Castration-resistant prostate cancer (CRPC) is usually treated with androgen deprivation therapy to reduce circulating androgens, slowing tumor growth. However, after an initial response, tumors can develop various mechanisms of resistance, resulting in bad prognoses. The human gastrointestinal tract hosts a wide range of bacteria that live in close contact with the host, usually with mutual benefit. Perturbations of this equilibrium can occur under pathological conditions, including cancer. So far, only a limited number of studies have investigated the role of the gut microbiota in prostate cancer initiation and progression.

The aim of Arianna Calcinotto, Nicolò Pernigoni, and Elena Zagato was to understand the role of gut microbiota in CRPC. Specifically, they investigated whether a disbalance of gut microbiota promotes CRPC progression and whether this effect can be counteracted through therapeutic intervention via microbiota manipulations. The researchers performed microbiota elimination experiments using broad-spectrum antibiotics in laboratory mouse strains which are susceptible to the development of CRPC. Moreover, through fecal transplantation experiments, they investigated, whether a new gut microbiota could accelerate or control tumor growth in mice and patients. 

In fact, the intestinal microbiota of CRPC-bearing mice and patients is enriched with specific bacterial species, capable of producing androgens, hence fueling tumor growth even under androgen deprivation therapy. The researchers showed that gut microbiota from both mice and humans with CRCP accelerated CRPC progression, enriching androgen-producing bacterial species in the hosts. In contrast, under antibiotic therapy, a delay in CRPC emergence could be observed in mice. The researchers identified a “favorable” bacterial signature, associated with a better prognosis, and an “unfavorable” bacterial signature, associated with poor clinical outcome.

The discovery that bacteria can contribute significantly to circulating androgens paves the way to potential adjuvant therapeutic strategies. Moreover, intestinal microbiota signatures might predict prostate cancer outcome. Clinical studies are required to examine these strategies.

Commensal bacteria promote endocrine resistance in prostate cancer through androgen biosynthesis. 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 6, 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. Science. 2021 Oct 8;374(6564):216-224.
* Contributed equally