EDITOR'S NOTE: This story was produced in collaboration with the Center for Global Health Journalism and supported by the Pulitzer Center.
As a young specialist in blood cancers such as leukemia, Dr. Marcel van den Brink mastered one of the most complex and risky tricks in medicine: beginning in the early 1990s, many of his seriously ill patients underwent complex procedures to restore or reinstall a new immune system.
During this procedure, called an allogeneic hematopoietic cell transplant, the patient's immune system is almost completely destroyed by powerful chemotherapy, paving the way for cells transplanted from a donor to replace it. Until these replacements take hold, the patient is extremely vulnerable.
Transplant patients were kept in figurative, and sometimes literal, bubbles, forced to spend months in rooms with carefully controlled air circulation to protect them from germs. "Nurses and family members interacted with patients through gloves that were transparent through the plastic," van den Brink recalls.
To maintain sterility until the new immune system had developed, patients were also exposed to high doses of broad-spectrum antibiotics. But despite all these 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 tissues.
Van den Brink says he and his colleagues on the ground concluded that this was partly the result of our own mistakes. "We were causing a lot of collateral damage with our aggressive treatment," he said.
This emerging understanding helped spark a new area of cancer research: the connection between the microbes in our gut and our immune system.
Attention to this issue was focused just last month, when U.S. Secretary of Health and Human Services Robert F. Kennedy Jr. visited California to attend a research symposium at City of Hope Cancer Center in Duarte, where van den Brink was named president in 2023. Addressing the group, National Institutes of Health Director Dr. Jay Bhattacharya called the recent research findings "mind-blowing.".
The symposium's title was impressive, calling the microbiome "the next frontier in cancer prevention and treatment." Indeed, a recent publication by the American Society of Clinical Oncology lists nearly 100 recent or ongoing studies testing various approaches to targeting the so-called gut microbiome for cancer treatment.
U.S. Secretary of Health and Human Services Robert F. Kennedy Jr. (left) tours the microbiome lab at City of Hope with Dr. Marcel van den Brink and Dr. Robert Yenck (right) on May 13 in Duarte, Calif. — Jordan Strauss/AP/City of Hope Content Service
The microbiome appears to play a particularly important role in immunotherapy, which uses drugs that target the body's own immune system to fight cancer more effectively.
In the coming days, a kidney cancer patient at the Seidman Cancer Center at University Hospitals Cleveland will become the first participant in the first late-phase trial testing probiotics as a way to enhance cancer treatment. The multicenter study is testing CBM588, a strain of Clostridium butyricum bacteria. . CBM588 is already a popular dietary supplement in Japan, where it is sold over-the-counter to treat gastrointestinal disorders.
Over the next few years, approximately 700 people with advanced renal cell carcinoma will receive CBM588 capsules along with standard immunotherapy. Dr. Pedro Barata, one of the three principal investigators of the study, is open about its ambition, stating, "We hope to change the standard of care.".
The National Cancer Institute-funded study follows several smaller studies focusing on kidney or lung cancer, including a study at City of Hope Cancer Center in Los Angeles that found CBM588 improved outcomes in people with renal cell carcinoma treated with immunotherapy.
Inspiration from chickens
Dr. Sumanta Pal, who led the study at City of Hope and is a co-investigator on the new clinical trial, says his interest in the microbiome began more than ten years ago. That's when he began communicating with Dr. Paul Frankel, a biostatistician at City of Hope, who explained that poultry farmers and other livestock producers were observing a correlation between the gut microbiome and the health of their animals.
«"If their chickens are healthy and growing well, they limit the frequency of litter cleaning when introducing new chickens," Frankel explained. Furthermore, he said, many animals are given probiotics or prebiotics to support a thriving microbiota. Pigs, for example, are given inulin. "It's essentially a fiber that's a prebiotic, and they use it to increase bifidobacteria. They knew exactly what they were doing.".
Commercial agricultural enterprises rarely publish research on these methods. However, the increased use of probiotics and prebiotics has coincided with the introduction of new federal regulations restricting the uncontrolled use of antibiotics—changes aimed at reducing their overuse and slowing the development of drug-resistant bacteria.
Cancer researchers have also come to a similar understanding of the enormous role antibiotics play in shaping the bacteria that live inside us. "People are now paying much more attention to the rational use of antibiotics," Pal said. "We would never discourage anyone from using antibiotics where indicated, but I think we're being more cautious. We've forced [doctors] to ask, 'Is this really the right decision for my patient in this particular situation?'"«
Dr. Sumanta Pal says he became interested in the potential of the microbiome after learning that poultry farmers had identified a link between gut microbiome and the health of their animals. — City of Hope
Dr. Ariel Elkrief, co-director of the CHUM Microbiome Centre at the Montreal Cancer Institute, says it's important to follow the principle of "first, do no harm." This is driven not only by concerns about drug resistance but also by research showing that intensive antibiotic use is independently associated with adverse outcomes.
At the CHUM Microbiome Center, patients are not prescribed antibiotics unless a bacterial infection is confirmed, except in rare cases. Doctors tailor treatment to the specific infection rather than relying on broad-spectrum antibiotics, which also kill beneficial bacteria as a side effect. According to Elcrif, after an intensive educational campaign in 2019, the proportion of lung cancer patients receiving antibiotics in the 30 days prior to immunotherapy decreased from 20% to 5%.
Many leading cancer centers take a similarly cautious approach to antibiotic use, including City of Hope.
«"As studies in mice and humans have shown, the less damage done to beneficial bacteria, the better the outcome. It improves performance," van den Brink said.
In his field of bone marrow transplantation, van den Brink and his colleagues analyzed stool samples from more than 1,300 people who had received cells from donors. They found that dysbiosis—an imbalance in which the gut microbiota has fewer beneficial species—is directly linked to mortality. Van den Brink says dysbiosis is also associated with lower survival rates in patients receiving autologous hematopoietic cell transplants. During this procedure, healthy cells are collected and frozen before chemotherapy and radiation therapy, and then injected afterward.
The reasons for these results are complex and are still being investigated. "There are many open questions," Elcrief said.
In some cases, the loss of beneficial bacteria allows harmful species to proliferate uncontrollably. A healthy human gut contains several hundred strains; van den Brink has documented extreme cases where all but one species of bacteria were eliminated from a patient's digestive tract.
«"It's crazy," he said. "You go from the Amazon rainforest, where there are 300 or 400 different bacteria living in a highly developed ecosystem, and then you find just one bacteria. Oh my God!"»
Other studies link dysbiosis to inflammation, which can lead to diarrhea and other problems, including the spread of dangerous bacteria from the gut into the bloodstream and other parts of the body.
Nutrition and immunity
The role of diet is another area of intense focus. In 2021, researchers from the University of Texas MD Anderson Cancer Center published a seminal paper showing that patients who consume a high-fiber diet respond better to melanoma treatment: for every 5-gram increase in fiber intake, the risk of cancer progression or death is reduced by 30%.
Subsequent research has demonstrated a close connection between the gut microbiota and the immune system. The surface area of the human intestine is approximately 20 times larger than the surface area covered by the skin. According to van den Brink, this vast surface area contains approximately a third of the body's T cells and B cells—the most important immune cells. Because they are immersed in a dense sea of bacteria, the gut serves as a testing ground for the immune system to learn to fight invaders and abnormal cells, such as tumor cells. This requires a healthy balance of bacteria.
The challenge, van den Brink explains, is learning to maintain this balance in critically ill patients with weakened immune systems who may require antibiotics to fight life-threatening infections.
For much of his career, van den Brink took precautions, including warning hematopoietic cell transplant patients to avoid fresh fruits and vegetables due to concerns about exposure to trace amounts of contaminants. In the first weeks after transplantation, many patients experience difficulty eating, and doctors often recommend a high-calorie diet rich in simple sugars.
«"For 20 years, I've been going around telling them, 'Oh, just drink an energy drink,'" van den Brink said. "But it turns out it's really bad for you!"„
The problem, he and other researchers have found, is that a high-sugar, monotonous diet provides fuel for harmful bacteria.
Kimberly Shipman (center) says the dining options at City of Hope were "really, really good." — Kimberly Shipman
In recent years, City of Hope has adopted a completely different menu. On a recent Tuesday, 60-year-old Kimberly Shipman, recovering from a transplant for acute lymphocytic leukemia, enjoyed an organic beet salad with chicken. "I'm eating like crazy, and the food here is really, really good," she said from her hospital room four weeks after surgery. "This salad is my favorite, but the soups are great too, and they have a special every day.".
According to hospital policy, new patients meet with a dietitian within three days of admission. Patients choose from a menu featuring fresh ingredients, and Adern Yu, director of clinical nutrition services at City of Hope, says patients are strongly encouraged to begin eating "real" food as soon as they can. She explained, "These people have weakened immune systems, so we still don't recommend foods like sprouts, blue cheese, or sushi," which are more susceptible to contamination. "But we tell them that fruits and vegetables are okay to eat as long as they're washed.".
Research already shows that eating a healthy diet, especially high-fiber foods, actually improves the response to immunotherapy and is associated with better treatment outcomes.
Dr. Robert Jenck, director of the microbiome program at City of Hope, was at MD Anderson when researchers there published a seminal paper on fiber. He explains that certain gut bacteria metabolize fiber into short-chain fatty acids. While the exact mechanism is unclear, these fatty acids appear to improve T-cell survival and function. They "also prevent the proliferation of harmful bacteria, nourish the colonic lining, and appear to suppress inflammation," Jenck said.
Dr. Jenny Paredes, a microbiologist in van den Brink's lab, is launching a study in which she will provide nutritional counseling, suggest high-fiber meals, and track every meal to hematopoietic cell transplant patients during their 40-day hospital stay and an additional 60 days at home, when they are 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, determine the optimal treatment. "Can I predict how this patient will respond to the food we provide in the hospital? Can I predict how it will affect their microbiome and metabolism?"«
Dr. Jenny Paredes is launching a study that will track the diets of hematopoietic cell transplant patients during a period of high risk for complications. — City of Hope
However, these ambitions face significant obstacles, most notably the dizzying complexity of our microbial landscape. The gut is home not only to several hundred common bacterial species, but also to viruses and phages. Moreover, as Dr. Armin Rashidi, a hematologist and associate professor at the Fred Hutchinson Cancer Center, puts it, "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 a million.".
Complicating the puzzle: bacteria behave differently and produce different metabolites depending on the other bacteria present, the state of their gut, and other factors, even the time of day. "The complexity problem is mind-boggling," said biostatistician Frankel. "The only problem is that we're remarkably good at making progress without having complete knowledge.".
Receives support from #2
If there's one approach that simultaneously reflects its complexity and relatively primitive state of knowledge, it's fecal microbiota transplant. This method involves collecting purified feces from either a healthy individual or a patient who has successfully undergone immunotherapy and administering the resulting mixture—often in pill form—to a new patient.
Rashidi is analyzing data from a study in which patients who had undergone hematopoietic cell transplants first received a fecal microbiota transplant. A Minnesota-based company collected stool samples from healthy donors, which were then tested for dangerous pathogens and genes associated with antibiotic resistance. The resulting material was filtered into a concentrated and purified form and placed in capsules. A total of 157 patients received either this microbial mixture or a placebo.
In an earlier study, Rashidi's team found that transplantation did indeed correct dysbiosis, but did not alter infection risk. "As much as I appreciate the idea that [fecal microbiota transplantation] helps restore the microbiome, I'm a little concerned that I don't understand how it happens," he said.
Less sophisticated fecal microbiota transplant methods were described as early as 4th-century China. In the past decade, they have been increasingly used to treat severe, life-threatening colon inflammation. A common cause of such problems is infection with Clostridium difficile bacteria, which can invade the colon if antibiotics kill competing species.
In the past few years alone, at least 40 clinical trials have been launched for cancer treatments, testing various fecal microbiota transplant options. "We know that patients who develop immunotherapy-related side effects have a different microbiome composition than patients who don't," Elcreef said. "The idea is that if we can replace their microbiome with one that resembles that of a healthy donor, we can potentially address the root cause of the problem and hopefully return them to immunotherapy.".
Over the past decade, fecal microbiota transplants—often in pill form—have increasingly been used to treat severe, life-threatening colon inflammation. —Amanda Kabaj
The study achieved impressive results. Elkrief and her colleagues from the CHUM Microbiome Center, combining immunotherapy with fecal microbiota transplants from healthy volunteers, doubled the number of people with lung cancer who responded to treatment and achieved similar results in the fight against melanoma. The study was published in the journal Nature Medicine. .
Using healthy donors helps circumvent a potentially serious limitation associated with fecal microbiota transplants. Other well-known studies have found impressive benefits, but only when using material from a single "superdonor": a cancer survivor who had previously shown a strong response to treatment. Beyond the obvious challenge of scaling up, there are examples where specific adverse effects have been linked to specific bacteria obtained from a single donor.
Alongside academic research, several commercial companies are developing or refining fecal microbiota transplant options. The first product to receive FDA approval was Ferring Pharma's Rebyota, designed to treat Clostridium difficile infection. Seres Pharmaceuticals (in which van den Brink has a financial stake) received FDA accelerated development approval for a product designed to reduce the incidence of infections and graft-versus-host disease in patients who have undergone hematopoietic cell transplantation.
A third company, Kanvas Biosciences, has two cutting-edge products—what CEO and co-founder Dr. Matthew Cheng calls "synthetic fecal transplants"—but with significant differences. One mimics a stool sample from a "super donor"—a former MD Anderson patient whose advanced cancer was completely cured by immunotherapy; the second uses a mixture created from samples from healthy donors who have never had cancer. The first product contains 145 bacterial species, the second "about 50," according to Cheng. Remarkably, he says, "there is not a single strain that matches both products.".
Pal argues that fecal microbiota transplants are not so much a long-term solution as a means of helping doctors understand which aspects of the microbiome are most valuable. "We really need to understand which specific elements within [the fecal microbiota transplant] determine the body's response.".
A late-stage probiotic study he's involved in uses a simpler approach, using a single ingredient. Other single-ingredient cancer-fighting approaches aimed at activating the microbiome include goat's milk, potato starch, and camu camu, a South American berry. An extract of the latter, combined with immunotherapy, helped people with melanoma and lung cancer in a small study conducted by Elcrif's group in Montreal.
Despite his enthusiasm for the emerging possibilities, Pal cautions against getting ahead of the evidence. "Since we started publishing results, I know many patients are taking these supplements," he said of CBM588 and other probiotics. "But I really encourage them to wait for the clinical trial data. I know it's very difficult, but I'm trying to study CBM588, and all drugs in this category, with the same rigor we apply to our leading [medicines].".
Meanwhile, unanswered questions haven't stopped City of Hope from changing its inpatient meal menu, organizing quarterly food distributions, and planting a garden where patients and staff can pick fresh vegetables.
Van den Brink philosophizes.
«"We're trying to turn diet into medicine," he said. "But we're only just beginning to understand how to manage it.".
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