, Zagato E, Calcinotto A, Troiani M, Mestre RP, Calì B, et al. Commensal bacteria promote endocrine resistance in prostate cancer through androgen biosynthesis. Science. 2021;374:216–24.

    Article  CAS  PubMed  Google Scholar 

  12. Segata N, Izard J, Waldron L, Gevers D, Miropolsky L, Garrett WS, et al. Metagenomic biomarker discovery and explanation. Genome Biol. 2011;12:R60.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Langfelder P, Horvath S. WGCNA: an R package for weighted correlation network analysis. BMC Bioinformatics. 2008;9:559.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Elsworth B, Lyon M, Alexander T, Liu Y, Matthews P, Hallett J, et al. The MRC IEU OpenGWAS data infrastructure. bioRxiv. 2020:2020.08.10.244293. https://doi.org/10.1101/2020.08.10.244293.

  15. Anderson MJ. Permutational multivariate analysis of variance. Department of Statistics, Univerisity of Auckland. 2005;26:32–46.

  16. Basaria S, Muller DC, Carducci MA, Egan J, Dobs AS. Hyperglycemia and insulin resistance in men with prostate carcinoma who receive androgen-deprivation therapy. Cancer. 2006;106:581–8.

    Article  CAS  PubMed  Google Scholar 

  17. Morgans AK, Fan KH, Koyama T, Albertsen PC, Goodman M, Hamilton AS, et al. Bone complications among prostate cancer survivors: long-term follow-up from the prostate cancer outcomes study. Prostate Cancer Prostatic Dis. 2014;17:338–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kelly TN, Bazzano LA, Ajami NJ, He H, Zhao J, Petrosino JF, et al. Gut microbiome associates with lifetime cardiovascular disease risk profile among bogalusa heart study participants. Circ Res. 2016;119:956–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Kure A, Tsukimi T, Ishii C, Aw W, Obana N, Nakato G, et al. Gut environment changes due to androgen deprivation therapy in patients with prostate cancer. Prostate Cancer Prostatic Dis. 2023;26:323–30.

  20. Zhong W, Wu K, Long Z, Zhou X, Zhong C, Wang S, et al. Gut dysbiosis promotes prostate cancer progression and docetaxel resistance via activating NF-κB-IL6-STAT3 axis. Microbiome. 2022;10:94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Fujita K, Matsushita M, Banno E, De Velasco MA, Hatano K, Nonomura N, et al. Gut microbiome and prostate cancer. Int J Urol. 2022;29:793–8.

    Article  CAS  PubMed  Google Scholar 

  22. Martins CDA, Rocha GDG, Gattass CR, Takiya CM. Pomolic acid exhibits anticancer potential against a docetaxel‑resistant PC3 prostate cell line. Oncol Rep. 2019;42:328–38.

    PubMed  Google Scholar 

  23. Matsushita M, Fujita K, Hayashi T, Kayama H, Motooka D, Hase H, et al. Gut microbiota–derived short-chain fatty acids promote prostate cancer growth via IGF1 signaling. Cancer Res. 2021;81:4014–26.

    Article  CAS  PubMed  Google Scholar 

  24. Ma Y, Zhu L, Ma Z, Gao Z, Wei Y, Shen Y, et al. Distinguishing feature of gut microbiota in Tibetan highland coronary artery disease patients and its link with diet. Sci Rep. 2021;11:18486.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Zapatero A, Guerrero A, Maldonado X, Alvarez A, Segundo CGS, Rodríguez MAC, et al. High-dose radiotherapy with short-term or long-term androgen deprivation in localised prostate cancer (DART01/05 GICOR): a randomised, controlled, phase 3 trial. Lancet Oncol. 2015;16:320–7.

    Article  CAS  PubMed  Google Scholar 

  26. Jain S, Samal AG, Das B, Pradhan B, Sahu N, Mohapatra D, et al. Escherichia coli, a common constituent of benign prostate hyperplasia-associated microbiota induces inflammation and DNA damage in prostate epithelial cells. Prostate. 2020;80:1341–52.

    Article  CAS  PubMed  Google Scholar 

  27. Tsai KY, Wu DC, Wu WJ, Wang JW, Juan YS, Li CC, et al. Exploring the association between gut and urine microbiota and prostatic disease including benign prostatic hyperplasia and prostate cancer using 16S rRNA sequencing. Biomedicines. 2022;10:2676.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Li L-Y, Han J, Wu L, Fang C, Li W-G, Gu J-M, et al. Alterations of gut microbiota diversity, composition and metabonomics in testosterone-induced benign prostatic hyperplasia rats. Military Med Res. 2022;9:12.

    Article  CAS  Google Scholar 

  29. Liu X, Tang H, Zhou Q, Zeng Y, Lu B, Chen D, et al. Gut microbiota composition in patients with advanced malignancies experiencing immune-related adverse events. Front Immunol. 2023;14:1109281.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Cai S, Yang Y, Kong Y, Guo Q, Xu Y, Xing P, et al. Gut Bacteria Erysipelatoclostridium and Its Related Metabolite Ptilosteroid A Could Predict Radiation-Induced Intestinal Injury. Front Public Health. 2022;10:862598.

  31. Freier TA, Beitz DC, Li L, Hartman PA. Characterization of eubacterium coprostanoligenes sp. nov., a cholesterol-reducing anaerobe†. Int J Syst Evol Microbiol. 1994;44:137–42.

    CAS  Google Scholar 

  32. Miller WL. Androgen biosynthesis from cholesterol to DHEA. Mol Cell Endocrinol. 2002;198:7–14.

    Article  CAS  PubMed  Google Scholar 

  33. Mohiuddin JJ, Baker BR, Chen RC. Radiotherapy for high-risk prostate cancer. Nat Rev Urol. 2015;12:145–54.

    Article  PubMed  Google Scholar 

  34. Mjaess G, Karam A, Roumeguère T, Diamand R, Aoun F, McVary K, et al. Urinary microbiota and prostatic diseases: the key for the lock? A systematic review. Prostate Cancer Prostatic Dis. 2022;26:451–60.

    Article  PubMed  Google Scholar 

  35. Lombardo R, Tema G, Cornu JN, Fusco F, McVary K, Tubaro A, et al. The urothelium, the urinary microbioma and men LUTS: a systematic review. Minerva Urol Nefrol. 2020;72:712–22.

    Article  PubMed  Google Scholar 

  36. Kwa WT, Sundarajoo S, Toh KY, Lee J. Application of emerging technologies for gut microbiome research. Singapore Med J. 2023;64:45–52.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Liu C, Cui Y, Li X, Yao M. microeco: an R package for data mining in microbial community ecology. FEMS Microbiol Ecol. 2021;97:fiaa255.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

Summary-level GWAS data for prostate cancer were obtained from the UK Biobank study (Neale Lab) and the FinnGen consortium. The 16S rRNA-seq data were obtained from the NCBI website which was uploaded by Prof. NG Chi Fai’s lab. We thank all investigators for sharing their public data.

Funding

The work was supported by grants from the Scientific Research Initiation Fund Project of Zhengzhou Central Hospital (KYQDJJ2023004).

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  1. Metabolic Disease Research Center, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, China

    Lin Wang

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Wang, L. Changes in the gut microbial profile during long-term androgen deprivation therapy for prostate cancer. Prostate Cancer Prostatic Dis (2023). https://doi.org/10.1038/s41391-023-00723-w

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