You may have heard the terms “gut microbiota” and “microbiome” and wondered what they mean and why they matter. Many researchers at Memorial Sloan Kettering Cancer Center (MSK) are studying how they influence the health of people with cancer and the general population, too.

Here, medical oncologist Marcel van den Brink, MD, PhD, answers common questions, including how your gut microbiota impacts your health, how to protect it, and the effect it has on diseases like cancer. Dr. van den Brink heads MSK’s Division of Hematologic Malignancies and holds the Alan N. Houghton Chair. He also leads a research lab in the Immunology Program of the Sloan Kettering Institute (SKI).

What is the microbiota, and how is it different from the microbiome?

Your “microbiota” is the collection of all the microbes that live on and inside your body. These microbes include viruses, bacteria, and other microorganisms.

The “microbiome” refers to all the genes that make up those microorganisms. The microbiome is a more extensive system than you may realize. In fact, the number of genes in the microbiome is much greater than the number of genes from cells in your body.

How does the gut microbiota affect your immune system and overall health?

Those of us who study the gut microbiota often refer to it as the “forgotten organ.” It can have a huge impact on a person’s health. Some microbes are associated with disease. Others are important for good health.

Most microbiome research has focused on the microbiota in the gut, but some scientists are studying the microbiome in other parts of the body as well.

It’s an exciting time. Advances in DNA sequencing technology and computational biology over the past decade have dramatically boosted scientists’ ability to analyze and observe changes in the gut microbiota and the overall microbiome. This technology gives us a much better picture of what’s happening inside the body. And we are starting to look at how we may be able to build therapies around our understanding of the microbiota.

How does the microbiome affect the development of diseases, including cancer?

There is a strong connection between the microbiome and the immune system, our natural way of fighting disease. The microbiome plays a fundamental role in training the immune system, and likewise, the immune system keeps the microbiome in balance.

Inflammation triggered by the immune system is strongly linked to many common conditions, including heart disease, some neurological conditions, and certain types of cancer. That’s why it’s important to study the relationships between the microbiota and the immune system. Our findings could also help understand the causes of some autoimmune diseases as well as to learn how people respond to vaccines.

Some researchers are studying how the microbiota may directly influence the formation of cancer. We already know that certain microbes contribute to cancer. For example, the human papillomavirus (HPV) causes many cancers of the cervix, anus, and head and neck. The bacteria Helicobacter pylori (H. pylori) has been implicated in many stomach cancers. It’s possible there are other connections we don’t yet know about.

What does it mean to have a healthy gut microbiota?

We still have so much to learn about which microbial species are the most beneficial for health and how to repair a microbiota that’s been damaged. It’s a complicated system.

But we know that a healthy microbiota is one that is as diverse as the Amazon rainforest — it contains many, many different species. This diversity prevents the domination of certain species that are harmful, including Clostridioides difficile (C. diff) infections and antibiotic-resistant Enterococcus infections. When these species take over, it can be life-threatening.

How can you improve and maintain a healthy microbiome?

Eating a healthy diet can help improve your microbiota. This means eating a diet with lots of fruits, vegetables, and fiber. Fiber supports the growth of many beneficial species in the gut.

Can taking probiotics improve your microbiota?

Many stores sell probiotics that claim to heal or restore your microbiota. But we don’t know enough about the microbiota to know all the species that are needed for a healthy balance. Also, the over-the-counter probiotic supplements that are currently sold do not contain the types of strains that are the most important contributors to the gut microbiota, called anaerobic bacteria.

For people whose immune systems are suppressed, including those recovering from stem cell and bone marrow transplants (BMTs), these probiotic products may actually be harmful. You should always talk to your doctor before taking a probiotic.

How does the gut microbiota affect people with cancer?

I am a blood cancer doctor interested in improving the outcomes of my patients who are receiving BMTs. When these transplants use donor cells (known as allogeneic), sometimes those donor cells attack healthy tissues in the patient. This is called graft-versus-host disease (GVHD). My research has found that protecting the gut microbiota in transplant patients can prevent GVHD and therefore improve their health.

In 2009, we united a group of investigators from across MSK — including clinical researchers and scientists at SKI — to launch a project to collect stool samples from patients having transplants. These samples allow us to study connections between the food and medication that goes into a person’s body, how they change the microbiota, and whether they contribute to GVHD and other clinically relevant outcomes. We now have about 100 scientists working on this project and other microbiome studies at MSK.

In addition, part of the BMT process requires wiping out a patient’s immune cells, in order for them to be replaced by a new immune system from a donor. This process offers a unique window to observe how the microbiota and the immune system interact with each other.

We are now expanding this project to study how the gut microbiome impacts patients’ responses to treatments with immunotherapy, including CAR T therapy and immune checkpoint drugs.

What has MSK learned about protecting the gut microbiota of people who have cancer?

• Antibiotics should be prescribed carefully. Transplant patients receive a lot of antibiotics, which can damage the harmless species of microbes in their guts and lower the diversity of the microbiota overall, allowing more dangerous strains to take over. Our studies have shown that patients with a more diverse microbiota do better after their transplants and have lower rates of GVHD.
• Diet plays a role in your microbiome. One study in mice found that animals that consume lactose (a sugar that’s naturally found in milk and dairy products) have higher levels of the harmful bacteria Enterococcus in their guts, which resulted in an increased risk of GVHD.
• We are studying currently whether fecal microbiota transplants may help patients who have received bone marrow transplants.

Besides antibiotics, do other medications also affect the gut microbiome?

Yes. Other drugs affecting the microbiome include laxatives, medicines for nausea, and opioids, according to a study led by Chi Nguyen, a talented graduate student in my lab, that was published June 8, 2023, in Cell.

We found that people who received certain drugs had higher levels of harmful microbes like Enterococcus. They did not do as well after their transplants. This research is another reason why studying all the effects of common medications is important for improving patient outcomes after BMTs.

Should people who don’t have cancer be concerned about how antibiotics affect the gut microbiome?

We have learned that one of the most important things you can do to preserve the diversity of your gut flora is to avoid unnecessary antibiotics. That’s because antibiotics can kill off much of the essential or harmless bacteria living in your gut. However, transplant patients and people with cancer in general will sometimes need to be treated with broad-spectrum antibiotics, especially when they are immunocompromised. We are currently performing a study in transplant patients to compare broad-spectrum antibiotics and determine which do less or more damage to your healthy gut flora.

Michael Szczerbienski had always been blessed with good health, so the day he found blood in his urine, he was quite alarmed. His doctor sent him for a CT scan, which revealed a tumor on his left kidney. Michael, whose kidney cancer was already advanced, went to Memorial Sloan Kettering Cancer Center (MSK), where he had surgery and then was given the chance to join a clinical trial of a drug combination that had never been tested before. Thanks to that trial, Michael’s cancer is still in remission more than three years later.

Michael, now 68, says “When you’re a patient at MSK, the people who are treating you are the best there is, hands down.”

Results of this first-of-its kind clinical trial were published in the May 11, 2023, issue of the New England Journal of Medicine (NEJM). Michael’s medical oncologist, MSK kidney cancer expert Robert Motzer, MD, was co-corresponding and senior author of the study.

The trial showed that adding a targeted therapy to a standard combination for stage 4 kidney cancer was more effective than giving the standard treatment alone. About 87% of patients getting the new combination saw their tumors shrink or stabilize, compared with 55% of those getting the standard treatment. Additionally, the average time it took for the disease to progress was 16.9 months in the experimental group compared with 11.3 months in the other group. However, there were significant side effects.

The targeted therapy tested was cabozantinib (Cabometyx®), which is already approved to treat kidney cancer either on its own or in combination with the immunotherapy drug nivolumab (Opdivo®). This study compared the addition of cabozantinib to nivolumab combined with another immunotherapy drug, ipilimumab (Yervoy®), to the immunotherapy combination plus a placebo. The two-immunotherapy combination also is currently a standard treatment for advanced kidney cancer.

Clinical Trial for Stage 4 Kidney Cancer Adds Targeted Therapy to Immunotherapy

The trial, an international phase 3 study, enrolled more than 850 patients, all of whom had stage 4 kidney cancer and had not yet received any drug treatments. Some of them had previously had surgery, including Michael, whose tumor was removed by MSK urologic surgeon Paul Russo, MD. After the surgery, Dr. Russo determined that Michael needed additional treatment due the aggressiveness of his cancer. Dr. Russo referred Michael to Dr. Motzer, who was able to offer Michael access to the clinical trial.

“When I started in the trial, I remember praying to God that I was in the group that got the extra drug and not the placebo,” Michael says. Although all the results from the study have not been unblinded yet, Dr. Motzer is certain that Michael was in the cabozantinib group based on the side effects he experienced that were likely related to the targeted therapy.

Studying the Side Effects of New Kidney Cancer Drug Treatments

The treatment side effects for Michael included pain and severe swelling of his legs. He was worried. Overall, 45% of people in the experimental group had reactions that were severe enough they had to stop treatment early, compared with 24% of those who got the older standard combination. The most common side effects seen in the trial were liver problems, skin problems, and gastrointestinal issues like diarrhea.

Michael was one of the patients who had to stop taking the drugs before the end of the trial. He is grateful that he was able to receive the treatment long enough to put his cancer into remission.

“Because of the severity of the side effects, it’s too early to determine whether this new combination will become a standard treatment,” Dr. Motzer explains. “Longer follow-up is needed to see if patients will live longer following treatment with the addition of the targeted drug compared to the standard immunotherapy program. Future research will focus on determining who is most likely to benefit from the addition of cabozantinib.”

MSK Treats Michael’s Kidney Cancer After It Spreads to his Brain

About two years after Michael finished his treatment on the clinical trial, he began feeling like he was in a mental fog. Eventually he started losing control of the left side of his body. An MRI showed that his kidney cancer had spread to an isolated spot on the right side of his brain. In May 2022, MSK neurologic surgeon Cameron Brennan performed surgery to remove the tumor.

“When I had my kidney surgery with Dr. Russo, I wasn’t scared, but with this operation on my brain, I was truly scared,” Michael remembers. “Dr. Brennan was absolutely fantastic. He explained everything to me so well, and he said, ‘You’re going to be fine.’ And that helped me tremendously.”

Michael also needed follow-up radiation treatments to his brain, which he was able to get at MSK-Monmouth near his home in New Jersey.

Recovery after the brain surgery and radiation treatments was difficult. Michael leaned on many care providers at MSK, especially physical therapist Lauren Moore, also at MSK-Monmouth. Eventually, he started feeling like himself again.

Michael Is Doing Well After Clinical Trial for Kidney Cancer

Today Michael, who retired in 2020 from a job in finance, remains cancer free. He enjoys taking walks with his wife, going to his favorite Italian restaurant on the New Jersey shore, and dining out in Manhattan with his two adult sons. This year he has several trips planned, including to his two favorite vacation spots: Williamsburg, Virginia, and Nantucket, Massachusetts.

“Words cannot express how I feel about MSK. Every person I met helped to make a crappy situation into something bearable,” Michael says. “And Dr. Motzer was the maestro of this whole journey. He took care of me every step of the way.”

This research was supported by Exelixis, the company that makes cabozantinib. Bristol Myers Squibb provided nivolumab and ipilimumab. Toni Choueiri, the study’s first and co-corresponding author, is supported in part by the Dana–Farber/Harvard Cancer Center Kidney Specialized Program of Research Excellence (2P50CA101942-16) and Program 5P30CA006516-56, the Kohlberg Chair at Harvard Medical School and the Trust Family, Michael Brigham, Pan Mass Challenge, Hinda and Arthur Marcus, and Loker Pinard Funds for Kidney Cancer Research at the Dana–Farber Cancer Institute. Patients treated at MSK were supported in part by National Institutes of Health grant P30 CA008748.

Researchers from Memorial Sloan Kettering Cancer Center (MSK) revealed new findings about hereditary cancers and genetics at the recent 2023 American Society of Clinical Oncology (ASCO) annual meeting.

Genetic mutations that are passed down through families cause a significant percentage of cancers — between 5 and 10%, and as high as 15 to 20% in people with advanced cancers. Patients with certain hereditary cancers may especially benefit from many of the latest cancer treatments, including targeted drugs and immunotherapies. Their families also may benefit from being monitored for early signs of cancer.

Among the recent advances in MSK’s research into understanding how inherited DNA mutations affect cancer development and treatment, four presentations at the ASCO meeting highlighted new analysis of early-onset disease, hereditary cancers in transgender people, a new gene linked to lung cancer, and the importance of genetic testing for younger people with gastrointestinal cancers.

What Defines Early-Onset Cancers and How Should They Be Treated?

Amid growing concern about an increase in cancers occurring in younger people, clinical geneticist and gastrointestinal oncologist Zsofia Stadler, MD, presented research that found the age for so-called “early-onset” cancer can vary widely depending on the type of cancer. Dr. Stadler stressed the need to have clear criteria to define early-onset cancers, because her research also found these cancers are more likely to be linked to an inherited genetic mutation. Knowing whether a cancer is caused by a hereditary mutation is important because it can make a difference in choosing the right treatment. It’s also a signal that members of a patient’s family should consider genetic testing.

“We know the incidence of early-onset cancer is increasing for some tumor types, but when we think about what early onset means, we realize it’s actually poorly defined,” says Dr. Stadler, Clinical Director of MSK’s Clinical Genetics Service. “These cancers are usually defined as those arising before the age of 50 for any type of solid tumor. But the fact is, there is a dramatic variation in the average age of onset across different tumor types.”

The research had two aims: The first was to determine what age should be considered early onset for a variety of solid tumors. The second was to determine how often different types of early-onset cancers were likely caused by inherited genetic mutations.

First, the investigators used a National Cancer Institute database to determine the average age at which patients typically developed 32 types of solid tumors. Based on those ages, researchers then used a formula to calculate what age would be considered early onset for each of these cancers. That age ranged from the late 30s for cervical and thyroid cancers to about 60 for mesothelioma and bladder cancer. “If we considered 50 the cutoff age for every type of solid tumor, there are a lot of early-onset cancers that we would miss,” Dr. Stadler explains.

To answer the study’s second major question, the researchers then used these new classifications to analyze how often early-onset cancers were linked to an inherited genetic mutation. (This is an alteration in DNA that is passed on by a parent and present in every cell in the body.)

Overall, researchers found that early-onset cancers were much more likely to be linked to hereditary mutations — 19% versus 15.5% in people whose cancers developed at an average age. For hereditary mutations defined as “high penetrance” (meaning they were extremely likely to cause cancer), the difference was even more dramatic: 13% of early-onset cancers were linked to inherited mutations versus 5% of cancers occurring at an average age.

Researchers arrived at this conclusion using data from about 29,000 patients whose DNA was analyzed with MSK-IMPACT®, a test that identifies genetic mutations linked to cancer. It can find mutations that are only in tumors as well as inherited mutations that may increase the risk of developing cancer.

“The diagnosis of an early-onset cancer is an impetus for doing genetic testing to look for inherited risk factors,” Dr. Stadler says. “The findings from this study illustrate how important it is that early-onset cancers be correctly classified.”

Caring for Transgender Patients With Hereditary Cancer Syndromes

Genetic counselor Megha Ranganathan, MS, CGC, participated in a panel discussion focused on caring for transgender patients with inherited mutations in the BRCA1 and BRCA2 genes. Mutations in these genes can increase the risk for several cancers, including breast, ovarian, and prostate cancer.

“There are more than 1.6 million people in the United States who identify as transgender, and that number is likely an underestimate,” Ranganathan says. “The data is so limited that many providers are often unsure how to best manage cancer risk in these people, especially those at higher risk due to an inherited genetic predisposition.”

Ranganathan and her co-presenters discussed two cases demonstrating the challenges for these patients. The first case involved a transgender woman (a person who is assigned male at birth but identifies as a woman). After her mother was diagnosed with ovarian cancer, genetic testing revealed the transgender woman had a BRCA2 mutation. “At that point, the patient had already been receiving gender-affirming estrogen therapy for about 10 years,” Ranganathan said. “We know that prolonged estrogen exposure is a risk factor for breast cancer, but it is unknown how much it increases her risk, especially because she has a BRCA2 mutation.

“Despite the lack of reliable data, increased breast cancer surveillance or risk-reducing surgery may be reasonable options,” she added. “We encourage these patients to talk to their doctors to determine the best option for them depending on their gender-affirming goals.” Another issue for this patient: Because she was assigned male at birth, she has a prostate, and this gene mutation puts her at increased risk for prostate cancer as well.

The second case involved a young transgender man (a person who is assigned female at birth but identifies as a man). He had a BRCA1 mutation and was considering top surgery (surgery to remove breast tissue and make the chest look more masculine). Would having top surgery reduce his risk for breast cancer? The panel suggested more extensive surgery such as a full mastectomy could be considered to prevent breast cancer in this situation.

Ranganathan and her co-presenters also discussed several ways healthcare providers can create a more inclusive environment for gender-diverse people. The panelists explained key concepts and terms, how to represent someone’s gender and sex assigned at birth on family trees, and how to request a patient’s chosen name and pronouns.

“Many transgender people avoid the healthcare system altogether because they fear discrimination and stigmatization. Research is lacking on how best to care for them,” says Ranganathan. “As an institution that is dedicated to reducing healthcare disparities, we at MSK want patients to be aware that this is something we’re thinking about and that we aspire to provide excellent care for all patients, regardless of gender identity.”

A New Gene Potentially Linked to Inherited Risk of Lung Cancer

Pediatric oncologist and clinical geneticist Michael Walsh, MD, presented new research that found for the first time that mutations in the cancer predisposition gene POT1 are associated with increased rates of lung cancer. Previously, mutations in POT1 have been associated with sarcoma, certain types of leukemia, and clonal hematopoiesis, a blood condition linked to aging.

“Compared with other cancers like breast, ovarian, and prostate cancers, we know less about the inherited risks of lung cancer,” Dr. Walsh says. “We know that lung cancer is strongly linked to environmental causes like smoking. These findings shine a light on potential inherited factors that may also play a role in causing lung cancer.”

Dr. Walsh and his team were able to make this discovery thanks to the cancer genetic test MSK-IMPACT. In addition to sequencing patients’ tumors, MSK-IMPACT can also analyze the genetics of normal tissue, so experts can determine whether a cancer is linked to an inherited genetic mutation or developed at random. In this case, a study of data from patients’ normal DNA allowed investigators to undercover new findings about inherited mutations in POT1.

“POT1 has been added to the list of genes detected by MSK-IMPACT relatively recently, so it hasn’t been studied as well as some other cancer genes,” Dr. Walsh explains. “But when we looked at data for about 7,000 patients, we found that the incidence of lung adenocarcinoma in people with this inherited mutation was much higher than expected.”

After the MSK-IMPACT analysis, Dr. Walsh and his colleagues found that other large databases of cancer genes supported their findings. They will continue studying the link.

Dr. Walsh says one day this discovery might provide insights leading to new treatments for cancer.

Increasing Genetic Testing for Younger People with Gastrointestinal Cancers

In response to the alarming increase in colorectal cancer cases in younger people, MSK clinical geneticist and family medicine physician Alicia Latham, MD, MS, urged more testing to determine possible inherited risks of cancer.

“As MSK offers genetic testing to more of our patients, we’re finding that some of these gene mutations are more common than we previously believed,” says Dr. Latham, who spoke at an ASCO session focused on gastrointestinal (GI) cancers. “But there are questions about whether these mutations are truly related to the cancer or are instead incidental findings.”

Dr. Latham specializes in treating people with Lynch syndrome. This hereditary condition carries an increased risk of certain types of cancer, including colon cancer and rectal cancers. Lynch syndrome cancers are characterized by a feature called microsatellite instability, which makes them especially responsive to immunotherapy drugs called checkpoint inhibitors.

Because these mutations have important implications for treatment, there is a move toward testing more patients with GI cancers for these genes, especially younger patients, Dr. Latham explains.

“This is a real change from what we’ve done in the past,” she says. “But because findings from these tests can have such important implications for treatment, we want everyone to be aware of these connections and the importance of testing.”

She adds that several collaborative advisory groups in North America and Europe are also backing the recommendations to test more patients for inherited conditions.

KRAS was one of the first cancer genes ever discovered, but for a long time the cancer-causing KRAS protein was considered “undruggable” with targeted therapy. That started to change in May 2021, when the Food and Drug Administration approved sotorasib (Lumakras®) for lung cancers caused by a particular KRAS mutation, called KRAS G12C. The landmark approval of sotorasib was based on years of lab research and clinical trials, much of that work led by physician-scientist Piro Lito, MD, PhD, and other investigators at Memorial Sloan Kettering Cancer Center (MSK).

But G12C is only one of many mutations in KRAS (pronounced “kay-rass”) known to cause cancer, and lung cancer is only one of many cancers linked to these mutations. In a paper published May 31, 2023, in Nature, investigators led by Dr. Lito reported exciting results for a new molecule that can block many more mutated forms of the KRAS protein. In the lab, the compound was effective at blocking the growth of multiple cancer cell lines, including lung cancer, colon cancer, and pancreatic cancer. It was also effective in mouse models of lung and colorectal cancers caused by KRAS.

“KRAS is the most frequently activated protein in cancer,” says Dr. Lito, a thoracic oncologist who also heads a lab in MSK’s Human Oncology and Pathogenesis Program. “Although they are important, the drugs that we have developed so far only help a limited number of people. The inhibitor described in this paper has key therapeutic implications for treating patients with more types of cancer and more KRAS mutations.”

Compound Inactivates a Range of KRAS-Mutant Proteins

KRAS-driven cancers have long been considered undruggable due to the protein’s uncommon shape. Because KRAS is smooth and round, it was difficult to find a targeted drug that could wedge in and block the protein’s activity. A decade ago, researchers discovered that the G12C version of the protein had a small pocket that opened and closed, depending on whether the protein was active. Within a few years, drugs were developed that could fit into that pocket and switch the protein off. But those drugs were ineffective against other forms of KRAS mutations that didn’t have the pocket.

BI-2865, the inhibitor analyzed in this study, binds to the KRAS protein in a different way, taking advantage of characteristics of the protein that were not previously known.

“We were surprised that BI-2865 was able to inactivate the most frequent cancer-causing KRAS mutants,” says Dongsung Kim, PhD, a research associate with Dr. Lito and the study’s first author. “These mutants were thought to be locked in an active state in cancer, but if that were true this drug would not work at all. This research opens a new direction in our understanding of how these mutations cause cancer.” In fact, studies in the lab showed that the new inhibitor was able to block 15 other versions of KRAS in addition to the G12C mutation.

Moving New KRAS Inhibitors into Clinical Trials

BI-2865 was developed by investigators from the pharmaceutical company Boehringer Ingelheim, who collaborated on this study and co-supervised it. It is a prototype that will need to be refined before testing in patients, but the company is working on new molecules that are optimized for clinical development. Dr. Lito plans to continue working with investigators from the company and hopes to have drugs that could be tested in clinical trials within a year.

“The ability to target multiple KRAS mutants with a single molecule provides more definitive evidence that KRAS is finally druggable after more than 40 years of research,” Dr. Lito says. “This work has the potential to benefit a large number of people with cancer, including lung, colorectal, and pancreatic cancers.”

At a worldwide gathering of the American Association for Cancer Research (AACR), Memorial Sloan Kettering Cancer Center (MSK) scientists presented new insights into the connection between cancer and the gut microbiome, often referred to as the “forgotten organ.” Their findings included:

• Clues that microbiomes might explain the increase in colorectal cancer among younger patients.
• Discoveries about how patients’ recovery from bone marrow transplants can be affected by their microbiome and the amount of fiber in their diet.

Studying the Connection Between the Gut Microbiome and Gastrointestinal Cancers, Especially in Younger People

In one study, researchers found a difference in the gut microbiomes of people diagnosed with colorectal cancer before age 50 and those after age 50.

This work was led by physician-scientist and gastrointestinal oncologist Karuna Ganesh, MD, PhD, and gynecological oncologist Melissa Lumish, MD. Dr. Ganesh, a medical oncologist specializing in the treatment of gastrointestinal cancers, also studies them in her lab. Her work investigates why these cancers metastasize (spread) to other parts of the body.

Dr. Ganesh says: “In recent years, we have been seeing younger and younger patients develop GI cancers, for reasons that are not explained by tumor genetics. We hypothesize that changes in environment and lifestyle factors, reflected in the bacteria that live inside us, may provide clues to what’s going on.”

Explaining Why GI Cancers Are Increasing in Younger People

The MSK team reported data on 53 patients with colorectal cancer and 23 patients with esophageal cancer.

For both groups, they collected “living” samples of tumor as well as normal tissue, blood, and stool bacteria from people who had been newly diagnosed with stage 3 disease and those with stage 4 disease. In the first part of the study, the team looked at whether differences in the microbiome samples might explain why certain people are more likely to have their disease progress. They didn’t focus on individual strains of microbes, but instead looked at the variety of bacteria that were present. In this part of the study, they didn’t see a marked difference.

However, when they divided the patients by age rather than stage of disease, they did find noticeable differences. The populations of bacteria in people who had early-onset cancers (developing before the age of 50) were not the same as they were in those who developed cancer at a later age. “These differences in bacteria might explain why these patients develop cancer at a younger age,” Dr. Lumish says.

Dr. Lumish adds that this research is still in its early stages and much more data collection is needed. For example, researchers would need to compare microbiome samples in those with early-stage GI cancers to those of people the same age who don’t have cancer. “Additionally, we know there are microbiome differences based on where people live,” Dr. Lumish says. “But we find this trend toward increased early-onset cancers across the globe.”

Understanding Why GI Cancers Progress

These findings suggest new areas of research for Dr. Ganesh to pursue in her lab, which is part of the Molecular Pharmacology Program at the Sloan Kettering Institute. Her lab has developed novel multi-tissue three-dimensional “organoid” models that re-create the interactions among cancer cells, immune cells, and microbes in a dish. “These models help us study how these three components are talking to each other and how this enables cancers to grow and become more aggressive,” Dr. Ganesh explains.

The team is reconstituting the tumor cells, gut bacteria, and immune cells from individual patients as multi-tissue organoids and studying how they interact. The investigators will also follow the patients in the study and collect additional samples. They are tracking whether changes in the microbiome might explain why the type of cancer a patient has changes — for example, if it no longer responds to treatment or advances from stage 3 to stage 4.

“About half of people with stage 3 colorectal cancer are cured of their disease, while the other half relapse and eventually die from it,” Dr. Ganesh says. “We hope that, through our lab research, we can improve outcomes for all patients.”

Studying How Dietary Fiber and Microbiota Affect BMT Outcomes

Another study looked at whether dietary fiber can improve outcomes for people receiving a bone marrow transplant (BMT) when using donor cells (allogeneic). The team was led by Marcel van den Brink, MD, PhD, and a research scholar in his lab, Jenny Paredes Sanchez, PhD, in collaboration with BMT expert Jonathan Peled, MD, PhD, who leads a laboratory at MSK devoted to studying the role of the intestinal microbiome in people with cancer.

The scientists analyzed data from 173 people having BMTs at MSK. The researchers collected details on everything the patients ate as well as regular stool samples to analyze their microbiomes. They found that patients who consumed more fiber had a greater diversity of bacterial strains in their guts — a sign of good gut health. One of the goals of the study is to ask whether there is a relationship between fiber intake and graft-versus-host disease (GVHD). GVHD is a potentially fatal complication of BMTs in which the donor’s immune cells attack the patient’s healthy tissues.

“When we think about the impact of diet on the microbiome, we can consider it a kind of drug,” says Dr. van den Brink. “If we want to learn how to maximize the potential benefits from a certain diet, we need to do a better job of monitoring what people eat when they are recovering from BMTs.” Dr. van den Brink is Head of MSK’s Division of Hematologic Malignancies and also has a lab in the Immunology Program of the Sloan Kettering Institute.

“Nutritional studies have been integrated into cancer research in the past, but this project used a much more rigorous approach,” Dr. Paredes says.

The Link Between Fiber and Microbiome Diversity

The investigators took what they observed in the clinic into the lab to learn more, using animal models of allogeneic BMTs. In the lab mice, the investigators focused on cellulose, a type of dietary fiber that’s found in raw vegetables, grains, and legumes like lentils and chickpeas.

“There have been a lot of studies on the benefits of fiber in general, but we decided to focus on one particular type,” Dr. Paredes explains. “Cellulose has a big impact on the microbiome, because humans don’t have the enzymatic machinery to break it down. We completely rely on our microbes to digest it.”

The researchers found that mice that consumed larger amounts of cellulose had more diversity in their microbiomes. This included beneficial strains that are known to produce a type of molecule called short-chain fatty acids. Previous studies from Dr. van den Brink’s lab have shown that these molecules protect the lining of the gut, helping to prevent GVHD. The presence of beneficial strains can also help prevent more harmful strains that can cause serious infections from taking over.

Both studies presented at AACR benefited from the Molecular Microbiology Facility, which was founded at MSK in 2010 to collect, process, and analyze human and mouse samples to analyze the microbiome.

Translating Lab Findings to Clinical Trials for BMT Patients

Dr. van den Brink notes these findings are important, but only the beginning of understanding how to help patients having BMTs. “Just like with a drug, we need to do clinical trials to determine the best ‘dose’ of fiber,” he says. “In the mice, we found that too much cellulose in the diet also caused problems.”

He adds that some studies have also suggested that short-chain fatty acids have a positive effect on the immune system, including promoting the growth of immune cells that protect against inflammation. “We are thinking about developing a trial to look at a lot of these things,” he says. “What we are learning in the lab can help to guide these studies.”