What does the population of bacteria in your gut (called the gut “microbiome”) have to do with prostate cancer? Just how important is this gut flora, or bacteria, anyway? It’s not even in the prostate!
Let’s look at the second question first. How important is your gut bacteria? It’s very important to your whole body: your brain, your heart, your immune system – and, although no one has proven it yet, we suspect that it is also very important to your prostate.
Recently, scientists studying colon cancer found that certain bacteria are found in half of all colon tumors and when the cancer spreads, the bacteria spread right along with them. In another study, scientists found that two different forms of bacteria work together, like fertilizer, to help colon cancers grow. In still other work, scientists studying melanoma found that the presence of certain gut bacteria can change how cancer patients respond to immunotherapy.
Could treating the bacteria help prevent prostate cancer, make it less likely to spread, or make immunotherapy more effective against it? PCF believes the answer may be yes to all of these questions, and has invested $1 million in research to help us understand more about the gut microbiome’s role in prostate cancer. Call it a “gut feeling.”
Eight Pounds of Your Body Is Just Bacteria
Consider this: A lot of us have been exposed to bad bacteria, but these bugs don’t kill us. In our large intestine, we have about eight pounds or so of trillions of bacteria; in fact, we have more bacteria than cells in our bodies. Some of them are good, and some of them are not so good.
But some people die from bacterial infections in the gut; what happens to make them more susceptible? Dysbiosis: an imbalance, where the bad bacteria take over. Here’s an example: say you have an upper respiratory infection, and you get antibiotics. Antibiotics wipe out bacteria. They don’t distinguish between good and bad species; they just kill ‘em all. The good bacteria are collateral damage, and sometimes this scorched-earth result creates an opportunity for very bad bacteria to thrive in your gut. What’s going to fix that, more antibiotics? Maybe, but not always. In fact, when you wipe out the gut flora with antibiotics, an even worse form of bacteria – something like C. difficile, for instance – can take over.
Again, what does this have to do with prostate cancer? Here we go: If antibiotics fail, the most effective way to cure intractable C. difficile is with a fecal transplant: basically, taking the poop of someone who does not have C. difficile, who has a healthy gut microbiome, and inserting it in your colon. It’s gross, but it can also save someone from chronic, miserable illness.
Johns Hopkins scientist Karen Sfanos, PhD, is one of a few pioneering cancer researchers wondering if the same principle could apply to treating prostate cancer. The first step for her and her colleagues at Hopkins and Thomas Jefferson is to look at gut bacteria – a heck of a lot of it, in at least a thousand patients undergoing various treatments for advanced prostate cancer. As principal investigator of a $1 million PCF challenge award to learn more about the relationship between the gut microbiome and metastatic prostate cancer, Sfanos is stockpiling gut bacteria and building a microbiome specimen repository that will serve as an international database for research.
Sfanos, a molecular microbiologist, has long been interested in the relationship between bacteria and prostate cancer; in fact, she is among a growing number of scientists who are proving that urine is not (as scientists supposed for decades) sterile, and was the first to describe the urinary microbiome in men with and without prostate cancer. Bacteria in the urinary microbiome may shed light on the presence of microbes that can cause prostate infections, including some that are sexually transmitted infections. These microbes may produce no symptoms but may lead to chronic inflammation – and this, in turn, may cause prostate cancer in some men.
Meanwhile, a few studies looking at other forms of cancer “started to indicate that the gut microbiome could have an influence on treatment response,” Sfanos says, “and that really got us thinking about whether the gut microbiome could influence how well men respond to prostate cancer treatment.”
In studies with PCF-funded investigator Julie Graff , MD, of Oregon Health & Science University, Sfanos has been working to see if there is a difference in the gut microbiome of men with widely metastatic prostate cancer who have responded dramatically well to the checkpoint-inhibiting immunotherapy drug, pembrolizumab.
Originally, Graff and colleagues suspected that the men who were exceptional responders to this drug had cancers with “microsatellite instability” (they had tumors with many genetic mutations) – which made the cancer cells stand out and be more easily recognizable as enemies to the immune system. And this is undoubtedly true, but it’s not the whole story.
In Graff’s initial small study , published in Oncotarget, three men out of 10 had dramatic responses: their metastatic tumors in the liver, brain, and elsewhere disappeared, and their PSA levels plunged. Tumor tissue from two of these men was available for further analysis and, indeed, one of the men’s tumors had microsatellite instability. But the other man’s tumor did not. The number of tumor mutations, explains Sfanos, “cannot fully explain those responses to immunotherapy,” in Graff’s and other studies. “People who do not have that phenotype are still having dramatic responses.”
For these men, “the gut microbiome could be contributing in several ways. If the immune system is blocked from recognizing the tumors,” because the cancer uses sneaky tricks and devious disguises to hide itself from the body’s roving immune system soldiers that would kill it, “the right mix of bacteria could help stimulate the immune system – and combining that with the immune checkpoint inhibitor might drive a robust anti-tumor immune response. So that could explain what’s happening in patients who do have this high mutational burden.”
What about the other people with various forms of cancer who do have microsatellite instability – the weird-looking, multi-mutated tumors that the immune system can see and say, “Hey, that’s not supposed to be here!” Why do only some of them respond well to immunotherapy? The gut may be helping them, too. Is it diet? Do these people just eat better, and thus have a healthier gut microbiome?
“Certainly, diet does have a profound influence on the composition of your gut flora,” says Sfanos. To understand more, it’s time to look at your poop – or rather, at the poop of men with advanced prostate cancer who are contributing to this repository – in a very high-tech way. With each fecal sample, Sfanos and colleagues extract all of the bacterial DNA and RNA. They’re generating “microbiome profiles” that include bacteria, viruses, fungi, and protozoa. Then, they are correlating the gut flora with the treatment the men are receiving – and hoping to find answers to so many questions.
“I am extremely interested in the interplay between bacteria and circulating hormones,” says Sfanos. Does ADT – androgen-deprivation therapy, which deprives prostate cancer of the androgens, or male hormones, that nourish it – change the makeup of bacteria in the gut? “It’s an under appreciated relationship: they influence each other. The gut bacteria influence the circulating androgen levels, and vice versa. They’re talking to each other.”
In one ongoing study , “we looked at the gut flora of men across the prostate cancer spectrum,” Sfanos notes – men without prostate cancer, men with localized prostate cancer, men with recurrent prostate cancer, and men with metastatic prostate cancer. “We were really interested in determining if there are differences based on what treatments the men were being given. Oral anti-androgens, including abiraterone and enzalutamide, “may directly interact with the gut flora. We found that these men in our study had measurable differences in the composition of their gut flora. Something specific is going on in the men taking oral anti-androgens.” In further analyses, Sfanos and colleagues found that in men taking these drugs, “there are bacteria capable of hormone biosynthesis in the gut: microbes able to synthesize and metabolize precursors that can be hormones. This could potentially influence treatment response.” In other words, some gut bacteria can synthesize androgens that “could maybe even continue to nourish the tumor. We are very actively studying this right now.”
The gut flora, she adds, are “absolutely linked” to some of the other health problems that can accompany ADT, particularly metabolic syndrome. “This is very understudied in men with prostate cancer.”
What might this research lead to? How could it help men with advanced prostate cancer fight their disease? Here’s one example Sfanos can envision. “Let’s say we discover a species of bacteria that’s capable of metabolizing an androgen,” a nasty bug that could counteract the effects of abiraterone by whipping up its own homemade batch of male hormones. “If depriving men of androgens leads to an outgrowth of some bacteria that can make their own androgen, we could check for them in a patient’s stool sample and try to get rid of them.”
Boosting the immune system: The epithelial barrier, the thin lining of the intestinal wall, is a virtual Checkpoint Charlie for immune system activity. This is a gateway with “a massive amount of immune cells on one side, and bacteria on the other side,” Sfanos notes. “Several studies have shown that certain species of bacteria are overrepresented in the gastrointestinal tract of people who respond to immunotherapy.” One research group has focused in on a group of bacteria called Ruminococcaceae, and another is studying a microbe called Akkermansia muciniphila. Either of these, or both, may turn out to be very important. “The idea is that if, for whatever reason, the presence of these microbes is essential to generate a response to immunotherapy, you would want to introduce these bacteria,” in a fecal transplant or perhaps in the form of a targeted prebiotic or probiotic.
There probably won’t turn out to be one “magic bullet” form of bacteria, which is why a fecal transplant might be helpful. It is an intriguing idea: taking the gut bacteria from someone who responds extremely well to immunotherapy, and transplanting that – in poop form – into the colon of someone whose gut bacteria is not as beefed up for cancer-fighting. Would this stimulate the immune system so that it would knock out the cancer? Could it turn flabby, couch potato bacteria into ripped, mighty, cancer-fighting bacteria? And could this beefed-up bacteria help put your cancer into remission?
It’s early days yet. But if the bacteria within our bodies can shape how our immune system functions, if it can help determine how we respond to cancer treatment – or even whether we get cancer at all – then understanding the very complicated interplay between gut bacteria and cancer could be a game-changer.
“Historically, many prostate cancer biobanks have not included fecal samples,” says Sfanos. This means that nobody has correlated the other markers for how prostate cancer develops or progresses – PSA, Gleason score, genetic mutations, or clinical outcomes – with what’s happening in the gut.
Thanks to Sfanos and colleagues, that’s not the case anymore. Stay tuned.