Colon Cancer Linked to Mouth Bacteria

By Maggie Chen

A healthy colon is a marvelously effective organ that squeezes nutrients and water out of food while pumping out waste. But sometimes small clumps of abnormal cells grow on the colon’s lining and turn into cancer. Colon cancer is relatively common but tricky to catch; it can only be confirmed with a colonoscopy or surgery. And a recent, so-far-unexplained rise in colon cancer rates among younger people has ramped up urgency in learning more about how the disease works—and how to prevent it.

Pinning down colon cancer’s genetic or environmental causes has been a complex and long-running quest, but a new study in Nature points to a promising clue: a bacterium typically found in the human mouth. The study found that a specific subtype, or clade, within a subspecies of Fusobacterium nucleatum was linked to colon cancer growth and progression. These results, the study authors say, could lead to better noninvasive diagnostic methods for colon cancer and could even suggest new therapies targeting these bacteria for tumor elimination.

F. nucleatum, associated with dental plaque and gingivitis, occurs naturally in the mouth microbiome. A decade ago scientists discovered that the bacterium was also found in colon cancer more often than in normal colon tissue. “This was particularly interesting because this microbe in noncancerous individuals is usually not present below the [mouth],” says the new study’s co-senior author Susan Bullman, a biologist at the Fred Hutchinson Cancer Center.

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To further explore the microbe’s relationship to colon cancer, Bullman and her colleagues conducted extensive sequencing on F. nucleatum within colon cancer tumors and looked at how the microbe influenced the intestinal environment. The team first analyzed the genomes of F. nucleatum found in colon tumors in order to compare them with those found in the mouth. It collected colon tumors from approximately 100 people and then broke up the tumors and placed them on agar plates to allow the microbes present to grow.

After isolating the F. nucleatum from these cultures, the scientists performed a process called long-read sequencing to get a comprehensive look at the bacterium’s genome. Most traditional sequencing methods rely on what scientists call “short reads”—which is like “assembling a puzzle where you’re not able to get the whole picture,” says the study’s first author, Martha Zepeda-Rivera. “With long-read sequencing, it’s like taking a picture with your camera, where you get the entire picture.”

The team compared these sequences from the colon cancer tissues with those of F. nucleatum from the mouth of healthy individuals. This revealed two main clades within a subspecies (called F. nucleatum animalis) that were distinguished by differences in DNA bases and patterns of encoded proteins. Bacteria in the two clades also had distinct appearances under the microscope: specimens in the second clade were longer and thinner than those from the first.

F. nucleatum animalis from the colon tumors fell overwhelmingly into the second clade. This clade’s genomes seemed to code for characteristics that would help the bacteria survive the perilous journey from the mouth to the intestine—such as the ability to gain nutrients in hostile environments (such as an inflamed gastrointestinal tract) or to better invade cells. These microbes also have “one of the most potent acid-resistant systems” found in bacteria, which lets them tolerate the stomach’s acidic environment, explains Christopher Johnston, a geneticist at Fred Hutchinson Cancer Center and co-senior author of the study.

The findings suggested that the microbes in the second clade were more strongly associated with colon cancer, leading the researchers to explore further how these microbes interacted with the intestine in a mouse model. They gave one group of mice a single oral dose of F. nucleatum animalis from clade 1 and another a dose of clade 2 and then counted the number of tumors that formed. Mice in the clade 2 group developed a significantly higher number of large intestinal tumors in comparison with those given clade 1 bacteria or a nonbacterial control.

When the scientists measured metabolic molecules inside tumors from the mice with clade 2 bacteria, they found more molecules associated with cellular damage from oxidative stress, cancer cell division and inflammation than mice in the control and clade 1 bacteria groups. “This supports the idea that clade 2 bacteria are contributing to this proinflammatory, pro-oncogenic environment,” Zepeda-Rivera says.

Identifying the F. nucleatum variant linked to colon cancer provides helpful insight into its role in disease development, says Shuji Ogino, a Harvard Medical School pathologist, who was not involved with the new study. He notes, though, that more evidence from a larger group of people with colon cancer is needed, as well as more research to see how exactly the bacteria might contribute to inflammation and cancer progression.

The study’s findings might also help in the search for a low-cost, noninvasive strategy to identify people at higher risk for colon cancer, says Cynthia Sears, a biologist at Johns Hopkins University, who peer-reviewed the study. “We need an approach that enables us to zero in on people with higher risk,” she adds. Sears says a test could be developed to simply screen for the presence of this bacteria with a mouth swab or stool sample; clade 2 bacteria were found to be more prevalent in fecal samples from those with colon cancer, too.

In addition to diagnostic tools to predict cancer progression, Bullman, Johnston and Zepeda-Rivera also envision developing a vaccine against the F. nucleatum animalis in clade 2. This approach would be similar to that used with the human papillomavirus vaccine, which targets specific virus subtypes that are most linked to disease.

The study authors say the new findings are an exciting and important step in learning how these microbes can be leveraged to tackle colon cancer. “These results are like a roadmap since we’ve identified the specific clade in tumors,” Johnston says. “And now we’ve outlined the differences that can be investigated moving forward.”