Researchers Uncover Protective Role of Mucosal IgA Against Colorectal Cancer

Antibodies that coat the lining of your gut may be playing an important role in preventing colon cancer from developing, Rockefeller University scientists have discovered. 

Mice that lack a specific class of antibodies, called immunoglobulin A (IgA), develop more than twice as many colon tumors as usual, the team reported in Nature. The study also explained why: When the antibodies bind to the cells lining the inside of the gut, it keeps those cells from dividing too quickly-which could lead to cancer.

When the researchers gave IgA-deficient mice oral doses of the antibodies, they no longer had a higher risk of developing tumors.

One intriguing aspect of this work is that it shows how a natural defense in the gut restrains the cell division that can lead to cancer. Most cancer research focuses on trying to destroy a tumor that already exists, but what if we could intervene before tumors form?"

Daniel Mucida, Rockefeller University

The discovery illuminates why people with IgA deficiency-who have few or none of these antibodies-are at a higher risk of developing colorectal cancer but also could shed light on other aspects of the complex interplay between the gut microbes, immune system, and cancer-even in otherwise healthy people.

A Common Antibody Filling the Gut

Scientists and clinicians have long known that the gut has high levels of IgA. Unlike many antibodies that are highly specific for one pathogen at a time, IgA is a broad-acting first line of defense in the immune system. A single IgA molecule can bind to a wide range of gut bacteria-as well as some healthy human cells-but researchers had long wondered why there were such high levels of IgA in the digestive system.

Mucida and his colleagues study how the intestine strikes a balance between protecting the body against invading pathogens and absorbing the nutrients the body needs. In the past, for instance, the lab has discovered the role that gut immune cells play in food intolerances and allergies.

In the new work, former Rockefeller postdoctoral fellow Gregory Donaldson-now an assistant professor at UCLA-wanted to tease out exactly how IgA antibodies interact with gut bacteria, and whether that could be relevant to colon cancer.

"We know these antibodies bind bacteria and by doing so can shape the microbiome," he says. "And because IgA deficiency, which affects about 1 in 500 people in the U.S., is linked to colorectal cancer, I wondered whether these interactions might be relevant to the disease."

Donaldson began by studying IgA-deficient mice that were raised alongside normal mice, ensuring that they were exposed to the same germs and food. The mice without IgA developed more colorectal cancers than those who had IgA-echoing what was already known to occur in humans.

"We found this was true for several different kinds of models of colon cancer, so that was a really convincing effect," says Donaldson.

Moreover, giving these mice an oral treatment of IgA molecules eliminated the increased risk of cancer.

Keeping the Brakes on Cell Division

Mucida, Donaldson, and the rest of their group zoomed in to the cells lining the gut, called epithelial cells-where colon cancers first form-to see how they were different in the mice lacking IgA. They discovered that changes in gene expression included ones related to cell division, or proliferation, and that these changes came before any tumors ever emerged.

"We assumed there must be some sort of receptor on the epithelial cells that was mediating this," Donaldson says.

Second author Gabriella Lima dos Reis, a graduate student in Gabriel Victora's lab, homed in on one receptor that is found on the surface of epithelial cells and that IgA can bind to. Called DMBT1, it had already been linked in multiple ways to some cancers, but its exact role in colon cancer was unclear.

The team went on to show that DMBT1, in the presence of gut bacteria, acts as a gas pedal for cell proliferation. But IgA, when it binds to DMBT1, acts as a brake. If IgA is completely absent, DMBT1 signaling is unrestrained, letting gut epithelial cells divide more than usual and form tumors. But without gut bacteria, without DMBT1 signaling, or with normal IgA levels, the epithelial cells are kept in check.

"If IgA is missing, epithelial cells that are performing their normal function-responding to bacteria by producing new cells-can keep dividing unchecked, leading to cancer," Mucida says. "We think this homeostatic effect is IgA's main function. This was a big surprise."

Lessons for Colon Cancer

By establishing DMBT1's natural function in epithelial cells for the first time, the findings may lay the groundwork for new interventions to reduce colon cancer risk.

"Based on the mechanism we discovered, perhaps we could influence epithelial cells to be less likely to develop into a tumor," Mucida says. "We know, for example, that having polyps increases your chances of getting colon cancer, so we think that there could be an opportunity to target this pathway after polyps are removed. Right now, there are no interventions available at that point."

"What is potentially even more exciting is that there is evidence that individual species of bacteria can have really specific effects on epithelial cells as well," Donaldson notes. "A lot of research has focused on bacteria that induce tumors or can exacerbate their growth, but we have some evidence that there are bacteria that could do the opposite, just as IgA does. To that end, perhaps we could develop a probiotic supplement that induces a protective IgA response. This is all very speculative, but it's one direction that we could look towards in the future."

Mucida adds, "Overall, there is a lot more to learn about how the dance between bacteria, antibodies, and epithelial cells in the gut works to maintain health."