Gut check

Scientist identify a complex link between gut bacteria and prostate cancer

A widely used treatment for advanced prostate cancer can be thwarted by gut microbiota.

In 1981, Barry Marshall had a hunch.

The Australian gastroenterologist believed a spiral-shaped bacteria called H. pylori was responsible for stomach lining inflammation, one of the first signs of stomach cancer. When his initial research on mice garnered a mixed response from his peers, he tried his hypothesis on himself.

Marshall and his mentor Robin Warren eventually won the Nobel Prize for discovering a link between gut bacteria and disease, a topic that’s now explored in every facet of medicine from inflammatory bowel disease to depression.

New research is pushing Marshall’s ideas forward, suggesting that a better understanding of gut bacteria could make prostate cancer therapies more effective.

In a study published Friday in the journal Science, researchers found one of the most widely used treatments for advanced prostate cancer — androgen deprivation therapy (ADT) — can be thwarted by gut microbiota. In turn, methods designed to target and hinder certain gut bacteria could help this type of cancer therapy become more successful.

What you need to know first — Prostate development is influenced by hormones — mostly growth and reproductive hormones called androgens — mostly produced by the testicles. Testosterone, for example, is an androgen.

Ruminococcus gnavus was found in patients who were less receptive to androgen deprivation therapy. Michael Henke/Harvard Medical School

“When the cells in the prostate age and become abnormal or cancerous, their growth is still controlled by the androgens that were responsible for the formation of the prostate in the first place,” Dr. Giorgio Trinchieri, chief of the National Cancer Institute’s Laboratory of Integrative Cancer Immunology, tells Inverse. Trinchieri is the co-author of a related perspective published alongside the new study.

Scientists have understood for decades that this control allows androgens to speed cancer growth. For this reason, ADT is one of the most widely used treatments for advanced prostate cancer.

Blocking androgen production usually slows cancer growth for a long time. However, cancer cells can eventually evolve to be able to grow without androgens and stop responding to ADT.

Ruminococcus gnavus is also found in higher proportions among people with Crohn’s disease.NIH

“This cancer treatment works better when the androgens are blocked as completely as possible, but in some cases, some androgens are still present in the prostate and the patients’ disease worsens faster,” Trinchieri explains.

In the new Science study, the research team finds this ADT resistance may be coming from an unsuspecting place — gut bacteria.

What’s new — The researchers discovered certain gut bacteria — Ruminococcus gnavus and Bacteroides acidifaciens in higher proportions among people who resist ADT and have an advanced stage of prostate cancer, called castration-resistant prostate cancer. These gut bacteria produce the very hormones ADT works to suppress.

By comparing the gut microbiomes of both mouse and human models, they were able to take the first step in creating a microbial blueprint of bacteria that influence prostate cancer outcomes.

Pinpointing how specific gut bacteria contribute to ADT resistance could help prevent the cancer treatment from failing. The team has already tested two courses of action in mice models.

For example, they found that using antibiotics to kill gut bacteria in mice delayed ADT resistance, though at the expense of all gut bacteria, good or bad. In some cases, fecal transplants from patients and mice who were susceptible to ADT — meaning the therapy was still working for them — were able to control tumor growth in resistant mice.

What’s next — Research around redesigning the gut microbiome to prevent cancer treatments from failing is still relatively new, and there are still questions future research will have to answer. For starters, the new study didn’t uncover why androgen-producing bacteria increase in some people during ADT.

However, the new research also unexpectedly uncovered new information about how current therapies work.

The gut, or gastrointestinal tract, stretches from the mouth to the anus and includes the stomach (seen here).BSIP/UIG Via Getty Images

There are two drugs currently used in ADT. One, androgen receptor blockers, prevent the effect of androgen from reaching prostate cells regardless of how or where the hormone is produced.

But drugs that block androgen production are theoretically only effective in blocking androgens produced through the normal pathways — not by bacteria.

“The authors somewhat unexpectedly show that at least one of these drugs, Abiraterone, also blocks the production of androgens from bacteria,” Trinchieri says. “The clinical application of these data may not necessarily or uniquely be the targeting of the microbiome.”

Doctors also have the bonus of better understanding which current drugs may work best for patients based on the bacteria living in their gut, and which drugs are able to target bacteria-produced androgens.

The future of cancer treatment

According to Trinchieri, research conducted in mice can’t always be applied to humans, since the two species differ in many ways.

But that doesn’t mean the new research isn’t promising. The fact that androgen-producing bacteria were found at higher levels in both human patients and in mice undergoing ADT means there's a strong possibility that the mouse treatments may be effective in humans too, he says.

“Antibiotics or a fecal transplant may reduce androgen-producing bacteria.”

The results are particularly promising since the gut microbiome has been implicated in other cancers as well.

For example, a small study published in July in Science targeted specific gut microbiota known to interfere with immunotherapy melanoma treatments. The researchers, including Trinchieri, conducted the first human trial that used fecal transplants to attempt to redesign the gut microbiome to be more conducive to cancer therapies. In six of the 15 patients, it worked.

According to Trinchieri, targeted treatments are key when working with an ecosystem.

“The relative number of bacteria in the gut depends on maintaining equilibrium with all the other bacteria. We really are not yet able to kill off one or two bacterial species while preserving the others,” says Trinchieri. “Antibiotics or a fecal transplant may reduce androgen-producing bacteria at the expense of killing other species and disrupting the ecosystem.”

Because ADT is a long-term therapy used to keep tumors from growing rapidly, rather than curing prostate cancer, future treatments for ADT resistance will need to be effective long-term.

“Using a species that ecologically competes with the androgen-producing bacteria may be a smart approach,” says Trinchieri.

Abstract: 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.
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