Gut Microbiome Emerges as the Next Frontier in Cancer Care, with Landmark Probiotic Trial Set to Launch
Key Insights
A landmark NCI-funded late-phase trial is about to enroll nearly 700 patients with advanced renal cell carcinoma (search) to test whether the probiotic CBM588 can amplify immunotherapy outcomes.
Research increasingly shows that gut microbiome composition directly influences cancer treatment response, with dysbiosis linked to higher mortality in transplant patients and fiber intake associated with a 30% reduction in melanoma (search) progression risk.
Fecal microbiota transplants combined with immunotherapy doubled response rates in lung cancer (search) and melanoma (search), according to a study published in Nature Medicine, while antibiotic stewardship programs have dramatically reduced unnecessary antibiotic use before immunotherapy.
A kidney cancer patient at University Hospitals Seidman Cancer Center in Cleveland is poised to become the first participant in the first late-phase clinical trial testing a probiotic as a strategy to amplify cancer treatment. The multicenter study, funded by the National Cancer Institute, will evaluate CBM588 — a strain of Clostridium butyricum already sold over the counter in Japan for gastrointestinal complaints — in nearly 700 people with advanced renal cell carcinoma (search), who will swallow capsules of the probiotic alongside their standard immunotherapy regimens.
"We're hoping to change the standard of care," said Dr. Pedro Barata, one of three principal investigators on the study, underscoring the ambition of a trial that could reshape how oncologists approach treatment.
The launch of this pivotal study marks a watershed moment for a field that has been quietly gaining momentum for decades: the connection between the gut microbiome and cancer outcomes. A recent publication by the American Society of Clinical Oncology lists nearly 100 recent or ongoing studies testing various ways to manipulate the gut microbiome to help treat cancer, and the microbiome appears to be especially critical when it comes to immunotherapy, which relies on medications that manipulate the body's own immune system to attack cancer.
From transplant complications to a new research frontier
The field traces its origins to the bone marrow transplant unit, where Dr. Marcel van den Brink — now president of City of Hope Cancer Center (search) in Duarte, California — began questioning the aggressive antibiotic regimens used to protect immunocompromised patients. In the 1990s, about a quarter of all allogenic hematopoietic cell transplant patients died from infections and other complications, including graft-versus-host disease (search).
"We were causing a lot of collateral damage with our aggressive treatment," van den Brink said.
That recognition spurred research into the gut-immune axis. Van den Brink and colleagues later analyzed fecal samples from more than 1,300 transplant recipients and found that dysbiosis — an imbalance in which the gut microbiome harbors fewer beneficial species — was directly linked to the likelihood of death. Dysbiosis was also tied to lower survival rates in patients receiving transplants of their own hematopoietic cells.
"It's crazy," van den Brink said, describing extreme cases in which a patient's entire digestive tract was reduced to a single bacterial species. "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!"
The fiber connection and dietary transformation
A seminal 2021 paper by researchers at the University of Texas MD Anderson Cancer Center demonstrated that patients eating a high-fiber diet responded better to treatment for melanoma (search): for every 5-gram increase in fiber intake, the risk of cancer progression or death fell by 30%.
Dr. Robert Jenq, director of the Microbiome Program at City of Hope, explained that certain gut bacteria metabolize fiber into short-chain fatty acids. While the exact mechanism remains unclear, these fatty acids appear 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.
The human intestine, with a surface area roughly 20 times larger than the skin, holds about a third of all the body's T-cells and B-cells, according to van den Brink. Immersed in a dense microbial ecosystem, the gut serves as a proving ground where the immune system learns to fight invaders and abnormal cells — a process that requires a healthy balance of bacteria.
This understanding has already transformed clinical practice at City of Hope, where van den Brink acknowledged past errors: "For 20 years, I went around telling them, 'Oh, just have an energy drink.' But it turns out that's really bad!" The sugar-heavy, unvaried diet, he and others discovered, fuels harmful bacterial species. The center now provides patients with fresh, organic meal options, requires nutritionist consultations within three days of admission, and urges patients to eat "real" food as soon as they are able.
Antibiotic stewardship gains traction
The recognition of the microbiome's importance has also driven a more cautious approach to antibiotics. Dr. Arielle Elkrief, co-director of the CHUM Microbiome Centre at the Montreal Cancer Institute, noted that heavy antibiotic use is independently associated with poor outcomes. After an intensive educational campaign launched in 2019 at her center, the proportion of lung cancer (search) patients receiving antibiotics in the 30 days prior to starting immunotherapy fell from 20% to 5%.
"People are a lot more focused on antibiotic stewardship now," said Dr. Sumanta Pal, who led the City of Hope research on CBM588 and is a co-investigator on the new trial. "We would never discourage someone from using antibiotics where they're indicated, but I think we use more discretion."
Fecal microbiota transplants show striking results
Among the most dramatic interventions under investigation are fecal microbiota transplants (FMTs). At least 40 cancer trials testing versions of FMTs have launched in the past few years alone. Elkrief and her colleagues at the CHUM Microbiome Centre doubled the number of people with lung cancer (search) who responded to treatment when they combined immunotherapy with fecal transplants derived from healthy volunteers, with similar results against melanoma (search). The study was published in the journal Nature Medicine.
"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."
Several commercial entities are advancing FMT-based products. Ferring Pharma (search)'s Rebyota became the first FDA-approved product for treating C. difficile infection. Seres Pharmaceuticals (search), in which van den Brink holds a financial stake, has received FDA fast-track designation for a product aimed at reducing infections and graft-versus-host disease (search) in hematopoietic cell transplant patients. Kanvas Biosciences (search) is developing "synthetic fecal transplants" — one modeled on a "super-donor" whose advanced cancer was completely reversed by immunotherapy (containing 145 bacterial species) and another based on healthy donors who never had cancer (containing around 50 species). Remarkably, according to CEO Dr. Matthew Cheng, "there isn't a single strain that overlaps both products."
Caution amid enthusiasm
Despite the excitement, researchers urge restraint. Dr. Pal warned that patients have already begun self-medicating with probiotics based on preliminary results. "Ever since we started publishing results, I know a lot of patients have been taking these supplements," he said. "But I really do urge them to wait for the data from the clinical trials to come out. 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."
The complexity of the microbiome remains a formidable challenge. Dr. Armin Rashidi, a hematologist at the Fred Hutchinson Cancer Center, noted: "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."
Dr. Jenny Paredes, a microbiologist in the van den Brink lab, is launching a trial that will provide dietary coaching and high-fiber meals while tracking every bite that transplant recipients consume during their 40-day hospital stay and an additional 60 days at home. The goal, she said, is to understand what is needed to prevent dysbiosis and guide treatment.
"We're looking to make diet into a drug," van den Brink said. "But we're only just starting to learn how to manipulate it."