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The gut microbiome plays an important role in how patients may respond to cancer treatments, and researchers are learning more about ways to alter it to benefit treatment outcomes.
On the same day in March 2018, three things happened in the life of Lorenzo Cohen, professor and director of the Integrative Medicine Program at The University of Texas MD Anderson Cancer Center in Houston. First, he and his wife signed off on the final draft of their book “Anticancer Living: Transform Your Life and Health With the Mix of Six,” focused on cancer prevention and improving outcomes for those with cancer. Next, he received an email from the Melanoma Research Alliance telling him they would fund his study on lifestyle factors in patients with melanoma. Finally, he learned that the node that had been growing in his left armpit in recent weeks was stage 3 melanoma with unknown primary location.
“That means the immune system did what it had to do to knock out the (original tumor that began the cancer) but not soon enough before a few cells started to grow in the (armpit),” Cohen, who holds a postdoctorate degree, explains. He started taking a combination of Yervoy (ipilimumab) and Opdivo (nivolumab) as neoadjuvant immunotherapy — treatment given before surgery to shrink the tumor first. It was soon obvious the immunotherapy was working. “The nodes just started melting away,” he says.
But he wanted to do more for his therapy. Cohen is an expert on lifestyle habits that reduce risk of cancer and improve outcomes in those with cancer, and he had studied how psychological factors influence hormones that then affect the immune system. He knew, for example, that chronic stress weakens the immune system and can alter the microenvironment around a tumor, making it more hospitable to cancer growth.
“Stress was the first thing I knew I had to manage better,” he says. He doubled down on yoga, meditation and exercise because “the evidence is overwhelming that regular physical activity makes a huge difference on immune function and activation,” he says. He also started taking a beta-blocker, a drug that lowers heart rate and blood pressure by blocking the effects of a stress hormone and potentially reducing the effect of stress within the tumor microenvironment. He then turned to his diet. Cohen was familiar with the research of his colleague, Dr. Jennifer Wargo, a surgical oncologist at MD Anderson who studies how melanoma patients respond to immunotherapy based on the bacteria in their guts. He planned to use current evidence to improve his own gut bacteria, but he would discover that trying to manipulate the makeup of bacteria in our bodies can be tricky.
Wargo discovered early in her career that bacteria in pancreatic cancer tumors could break down chemotherapy into its inactive form. She began studying the millions of microbes that grow in a tumor alongside the cancerous cells, which is known as the tumor microbiome. Soon she was investigating the human gut microbiome, a community of organisms that has a far bigger effect on human health than researchers realized even a decade ago.
“In our bodies, there are hundreds of trillions of microbes that outnumber our cells,” Wargo says, adding that only a fraction of cells in our bodies are human. The rest are bacteria, viruses, fungi and other microbes. “There are more microbial genes in our body than there are stars in the galaxy,” she says. “It goes without saying that these microbes could have an impact on the way our body functions and how it may react to cancer treatment.”
Scientists have learned that these bacteria can help break down food and fight illness, or they can cause inflammation or contribute to chronic disease. It all depends on the balance of “good” and “bad” microbes in the gut, where the majority of the microbiome flourishes. Though researchers are still learning what makes a healthy microbiome, they know genetics, age, diet, lifestyle, medications, the environment and other factors can affect it. Antibiotics, for example, can wipe out good bacteria. Cancer treatments, including surgery, chemotherapy and radiation, also can disrupt the microbiome’s balance.
Research into the microbiome has touched nearly every area of medicine, from gastrointestinal disorders to heart disease, autism to Alzheimer disease, obesity to cancer. But scientists are in the earliest stages of learning how to alter the microbiome or restore imbalances. One way to modify gut bacteria is increasing or decreasing probiotic intake — the microorganisms themselves — or prebiotics, the fibrous foods that feed the bacteria. For example, taking probiotic supplements or eating fermented foods rich with bacteria can sometimes offset the negative effects of antibiotics that kill off too much good bacteria.
Another option is a fecal microbiota transplant, in which fecal matter of a healthy donor (first screened for harmful, infectious germs) is transplanted into another person’s gastrointestinal (GI) tract to restore the balance of healthy bacteria. This is done through a colonoscopy or through a pill or liquid. Fecal transplants are already the standard of care for recurrent Clostridium difficile infections, which occur in up to 10% of patients with cancer undergoing chemotherapy and 20% of all people with cancer.
But aside from those treatments, fecal transplants for other conditions are still only in trials, not treatment rooms, explains Dr. Saranya Chumsri, an oncologist specializing in breast cancer at Mayo Clinic in Jacksonville, Florida.
“We’re not quite there yet in the cancer world,” she says, but scientists are making headway. Chumsri has been conducting studies with over-the-counter probiotics to learn whether these supplements or other microbiome restoration products can improve treatment responses in patients with breast cancer, but it’s tricky to figure out the best combination of bacteria to offer.
“Studies show that if you have diverse gut microbiome — not just species but more diversity of the type of bacteria in the gut — it’s actually more protective for cancer,” she says. But it’s not always as simple as taking pills from the store.
“The problem with over-the-counter probiotic capsules is that they break apart in the stomach,” Chumsri explains. The stomach’s low pH can kill the bacteria before it reaches the rest of the gut, so researchers are looking at other options.
As scientists have learned how integral gut bacteria is to the immune system, the microbiome has received more attention in cancer research.
“Although our immune (system) originally evolved to fight microbes, it has actually become tolerant of some of them, and they shape how our immune system functions,” Wargo says. “Depending on what the bugs look like, your gut can influence your response to immunotherapy.”
Two studies in 2015 found that the microbiomes of mice can affect how well they respond to checkpoint inhibitor drugs and that researchers could change their microbiomes to improve the mice’s response. More recent research involving patients with cancer has found that differences in gut bacteria composition are linked to survival rates after bone marrow/stem cell transplants and may be able to reduce GI side effects from cancer treatment.
“I see a lot of patients referred to me with diarrhea and colitis,” says Dr. Pankaj Vashi, a gastroenterologist and vice chief of staff at Cancer Treatment Centers of America (CTCA) in Chicago. “If you give them doses of good bacteria (during) immunotherapy, it can reduce the incidence of colitis.” Vashi has seen other patients experience lower levels of toxicity to immunotherapy for kidney or lung cancer if their gut microbiome has the right mix of bacteria.
The question is whether it’s possible to modify patients’ microbiomes to achieve better response rates or less toxicity with cancer treatments. The most progress with these experiments is seen in patients with melanoma.
A study published in 2017 by Wargo and colleagues examined the gut microbiome of 112 patients with melanoma receiving anti-PD-1 immunotherapy, which not only kill cancer cells directly but block a pathway that protects tumor cells from the components of the immune system that fight cancer. Patients who responded to the therapy had higher rates of diversity and more Ruminococcaceae bacteria. It was research such as this that inspired Cohen to see if he could improve the diversity of his microbiome.
“Your microbiome is totally dependent on what you eat,” Vashi says. “If you eat a lot of fast foods and synthetic foods, you’re going to have issues with your gut microbiome.”
Those who eat lots of fruits, vegetables, lentils and legumes, however, tend to experience fewer side effects and have better outcomes overall.
Cohen was already eating a mostly whole food vegan diet, with occasional eggs or cheese. But after receiving his diagnosis, he increased his intake of probiotic-rich foods and reduced his carbohydrates, having read that spikes in insulin after eating carbs can negatively affect tumor microenvironments. He swapped out healthy grains such as oatmeal and quinoa for fermented foods such as miso, kombucha, sauerkraut, a liquid probiotic drink and nondairy yogurts fortified with extra bacteria.
He signed up as a participant in his own study — the one he was conducting with Wargo and others that had received funding the day he received his diagnosis — so he could analyze changes in his microbiome. Three months after his initial microbiome sample, he was startled to find less biodiversity in his gut than when he started. He stayed on the diet and analyzed another sample three months later: Again, it had less biodiversity than his first sample.
“I needed to do something, so I decreased the amount of probiotic food and increased healthy grains — quinoa, buckwheat, oatmeal, maybe 2 to 3 tablespoons a day of a healthy whole-grain mush,” he says. Another three months later, his microbiome’s diversity was better than it had been at the start of the study. Though he can’t be sure of the exact cause, it seemed that increasing his healthy microorganisms with extra food-based probiotics while decreasing prebiotics led to dysbiosis, an imbalance in his gut bacteria, and a decrease in the diversity of his gut bacteria.
Cohen, Wargo and their colleagues presented preliminary findings of that study in 2019. Among 46 patients with melanoma, those who ate a high-fiber diet rich in whole grains, fruits and vegetables were five times more likely to respond to anti-PD-1 therapy than those who had a low-fiber diet. And those who took probiotic supplements tended to have lower microbiome diversity.
“What’s interesting about the microbiome is that it’s far more complex than we know,” Cohen says. Cohen underwent surgery in June 2018 that removed the entire tumor and then continued taking Opdivo. He has had no evidence of disease since then.
The most recent breakthrough has replicated in humans a study previously done in mice. Two studies in February 2021 showed that fecal transplants from patients with melanoma who responded to checkpoint inhibitor therapy could turn some nonresponders into responders. In the phase 1 trial led by Dr. Gal Markel of the Sheba Institute in Israel, in which Wargo was involved, 10 patients with metastatic melanoma who had not responded to anti-PD-1 therapy received fecal transplants from patients who had responded. Two of the 10 patients then partially responded, and one had a complete response.
The other study, from the University of Pittsburgh Medical Center, involved 15 patients with advanced melanoma who had not responded to a combination treatment with Keytruda (pembrolizumab) and Opdivo.
After undergoing fecal transplants and then further treatment with Keytruda, six of the 15 saw a reduction in tumor size or no more progression. Those six had higher amounts of bacteria previously linked to immunotherapy response. The researchers suspect the changes to a patient’s gut microbiome may influence a tumor’s microenvironment to make it more susceptible to immunotherapy, but this is only one possible explanation for why changing the gut microbiome appeared to improve responses. Currently approximately 40% of patients with advanced melanoma do not respond to immunotherapy, so researchers hope larger trials will show this treatment can increase how many patients respond.
Research into modulating the microbiome has expanded to colorectal cancer, but doctors such as Vashi have been counseling their patients for years on how to find the right diet for their cancer, body type and health. One of those patients is Dwayne Copeland, a 57-year-old middle school teacher in Florence, Alabama. During the summer of 2010, while in Maryland for professional development, Copeland began feeling sick each afternoon. After he returned home, Copeland, also a football coach, began feeling sick during practice. When blood showed up in his stool, he called his family doctor. That October, he found out that he had colorectal cancer in all three parts of his large intestine. The first oncologist he saw recommended immediate surgery but told him he had only one to three years to live, so Copeland got a second opinion at CTCA.
“They told me I did not have an expiration date. That was really good to hear,” he says. He underwent 60 doses of chemo and 36 radiation visits before a total colectomy in January 2011, which left him with 3 inches of his rectum and 12-inch J-pouch — a surgery that allows a person to have control over their bowels without a complete colon — that enabled him to continue his active lifestyle without needing a colostomy bag. He also learned he has the hereditary condition MUTYH (MYH)-associated polyposis in which too many copies of the same cell are created, increasing the risk of colorectal cancer.
“It wasn’t if I’d have cancer again, it was when,” Copeland says. Vashi and his treatment team taught him what to eat to keep his microbiome balanced and reduce the likelihood of recurrence. As a science teacher, Copeland had read about the microbiome, “but I did not realize it was that important until I had cancer and needed to maintain a good gut balance,” he notes. Though he no longer coaches, he walks six days a week, maintains muscle mass with body weight and dumbbell exercises, takes a probiotic supplement, eats an apple and banana every day, and eats plenty of whole wheat bread and fish.
“The one thing I refrain from is sugar,” he says. “Anything (such as) desserts with a lot of sugar, that’s a risk-reward thing for me because I know it’ll cause problems with my gut bacteria.” He can tell within 45 minutes of eating if his gut is rebelling against what he ate.
As researchers continue exploring the relationship between the microbiome and cancer treatment, each discovery brings up more questions. It’s not clear how to determine which patients might benefit from a treatment that alters their microbiome, who the best donors are for fecal transplants, when patients should receive the transplant during treatment or what is the best method for fecal transplant. But it is clear from Cohen’s experience that even seemingly positive changes in diet can backfire. And over-the-counter probiotics aren’t necessarily beneficial, especially since they are not regulated by the Food and Drug Administration for quality.
“We haven’t yet figured out a magic pill that can work, and currently we focus more on a whole foods-based approach,” Wargo says. Her colleague, Nadim Ajami, executive director of scientific research for the Program for Innovative Microbiome and Translational Research at MD Anderson, points out that many probiotic supplements are a single organism. “We’re also seeing with cancer patients that diversity is good,” he says. “You wouldn’t want to miss the opportunity to increase diversity, but that is not the only ingredient.”
Vashi recommends that patients who want to learn more about ensuring a healthy microbiome should ask their oncologist for a referral. Many oncologists still haven’t recognized the importance of probiotics, prebiotics and microbiome balance to cancer care, but they should be willing to refer patients to dietitians or others who are familiar with the evidence.
Cohen pointed out the risks of making recommendations with incomplete evidence. After giving a lecture on the microbiome, he heard from a patient whose oncologist recommended taking probiotics based on Wargo’s early findings. That was before the findings that patients with melanoma taking probiotic supplements had less diversity were presented.
“This well-intentioned physician was potentially harming a patient because he was getting just a little bit ahead of what the evidence actually showed,” Cohen says. “There’s never been a clinical trial of probiotic supplementation with melanoma patients to say it helps the gut. Maybe the fecal microbiome transplant may help, but you can’t get that over the counter.”
The key appears to be a well-rounded diet that doesn’t tip too far in any direction. “Now the only recommendation we can really make is to try to achieve good gut health through a whole food, plant-centered, high-fiber diet,” he says. “Healthy gut bacteria for the majority of people will thrive and grow and proliferate in a positive way if they’re fed healthy foods.”
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