Microbiome Patterns Vary Among Individuals with Different Cancer Types and Onset Age

Mayo Clinic researchers have discovered that adults aged 50 years or younger with colorectal and breast cancers have distinct gut microbiome patterns compared with individuals diagnosed later in life. The new finding results from the team’s analysis of stool samples from 1,364 cancer patients across cancer types, stages and treatments, enrolled into the Mayo Clinic Cancer Microbiome (MCCM) cohort, a real-world study that recruited cancer patients at Mayo Clinic in Arizona, Florida and Minnesota, representing 40 states. Stool samples were collected before treatment began and linked to detailed clinical data on side effects and outcomes.

Purna Kashyap, MBBS, director of the Mayo Clinic Microbiome Program and Bernard and Edith Waterman Director, Microbiomics Program, Mayo Clinic Center for Individualized Medicine, and Ruben Mars, PhD, a microbiome researcher at Mayo Clinic in Minnesota, are co-corresponding authors of the researchers’ published paper in Cell, titled “Microbiome signatures linked to cancer and treatment adverse events in a real-world cohort.”

“The gut microbiome reflects an individual’s environment, lifestyle, diet, and physiological state, making it a sensitive barometer of overall health,” the authors wrote. Increasing evidence is implicating the gut microbiome in cancer biology, pointing to links between composition and function to disease development and treatment outcomes. “As the field shifts from association to causality, a key challenge is prioritizing microbes and pathways most likely to drive specific cancers.”

For their reported study the investigators conducted a real-world study of 1,364 Mayo Clinic Cancer Microbiome cohort patients with different cancer types, before starting a new treatment. “This cohort captures the diversity of cancers and treatments encountered in clinical practice, providing a robust foundation for uncovering microbiome signatures specific to individual cancers,” they wrote.

The investigators compared the cancer patients with 287 people without cancer to identify broad microbiome differences. Comparisons across cancers then revealed more specific signals. After accounting for other health conditions, researchers pinpointed 341 bacterial species associated with five cancer groups.

Among those, neuroendocrine tumors showed a broad loss of common health-associated gut bacteria. Liver and intrahepatic bile duct cancers had higher levels of several bacteria, including Enterococcus faecalis. Esophageal cancer had higher levels of six species, including Streptococcus bacteria. Distinct links were also found in lymphoid leukemia and multiple myeloma and related plasma cell cancers.

“We can now narrow the search to those microbial changes that are most specific to individual cancers,” said Mars. “Those are the signals we need to understand first if we want to determine whether the microbiome plays a causal role in cancer and ultimately develop targeted interventions.”

The study findings indicated that among younger patients, those with colorectal cancer had higher lactate levels and more Veillonella parvula, a gut bacterium that feeds on lactate. Tumors can produce high levels of lactate, which V. parvula uses to grow. Whether that relationship plays a role in early-onset disease is not yet known.

Early-onset (EO) breast cancer showed changes across 64 bacterial species and lower levels of primary bile acids. In breast cancer, one of the 64 species that differed in younger patients was Clostridium scindens, a bacterium involved in bile acid and steroid metabolism.

Colorectal and breast cancer rates are rising among younger adults, the authors stated. Colorectal cancer incidence is increasing about three percent a year among adults ages 20 years to 49 years, while breast cancer incidence is rising 1.4% a year among women younger than 50 years, according to the American Cancer Society. And while the colorectal and breast cancer findings do not establish that these microbial or metabolic differences cause early-onset disease, but they identify links that warrant further study. No comparable age-related microbiome differences were found in brain cancer, the third cancer examined in the early-onset analysis.

Researchers identified gut bacteria associated with survival in colorectal, liver and intrahepatic bile duct, ovarian and prostate cancers, and melanoma. In liver and intrahepatic bile duct cancer, Bifidobacterium longum was associated with longer survival and Blautia A massiliensis with shorter survival.

Researchers also studied whether the gut microbiome before treatment was associated with diarrhea during chemotherapy, a side effect that can make treatment harder to tolerate. Among patients receiving 5-fluorouracil, or 5-FU, a chemotherapy used to treat many types of cancer, those who later developed diarrhea had lower levels of bacterial genes capable of breaking down the drug. Much of that function came from Anaerostipes hadrus, a common gut bacterium. “This example underscores the potential of leveraging our real-world mixed-cancer, mixed-treatment cohort to identify microbiome-driven mechanisms underlying cancer treatment-related adverse effects,” they wrote. The same signal was not linked to diarrhea in patients receiving carboplatin, another chemotherapy drug, suggesting the finding was specific to 5-FU.

“The microbiome is not the sole driver of cancer or treatment outcomes, but it is an underappreciated component that has not traditionally been considered in therapeutic approaches,” said Kashyap. “This gives us a proof of concept that we can begin to understand why some patients experience a particular side effect and identify a target that could potentially be acted upon.”

The researchers next aim to investigate whether cancer-specific microbial signals play a causal role in disease and validate the microbiome’s potential to predict treatment side effects in larger patient groups. In their paper the team concluded, “Our findings illustrate how MCCM, a large, real-world mixed-cancer, mixed-treatment cohort, complements traditional case-control designs by more precisely identifying microbial contributions to cancer pathogenesis, EO cancer, and treatment-related adverse events … These findings demonstrate the strength of our cohort and provide a foundational resource for the discovery of cancer-specific microbiome signatures and predictive biomarkers.”

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