What is already known on this topic
Androgens promote the growth of prostate tumor cells, so androgen deprivation therapy (ADT) is the most common treatment for people with advanced prostate cancer. However, some individuals develop resistance to ADT, which leads to tumor growth.

What this research adds
Researchers found that ADT promotes the expansion of specific gut bacteria that can synthesize androgens, both in mice and people. In rodents, microbial-derived androgens that circulate in the body led to tumor growth, but using antibiotics to kill off the gut bacteria significantly slowed tumor progression. Fecal transplants from people and rodents who responded to ADT could control tumor growth in ADT-resistant mice.

Conclusions
The findings could help explain why some people develop resistance to ADT, and may lead to the development of microbiota-based treatments to overcome this resistance.

Androgens promote the growth of prostate tumor cells, so androgen deprivation therapy (ADT) is the most common treatment for people with advanced prostate cancer. However, some individuals develop resistance to ADT, which leads to tumor growth. Now, researchers have found that ADT promotes the expansion of specific gut bacteria that can synthesize androgens, thus promoting tumor progression

The findings, published in Science, could help explain why some people develop resistance to ADT, and may lead to the development of microbiota-based treatments to overcome this resistance.

Several studies have shown that the microbiota is important for the activity of anticancer therapies, and it can promote favorable responses to treatment in cancer patients. Previous research on prostate tumor in mice and people suggests that the prostate microbiota can support tumor growth by promoting long-term inflammation. However, the role of the gut microbiota in prostate cancer initiation and progression remains unclear. 

“Given the role played by the gut microbiota in cancer, an intriguing hypothesis is that the intestinal microbiota of patients suffering from prostate cancer could also participate in the host’s hormone metabolism, thus affecting prostate cancer growth,” the researchers say.

Andrea Alimonti at the Università della Svizzera Italiana and his colleagues analyzed the gut microbiota of prostate cancer patients treated with ADT and of two mouse models of ADT-resistant prostate cancer.

Driving resistance

Advanced prostate cancer patients on ADT showed an altered gut microbiota composition, with increased abundances of bacterial species that can synthesize androgens, the researchers found. In particular, the gut microbiota of people with ADT-resistant prostate cancer had increased levels of Ruminococcus species.

Similarly, androgen deprivation in mice promoted the expansion of gut bacteria such as Ruminococcus gnavus and Bacteroides acidifaciens. The presence of these species, which can produce androgens that circulate in the body, promoted tumor growth and progression.

To kill off gut bacteria, the team treated tumor-bearing mice with a cocktail of broad-spectrum antibiotics. Tumor progression was significantly slowed in rodents treated with antibiotics, the researchers found. Antibiotic treatment also reduced the levels of the androgen hormone testosterone.

Bacterial signature

To assess the role of gut microbes in sustaining ADT-resistant prostate cancer growth, the researchers performed fecal microbiota transplants. Transferring fecal microbes from people and mice who responded to ADT into rodents with ADT-resistant prostate cancer could control tumor growth in ADT-resistant mice.

Feeding mice with Prevotella stercorea also decreased the growth of ADT-resistant tumors, likely because the microbe competes with androgen-producing bacteria. The presence of P. stercorea microbes in the gut microbiota was associated with improved survival of prostate cancer patients, whereas the presence of Oscillospiraceae bacteria was associated with decreased survival, the researchers found.

“Our findings, if further validated in the clinic, may provide novel opportunities for the therapy of prostate cancer patients,” the researchers say. What’s more, the team identified a microbial signature associated with reduced survival in people with advanced prostate cancer. If confirmed in larger studies, the team adds, “this signature might be used as a minimally invasive biomarker to identify patients that could benefit from microbiota manipulation strategies.”