While the incidence of colorectal cancer has decreased among the U.S. population overall, there has been a gradual, and alarming, increase in diagnoses among Americans under age 50. Earlier this year, the American Cancer Society reported that Americans born around 1990 have twice the risk of colon cancer compared with people born in the 1950s.

Johns Hopkins infectious diseases professors Cynthia Sears and Jessica Queen suspect the problems — and maybe the solutions — are hidden among the trillions of tiny bugs that live in our intestines.

Late last year, Sears and Queen led a team that published a review article in the journal Nature Cancer. “Understanding the Mechanisms and Translational Implications of the Microbiome for Cancer Therapy Innovation” presents recent insights in a field with which it can be hard to keep up.

“The whole topic has gotten huge,” says Sears, who has studied the microbiome for more than 20 years and was recently named a fellow of the American Association for the Advancement of Science. “There are thousands of studies now. The field has advanced in so many ways.”

In the article, the authors discuss how individual organisms, as well as complex communities of microbes, can be factors in the earliest stages of tumor growth.

“We all know that colon polyps can turn into cancer,” says Sears. “That’s not new. But we know more about how that happens, thanks to all this research.”

“First, these little polyps appear. And if you take them out, you remove the risk of cancer. But if we don’t take them out and they get bigger, we start to see the microbiota stick to them and go down deeper, into the crypts, where new cells are generated.”

Queen says that, although investigations are in their early stages, there’s reason to be encouraged.

“The colon holds trillions of bacteria — it represents the most dense population of microorganisms in the human body,” she says. “These bacteria are in constant contact with cells of the colon and the immune system, and it makes sense that these interactions could be really important for colorectal cancer development and progression.”

The authors detail the mechanics by which four distinct bacteria — H. pylori, E. coli, B. fragilis and F. nucleatum — promote formation and growth of tumors in the gut.

They also discuss the negative effects that tumor neoantigens (the new proteins that form on cancer cells as a result of tumor DNA mutations) can have on cancers. Those same neoantigens, say the authors, can be useful in treating colon cancer.

“Bacteria are the big mystery,” says Sears. “We’ve done pretty well with viruses and how they relate to cancer. We know the viral causes of certain kinds of liver cancer, for example. But we know much less about bacteria and how they work together in tumorigenesis.”

If scientists find 30 different bacteria on a tumor, she says, the question is what role each plays:

Which ones matter? Where are they located? If they’re present at the beginning, did they cause the cancer? Or once the tumor growth starts, are they affecting what happens? What molecules and proteins they’re making and what combinations are most important are tough, tough questions.

As early-onset colorectal cancer continues to rise, Sears says, screening colonoscopies can be life saving.

“Nearly every agency in the field recommends that preventive screening colonoscopies begin at age 45,” she says. “Since most early colorectal cancer is in individuals in their 40s to early 50s, starting preventive care on time should have impact on patient well-being.”

The greatest challenge Sears and Queen see, though, is convincing the health care and pharmaceutical research industries to spend enough money to translate research into therapeutics that can actually affect patient care.

“The most important thing we can do in the research community is to put the microbiome into action,” Sears says. “If we don’t do longitudinal studies in humans, then we’re not following what we’ve learned from the science.”

Queen says stool samples and biopsies from patients with cancer show that several specific bacteria are commonly associated with specific cancers.

“The field is largely focused now on understanding what those bacteria may be doing mechanistically,” says Queen. “And as helpful as mice are as models, they are not humans. We need more data from clinical samples and longitudinal follow-up of patients to better understand how the microbiome impacts progression of disease and response to treatment.”

Sears says that rigorous, well-funded studies have helped researchers learn that mucous-invasive groups of microorganisms (polymicrobial biofilms) are present on more than half of colon cancers and surgically removed polyps.

“To date, the strongest experimental evidence for biofilms as direct tumor promoters comes from studies of human colon biofilms,” says Sears. “Yes, it’s expensive. But that’s science, right? Answering questions leads to more questions. And that’s what pushes us in the right direction.”