THE POPULATION OF TRILLIONS OF BACTERIA and other microscopic organisms living in our body, known collectively as the microbiome, has a profound influence on our health. Microbes in our body outnumber human cells 10 to 1. A whopping 99% of the unique genes in our body are bacterial.
These microbes—mostly bacteria, but also viruses, fungi and other tiny organisms—live in complex ecosystems across multiple tissues and organs. We get our first microbes from our mothers the moment we’re born, and for the rest of our lives, our environment—including the food we eat and the air we breathe—shapes our microbiome. We live in balance with these bugs, who use food as fuel and repay us through a wide array of processes.
Beneficial microbes such as Lactobacillus and Bifidobacteria—names you might see listed on the packaging for probiotic supplements, Greek yogurt and kombucha—help us break down food and shape our immune system. They provide proteins and chemicals that help us build vital nutrients, protect us from infection and toxins, promote healing and even grow healthy brains. When our microbiome falls out of balance—meaning a few opportunistic species start to overtake others, or harmful species such as toxic strains of E. coli show up where they don’t belong—it can cause problems with all these processes.
Recently, cancer researchers have focused their attention on these microorganisms in the digestive tract, which houses the majority of the body’s bacterial residents. Increased understanding of so-called good and bad bacteria in modulating our immune response has led many researchers to examine the role of these microorganisms in response to immunotherapy, a class of treatments that enable the body’s immune system to fight certain cancers.
The Link Between Microbes and Cancer
Studies have hinted at both the benefits and dangers of various bacterial species in the gut both in cancer development and treatment response. For example, one study suggests that people with colorectal cancer are more likely to carry certain strains of E. coli compared to those who do not have cancer. Cell studies show these bacteria could spur colorectal cancer by releasing a toxic chemical called colibactin, which can cause breaks and mutations in our DNA. In addition, certain bacteria, including Klebsiella pneumoniae and some E. coli strains, can inactivate chemotherapy drugs or make cancerous cells more resistant to therapy. Other types of bacteria may have the ability to make chemotherapy drugs more potent—even toxic.
Our microbes can also affect responses to immunotherapy. Beneficial bugs can bolster our population of active cancer-fighting T cells, says Saranya Chumsri, a breast oncologist at the Mayo Clinic in Jacksonville, Florida. When certain bacteria stick to the lining of the gut, for example, studies have shown that this prompts the body to make multiple kinds of immune cells, including T cells, which could improve immune response.
Studies show that patients who respond to checkpoint inhibitors, a type of immunotherapy that releases the brakes on immune response, have more diverse microbiomes and higher levels of certain beneficial species. These patients also have higher levels of cancer-fighting immune cells in their tumors. “These cells are basically the sign of patient immunity attacking the tumor,” says Chumsri. “When you have a diverse, healthy gut microbiome, it actually helps create the T cells that are ready to fight cancer.”
Purna Kashyap, a gastroenterologist who studies microbes and gastrointestinal diseases in his lab at the Mayo Clinic in Rochester, Minnesota, notes that scientists have yet to fully characterize what constitutes a balanced and “healthy” gut microbiome. However, evidence suggests that certain changes in the gut microbiome are associated with lower immune defenses, he says.
Overcoming Treatment Resistance and Side Effects
There are two common hurdles to immunotherapy. One is that the treatment does not always work—in fact, estimates suggest only between 15% and 20% of patients who receive immunotherapy will experience a treatment response. The other challenge is that many patients experience dangerous and sometimes life-threatening immune reactions. But researchers have isolated aspects of the gut microbiome in cancer patients who respond to immunotherapy treatment and those who don’t, as well as in patients who experience severe side effects after receiving the treatment.
One 2018 study analyzed the stool of melanoma patients who were starting an anti-PD-1 therapy, a type of immune checkpoint inhibitor. The patients who responded to treatment tended to have a more diverse microbiome with different types of bacteria and a particular abundance of Faecalibacterium species. Meanwhile, people who had higher levels of certain other species, including Bacteroides and E. coli, were less likely to respond to the treatment. Furthermore, melanoma patients with high levels of Bacteroides species in the gut have been shown to experience more toxic effects, such as severe colon inflammation, from immune checkpoint inhibitors.
Antibiotics, an essential tool for treating cancer patients who can develop bacterial infections both as a result of their cancer and its treatment, can also alter the composition of gut microbiota. A review of 12 studies, published Feb. 9, 2022, in Frontiers in Oncology, found that the use of antibiotics while taking immune checkpoint inhibitors shortened survival in patients with different types of cancer, including lung and kidney cancer and melanoma. Another study, published March 14, 2022, in Nature Medicine, found that cancer patients who received CAR T-cell therapy, a type of immunotherapy that uses a person’s own genetically altered T cells to attack cancer, had both significantly worse survival and more neurotoxic side effects if they took antibiotics leading up to treatment.
Perhaps the clearest proof of principle for the microbiome’s potential arises from clues within the gut itself. A fecal transplant, which is a procedure that removes and processes stool from a healthy donor and transplants it to a recipient using a colonoscopy, enema or pill, has showed promising results in increasing treatment response to immunotherapy. Experts think that these transplants directly change the composition of microorganisms in the intestines to a more immunotherapy-friendly population of bugs, giving the body specific microbial tools to help fight their cancer.
Two separate trials published Feb. 5, 2021, in Science showed this promise. In one trial, six of 15 people with immunotherapy-refractory melanoma responded to the checkpoint inhibitor Keytruda (pembrolizumab) following a fecal transplant. Three patients’ cancers stopped progressing, while the other three patients’ tumors started to shrink. In the other trial, three out of 10 people who had melanoma that didn’t respond to immunotherapy responded to treatment with Opdivo (nivolumab) after they received fecal transplants.
“I think there is all the reason to believe that if you can modulate the gut microbiome to increase response to immunotherapy, this might possibly be applicable to all immunotherapy-sensitive tumors,” says Hassane M. Zarour, a dermatologist and cancer immunologist at the UPMC Hillman Cancer Center in Pittsburgh, who co-led one of the studies. These tumors include melanoma, lung, kidney and bladder cancer, he adds. Zarour hopes to embark on a larger follow-up trial that will study fecal transplants in these and other cancers.
Research on fecal transplants also provides an opportunity for scientists to learn more about the makeup of bacterial signatures that are associated with treatment responses. Zarour hopes to eventually develop targeted probiotics based on the beneficial bacteria isolated from those who respond to immunotherapy. “In the future, we want to move towards something that is more translatable and easier to do,” says Zarour, who notes that giving a cocktail of well-defined bacteria would be less tedious than the fecal transplant procedure.
The Promise of Probiotics
Researchers are exploring whether probiotics, which are supplements that contain cultures of live beneficial bacteria, could improve the microbial population in people who are receiving immunotherapy and potentially make them more responsive by boosting their populations of T cells.
Studies conducted in mice suggest that Bifidobacterium, which is available in many probiotics produced by different companies, has been linked to a stronger response to immune checkpoint inhibitors. A paper published Feb. 28, 2022, in Nature Medicine found that when given a probiotic called CBM588, which is thought to restore the balance of Bifidobacterium in the gut, patients with metastatic kidney cancer receiving checkpoint inhibitors survived without their cancer progressing or needing to start a new treatment for nearly 13 months, compared to only 2.5 months among people who did not take the probiotic.
Understanding how what you eat can affect your microbiome.
Food can enrich the gut microbiome and play a role in promoting overall health, but it can be particularly important for cancer patients, who undergo many stresses in the course of treatment. The frequent use of antibiotics and the havoc of cancer treatments themselves can throw off the delicate balance of microorganisms within the gut.
“If you have a more diverse microbiome to start with, it’ll be more resilient to these kinds of insults,” says Purna Kashyap, a gastroenterologist who studies microbes and gastrointestinal disease in his lab at the Mayo Clinic in Rochester, Minnesota.
Microbes have the ability to digest complex dietary carbohydrates into certain chemicals, called short-chain fatty acids, that can keep our bodies and immune system healthy. Studies have found that patients with high concentrations of certain short-chain fatty acids have better responses to immune checkpoint inhibitors.
One study, published in JAMA Network Open on April 16, 2020, found that patients with solid tumors who had high gut concentrations of short-chain fatty acids—metabolites that are released from the bacteria as they gobble up fiber—had longer progression-free survival when taking checkpoint inhibitors.
A potential future line of research involves looking into whether specific metabolites might be given directly to patients to improve treatment response, says Melody Smith, a physician-scientist and immunologist at Stanford University School of Medicine in California. In addition, scientists are exploring the role of fermented foods, called prebiotics, which are a source of nutrients for our gut microbes rather than a form of the bacteria themselves. Clinicians are also beginning to make a more deliberate effort to gather in-depth information about a patient’s diet when assessing their cancer treatment options—something that is often overlooked.
Experts advise eating a diet with plenty of fiber and lots of plant foods like vegetables, whole grains, nuts, seeds, beans and fruit, and avoiding alcohol and added or processed sugar. Healthy eating habits may not only lower the risk of cancer in the first place but can increase the diversity of the microbiome to help bolster the body’s natural defenses.
In 2020, Chumsri wrapped up a clinical trial that measured tumor-infiltrating lymphocytes in breast cancer in people who took over-the-counter probiotics that contained a diverse set of about a dozen different beneficial bacterial species, including Bifidobacterium. Results have not yet been published, but Chumsri notes that some patients, especially those who had triple-negative breast cancer, had significant increases in tumor-infiltrating lymphocytes in their cancer cells after taking the probiotics. “We’re modulating the gut microbiome to improve the immune response for patients in their whole entire body,” says Chumsri. The next trial on the docket, Chumsri says, will explore whether this increase in tumor-infiltrating lymphocytes translates to a better response to immunotherapy.
Kashyap cautions that patients diagnosed with cancer should not start taking probiotics to gain renewed control of their gut health and treatment without first speaking with their doctor. While probiotics are generally thought to be safe, people with cancer, who have compromised immune systems, may be vulnerable to infection when exposed to new microbes, says Kashyap.
The Right Signature
Finding the right microbial signature for treatment response is still the holy grail of this research, says Chumsri. Each person’s gut microbiome is unique, not to mention dynamic and ever changing. Our individual genetic makeup, as well as our environment, also influences the way our microbiome behaves. Furthermore, cancer itself is a hugely variable disease that arises from multiple mechanisms. “Trying to define what is a good gut microbial signature is a complex question because there are so many variables,” says Zarour.
The potential for understanding these microbial signatures could help provide more personalized approaches, says Kashyap. For example, startup companies are exploring whether diagnostic tests could use a person’s unique microbial signatures to predict whether they would respond to a given drug or would be likely to develop side effects. This predictive insight would be a huge step for personalized care, says Kashyap, which could help health care providers understand which treatments are most likely to be effective and to make recommendations accordingly.
The microbiome is likely just one part of a complex equation. “You have to think of it as a piece of the puzzle and not necessarily the whole story,” says Kashyap. But researchers are working to decode the mysteries of our microorganisms. “We’re extremely happy that this work has increased enthusiasm in the field to push forward,” Zarour says.
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