Solving Mysteries of the Microbiota

The microbiota has become a hot topic recently, thanks in part to work conducted by immunologist Thirumala-Devi Kanneganti, PhD, of St. Jude Children’s Research Hospital.

In one study, she and her colleagues explored the influence of diet on the microbiota, as well as on a variety of autoimmune disorders. Another study led to groundbreaking discoveries about colon cancer, which may provide hope to thousands of patients diagnosed with the disease each year.

Diet and disease

Scientists have long known that diet can affect disease. But until Kanneganti conducted her research, they did not understand exactly how that happened.

“When I started studying the microbiota more than 10 years ago, I was skeptical about whether it could be used to control diseases,” Kanneganti says. “But seeing is believing. In our lab, I have seen several disease models in which we changed the microbiota and the disease outcome was different.”

In particular, the St. Jude team found that diet can change the composition of bacteria in the intestines—which in turn can modify the immune response.

Autoinflammatory diseases occur when the immune system does not work correctly. The innate, or inborn, immune system attacks the body’s own tissues and causes inflammation.

Kanneganti and her colleagues showed that a nutrient-rich diet offered protection from the bone destruction that accompanies osteomyelitis, an autoinflammatory bone disease that can affect children. The special diet restricted the development of Prevotella bacteria in the gut. These bacteria are associated with osteomyelitis, arthritis and other disorders. Of course, diets that have high levels of certain fatty acids carry their own risks, so identifying the specific components within the special diet would help scientists to check whether adding these components into a normal diet would be beneficial. Scientists were also happy to learn that a regular diet and antibiotics had a similar effect.

The confirmation that diet influences inflammatory disorder symptoms may extend beyond the lab to humans.

“By changing diet, we were able to prevent complete bone destruction,” Kanneganti says. “We think diet modification is applicable to other diseases, too.”

The microbiota and colon cancer

For years, an immune system protein called AIM2 remained a mystery to scientists, aside from the fact that it was absent in many types of cancer.

Then Kanneganti led a team that explored AIM2’s influence on the microbiota. She and her collaborators discovered that AIM2 helps prevent colon cancer. The protein stops intestinal cells from uncontrolled growth—a hallmark of cancer. AIM2 also encourages “good” intestinal bacteria to flourish and prevents the growth of “bad” bacteria.

The discovery could offer hope to children and adults who have colon cancer or are at risk for the disease.

“By increasing AIM2 activity and providing patients with healthy donor bacteria, colon cancer may be treated or even prevented,” Kanneganti says. “This discovery could enable new treatments in the future.”

Kanneganti says colon cancer may be prevented, or its progression slowed, by therapies that boost AIM2 activity and by giving patients healthy bacteria. By measuring AIM2 activity in patients who already have colon cancer, physicians may be able to predict how aggressive the cancer will be.

The scientists also found that AIM2 controls the abnormal growth of stem cells in the colon. Stem cells are immature cells that differentiate into adult cells and replace old or dying cells.

“We clearly showed that AIM2 is important in controlling stem cell proliferation,” Kanneganti says. “This is a big breakthrough. It is intriguing to see how the microbiota can influence stem cell proliferation in the intestine.”

Understanding the microbiota’s role

Kanneganti and her team intend to expand their study of the microbiota and determine how it can be manipulated to cure diseases.

 “My goal is to understand the role of microbiota and how it modulates the outcome of cancer, bone diseases and some autoimmunity and skin problems,” she explains. “By studying the role of the microbiota, we may not only be able to treat several diseases, including cancer and autoimmunity, but cure them as well.”

From Promise, Winter, 2016