A healthier gut may be key to cancer care

Dr. Marcel van den Brink says he and his colleagues came to recognize that some aggressive cancer treatment was "causing a lot of collateral damage." (Credit: City of Hope via CNN Newsource)

As a budding specialist in bloodborne cancers like leukemia, Dr. Marcel van den Brink learned how to perform one of the most delicate high-wire acts in medicine: Starting in the early 1990s, many of his seriously ill patients had sophisticated procedures to rebuild, or reinstall, a new immune system.

In this procedure – called an allogenic hematopoietic cell transplant – the patient’s immune system is virtually wiped out with potent chemotherapy, clearing the way for cells transplanted from a donor to replace it. Until that replacement takes root, the patient is exquisitely vulnerable.

Transplant patients were kept in figurative and sometimes literal bubbles, spending months at a time in suites with carefully controlled airflow to guard against microorganisms. “Nurses and family would deal with patients through gloves that stuck through the plastic,” van den Brink recalled.

To maintain a germ-free state until the new immune system took over, patients were also blasted with high doses of broad-spectrum antibiotics. But despite all precautions, in the 1990s, about a quarter of all patients died from infections and other complications, including graft-versus-host disease, in which transplanted immune cells attack the body’s own tissue.

Van den Brink says he and his colleagues in the field came to recognize that some of this was self-inflicted. “We were causing a lot of collateral damage with our aggressive treatment,” he said.

That dawning recognition helped launch a field of cancer research: the connection between microbes in our gut and our immune systems.

The focus was highlighted just last month, when U.S. Health and Human Services Secretary Robert F. Kennedy Jr. went to California for a research symposium at the City of Hope Cancer Center in Duarte, where van den Brink was named president in 2023. Speaking to the group, U.S. National Institutes of Health Director Dr. Jay Bhattacharya called recent research findings “mind-blowing.”

The symposium’s title was grand, dubbing the microbiome “the next frontier of cancer prevention and care.” In fact, a recent publication by the American Society of Clinical Oncology lists nearly 100 recent or ongoing studies testing various ways to manipulate what’s known as the gut microbiome to help treat cancer.

The microbiome appears to be especially critical when it comes to immunotherapy, which relies on medications that manipulate the body’s own immune system in order to better attack cancer.

In the coming days, a kidney cancer patient at University Hospitals Seidman Cancer Center in Cleveland will become the first participant in the first late-phase trial testing probiotics as a way to amplify cancer treatment. The multicentre study is testing CBM588, a strain of bacteria called Clostridium butyricum. CBM588 is already a popular dietary supplement in Japan, where it’s sold over the counter to deal with gastrointestinal complaints.

Over the next few years, nearly 700 people who have advanced renal cell carcinoma will swallow capsules of CBM588 along with their regular immunotherapy treatments. Dr. Pedro Barata, one of three principal investigators on the study, isn’t shy about its ambition when he says, “We’re hoping to change the standard of care.”

The study, which is funded by the National Cancer Institute, follows a handful of small studies involving kidney or lung cancer, including one at City of Hope Cancer Center in Los Angeles that found that CBM588 improved outcomes in people with renal cell carcinoma who received immune-based treatment.

Inspiration from chickens

Dr. Sumanta Pal, who led the City of Hope research and is a co-investigator on the new trial, says his interest in the microbiome was launched over a decade ago. That’s when he started talking with Dr. Paul Frankel, a biostatistician at City of Hope who shared that poultry operations and other livestock producers saw a correlation between gut bacteria and the health of their animals.

“If their chickens are [healthy and growing well], they’ll limit how often they clean the litter when they put in new chickens,” Frankel explained. What’s more, he says, many animals are given probiotics or prebiotics in order to keep their microbiota flourishing. Pigs, for example, are fed inulin. “It’s basically a fibre product that is a prebiotic, and they use that to boost the Bifidobacteria. They knew exactly what they were doing.”

Commercial agriculture operations don’t often publish research on these practices. But expanded use of probiotics and prebiotics coincided with new federal rules to limit unchecked use of antibiotics, changes meant to reduce overuse and slow the development of drug-resistant bacteria.

Cancer researchers have developed a similar appreciation for the outsize role played by antibiotics in shaping the bacteria that live inside us. “People are a lot more focused on antibiotic stewardship now,” Pal said. “We would never discourage someone from using antibiotics where they’re indicated, but I think we use more discretion. We’ve gotten [doctors] to ask, ‘Gosh, is this really the right thing for my patient, in this particular situation?’”

Dr. Arielle Elkrief, co-director of the CHUM Microbiome Centre at the Montreal Cancer Institute, says it’s important to follow the adage of “first, do no harm.” That’s driven not just by concern over drug-resistance but by studies that find that heavy antibiotic use is independently associated with poor outcomes.

At the CHUM Microbiome Centre, patients aren’t given antibiotics unless a bacterial infection is confirmed, except in rare cases. Doctors tailor treatment to the specific infection rather than leaning on broad-spectrum antibiotics that also wipe out beneficial species as collateral damage. According to Elkrief, after an intensive educational campaign was launched in 2019, the proportion of lung cancer patients receiving antibiotics in the 30 days prior to starting immunotherapy fell from 20% to five per cent.

Many leading cancer centres have developed a similarly cautious approach to antibiotics. That includes City of Hope.

“What we’ve found both in mouse and man is that the less damage you do to [beneficial] bacteria, the better off you are. You have better outcomes,” van den Brink said.

In his own realm of bone marrow transplants, van den Brink and colleagues analyzed fecal samples from more than 1,300 people who got cells from donors. They found that dysbiosis – an imbalance in which the gut microbiome has fewer beneficial species – was directly linked to likelihood of death. Van den Brink says dysbiosis is also tied to lower survival rates in patients who receive transplants of their own hematopoetic cells . In that procedure, healthy cells are collected and frozen prior to chemotherapy and radiation treatment, then infused afterward.

The reasons for these results are complex and still being teased out. “There are a lot of open questions,” Elkrief said.

In some cases, the loss of beneficial bacteria allows harmful species to run rampant. A healthy human gut contains a few hundred strains; van den Brink has documented extreme cases in which everything in a patient’s digestive tract was wiped out except for a single species.

“It’s crazy,” he said. “You go from having an Amazon rainforest, with 300 or 400 different bacteria living in a finely developed ecosystem, and you go to having a single bug. I mean, my God!”

Other research links dysbiosis with inflammation, which can lead to diarrhea and other problems, including leakage of dangerous bacteria from the gut to infect the bloodstream and other parts of the body.

Food and immunity

The role of food is another area of intense focus. A seminal 2021 paper by researchers at the University of Texas MD Anderson Cancer Center showed that patients eating a high-fibre diet responded better to treatment for melanoma: For every five-gram increase in fibre intake, the risk of cancer progression or death fell 30 per cent.

Other studies have followed, and there appears to be a strong connection between gut bacteria and the immune system. The surface area of the human intestine is about 20 times larger than the area covered by our skin. According to van den Brink, this vast landscape holds about a third of all the body’s T-cells and B-cells – crucial immune cells. And because they are immersed in a thick sea of bacteria, the gut is a proving ground where the immune system learns to fight invaders and abnormal cells like those found in tumors. This requires a healthy balance of bacteria.

The challenge, van den Brink explains, is learning how to preserve that balance in desperately sick patients with fragile immune systems, who may need antibiotics to fight life-threatening infections.

For most of van den Brink’s career, precautions included warning hematopoietic cell transplant recipients to avoid fresh fruits and vegetables, out of concern that they might be exposed to trace contaminants. In the first weeks after transplant, many patients have trouble eating and are often encouraged by doctors to rely on high-calorie nutrition with a lot of simple sugars.

“For 20 years, I went around telling them, ‘oh, just have an energy drink,’” van den Brink said. “But it turns out, that’s really bad!”

The problem, he and others discovered, is that a sugar-heavy, unvaried diet is rocket fuel for harmful species of bacteria.

In recent years, City of Hope developed a very different menu. On a recent Tuesday, 60-year-old Kimberly Shipman, recuperating from a transplant to treat acute lymphocitic leukemia, savoured an organic beet salad topped with chicken. “I’ve been eating like crazy, and the food has been very, very good here,” she said from her hospital bed four weeks after the procedure. “This salad is my favorite, but the soups are great, and they have a special every day.”

Per hospital policy, new patients meet with a nutritionist within three days of admission. Inpatients choose from a menu of fresh options, and Adern Yu, the director of clinical nutrition services at City of Hope, says patients are urged to eat “real” food as soon as they’re able. She explained, “These people are immunocompromised, so we still don’t recommend things like sprouts or blue cheese or sushi,” which are more prone to contamination. “But we tell them fruits and vegetables are fine, as long as you wash them.”

Studies already show that eating healthy food, particularly a high-fibre diet, actually improves the response to immunotherapy and is associated with better outcomes.

Dr. Robert Jenq, director of the Microbiome Program at City of Hope, was at MD Anderson when the seminal paper on fibre was published by researchers there. He says certain gut bacteria metabolize fibre into short-chain fatty acids. While the exact mechanism is unclear, these fatty acids seem to improve the survival and function of T-cells. They “also prevent harmful bacteria, function as nutrition for the lining of the colon and seem to suppress inflammation,” Jenq said.

Dr. Jenny Paredes, a microbiologist in the van den Brink lab, is launching a trial in which she’ll provide dietary coaching and high-fibre meals, as well as tracking every bite that hematopoietic cell transplant recipients eat during the 40 days they typically stay in the hospital and an additional 60 days at home, when they’re still at high risk for graft-versus-host disease and other complications.

Paredes says the goal is to better understand what’s needed to prevent dysbiosis and, ultimately, guide treatment. “Can I foresee how this patient will react to the food we’re providing in the hospital? Can I foresee what it does to their microbiome and metabolism?”

But that ambition faces steep hurdles, first and foremost the dizzying complexity of our microbial landscape. Not only are there several hundred common species of bacteria in the gut, there are viruses and phages, as well. What’s more, says Dr. Armin Rashidi, a hematologist and associate professor at the Fred Hutchinson Cancer Center, “even if you understand what each microbe does and how any two of them interact with each other, you still can’t predict what will happen if you put three of them together – let alone if you put a million of them together.”

Multiplying the puzzle: Bacteria behave differently and produce different metabolites depending on which other bacteria are present, on the condition of the gut and other factors, even the time of day. “The complexity problem is humbling,” said Frankel, the biostatistician. “The comforting thing is that we’ve been remarkably good at making progress without complete knowledge.”

Getting a boost

If there’s an approach that embodies both the complexity and the relatively primitive state of knowledge, it’s the use of fecal microbiota transplants. This involves taking purified feces from either a healthy person or from a patient who has successfully responded to immunotherapy, and giving the mixture – often in the form of a pill – to a new patient.

Rashidi is analyzing data from a study in which patients undergoing hematopoietic cell transplants were first primed with fecal microbiota transplants. Collaborators in Minnesota gathered stools from healthy donors, which were then screened for dangerous pathogens and genes associated with antibiotic resistance. That material was filtered into a concentrated and purified form and put into capsules. A total of 157 patients received either this microbial mix or a placebo.

In an earlier study, Rashidi’s team found that transplants did correct dysbiosis but didn’t change the risk of infection. “As much as I love the fact that [fecal transplant] works in fixing the microbiome, I’m kind of bothered by the fact that I don’t understand how this happens,” he said.

Less sophisticated fecal transplants were reported as far back as fourth-century China. Increasingly over the past decade, they’ve been used to treat severe, life-threatening inflammation of the colon. A common cause of this trouble is an infection with C. difficile bacteria, which can overrun the colon if antibiotics wipe out competing species.

In the past few years alone, at least 40 cancer trials have been launched, testing versions of fecal microbiota transplants. “We know patients who develop toxicities related to immunotherapy have a distinct microbiome composition compared to patients who don’t,” Elkrief said. “The thought is, if we can replace their microbiome with the microbiome of something resembling a healthy donor, we could potentially heal the source of the problem and hopefully get them back on their immunotherapy.”

The work includes some striking success. When they combined immunotherapy with fecal transplants derived from healthy volunteers, Elkrief and her colleagues at the CHUM Microbiome Centre doubled the number of people with lung cancer who responded to treatment and had similar results against melanoma. The study was published in the journal Nature Medicine.

The use of healthy donors helps sidestep a potentially severe limitation on fecal transplants. Other prominent trials have found impressive benefits, but only when using material from a single “super-donor”: a cancer survivor who previously showed a strong response to treatment. Aside from the obvious challenge of scaling that up, there are examples in which specific adverse events were linked to specific bacteria derived from a single donor.

Along with academic research, several commercial entities are developing or refining versions of fecal transplants. The first product to receive U.S. Food and Drug Administration (FDA) approval was Ferring Pharma’s Rebyota, which is designed to treat C. diff infection. Seres Pharmaceuticals (in which van den Brink has a financial stake) has received an FDA fast-track designation to develop a product meant to reduce infections and graft-versus-host disease in patients undergoing hematopoietic cell transplants.

At a third company, Kanvas Biosciences, the two most advanced products are both what CEO and co-founder Dr. Matthew Cheng describes as “synthetic fecal transplants,” but with stark differences. One mirrors a fecal sample from a “super-donor,” a former patient at MD Anderson whose advanced cancer was completely reversed by immunotherapy; the second uses a mix modeled on what was found in healthy donors who never had cancer. The first product includes 145 species of bacteria, the second “around 50,” according to Cheng. Remarkably, he said, “there isn’t a single strain that overlaps both products.”

Pal argues that fecal transplantation is less a long-term solution than a means of helping clinicians understand which aspects of the microbiome are most valuable. “What we really need to learn is what specific element is it, in the composition of the [fecal transplant], that’s driving the response.”

The late-phase probiotic study that he’s helping lead is a simpler approach, using a single ingredient. Other single-ingredient interventions seeking to recruit the microbiome to fight cancer utilize goat milk, potato starch and camu-camu, a South American berry. An extract from the latter, in combination with immunotherapy, helped people with melanoma and lung cancer in a small study run by Elkrief’s group in Montreal.

For all his excitement about the possibilities, Pal warns against outpacing the evidence. “Ever since we started publishing results, I know a lot of patients have been taking these supplements,” he said of CBM588 and other probiotics. “But I really do urge them to wait for the data from the clinical trials to come out. I know it’s really hard to do, but I’m trying to look at CBM588, and really all the drugs in this category, with the same rigor that we would with our advanced [drugs].”

In the meantime, the unanswered questions haven’t kept City of Hope from changing its inpatient food service menu, running a quarterly food pantry or planting a garden where patients and staff can grab fresh vegetables.

Van den Brink is philosophical.

“We’re looking to make diet into a drug,” he said. “But we’re only just starting to learn how to manipulate it.”