The microbiota comprises the microorganisms that live in close contact with the host, with mutual benefit for both counterparts. The contribution of the gut microbiota to the emergence of castration-resistant prostate cancer (CRPC) has not yet been addressed. We found that androgen deprivation in mice and humans promotes the expansion of defined commensal microbiota that contributes to the onset of castration resistance in mice. Specifically, the intestinal microbial community in mice and patients with CRPC was enriched for species capable of converting androgen precursors into active androgens. Ablation of the gut microbiota by antibiotic therapy delayed the emergence of castration resistance even in immunodeficient mice. Fecal microbiota transplantation (FMT) from CRPC mice and patients rendered mice harboring prostate cancer resistant to castration. In contrast, tumor growth was controlled by FMT from hormone-sensitive prostate cancer patients and Prevotella stercorea administration. These results reveal that the commensal gut microbiota contributes to endocrine resistance in CRPC by providing an alternative source of androgens.
Science (New York, N.Y.). 2021 Oct 07 [Epub]
Nicolò Pernigoni, Elena Zagato, Arianna Calcinotto, Martina Troiani, Ricardo Pereira Mestre, Bianca Calì, Giuseppe Attanasio, Jacopo Troisi, Mirko Minini, Simone Mosole, Ajinkya Revandkar, Emiliano Pasquini, Angela Rita Elia, Daniela Bossi, Andrea Rinaldi, Pasquale Rescigno, Penny Flohr, Joanne Hunt, Antje Neeb, Lorenzo Buroni, Christina Guo, Jonathan Welti, Matteo Ferrari, Matteo Grioni, Josée Gauthier, Raad Z Gharaibeh, Anna Palmisano, Gladys Martinetti Lucchini, Eugenia D'Antonio, Sara Merler, Marco Bolis, Fabio Grassi, Antonio Esposito, Matteo Bellone, Alberto Briganti, Maria Rescigno, Jean-Philippe Theurillat, Christian Jobin, Silke Gillessen, Johann de Bono, Andrea Alimonti
Institute of Oncology Research, Oncology Institute of Southern Switzerland, CH-6500 Bellinzona, Switzerland., Medical Oncology Unit, Oncology Institute of Southern Switzerland, Ente Ospedaliero Cantonale, 6500 Bellinzona, Switzerland., Theoreo Srl, Montecorvino Pugliano, 84090 Salerno, Italy., Candiolo Cancer Institute, FPO-IRCCS, Candiolo, 10060 Turin, Italy., Institute of Cancer Research and Royal Marsden NHS Foundation Trust, London, UK., Cellular Immunology Unit, IRCCS Ospedale San Raffaele, 20100 Milan, Italy., Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Florida College of Medicine, Gainesville, FL, USA., Experimental Imaging Center, San Raffaele Scientific Institute, 20100 Milan, Italy., Clinical Microbiology Unit, Ente Ospedaliero Cantonale, EOC, CH-6500 Bellinzona, Switzerland., Department of Medicine, Venetian Institute of Molecular Medicine, University of Padova, Padova, Italy., Institute for Research in Biomedicine, Faculty of Biomedical Sciences, Università della Svizzera Italiana, 6500 Bellinzona, Switzerland., Division of Oncology, Unit of Urology, URI, IRCCS Ospedale San Raffaele, Milan, Italy., IRCCS Humanitas Research Hospital, 20089 Rozzano, Milan, Italy., Faculty of Biomedical Sciences, Università della Svizzera Italiana, CH-1011 Lugano, Switzerland.