The Body on Fire

Without the immune system, humans would fall victim to any virus, bacteria or germ they face, says Jian-Dong Li, director of the Institute for Biomedical Sciences and a Georgia Research Alliance Eminent Scholar in inflammation and immunity. And inflammation is one of the biggest weapons in your immune arsenal.

“It is a natural response that’s required to keep us healthy,” says Li.

Under normal circumstances, inflammation is short-lived. A few days later, the cut heals, the redness fades and the swelling diminishes. Yet “there can be too much of a good thing,” says Li. If the immune response doesn’t subside, the body can remain in a state of simmering inflammation for months or even years.

Chronic inflammation isn’t something you can feel, like a swollen, throbbing scratch. Instead, it’s more like a silent, slow burn — one with a profound impact on the body. Research shows runaway inflammation can damage healthy tissue, feed tumors and leave the door open for illness and disease. It’s a hallmark of most chronic diseases and of some of the leading causes of death in the United States, including neurological disorders, cardiovascular disease, pulmonary diseases, cancer and obesity.

But how exactly is inflammation involved? Does it cause these diseases or simply make them worse? Scientists across Georgia State University are working to better understand the relationship between chronic inflammation and a number of serious health conditions. They’re also striving to uncover what fuels uncontrolled inflammation and pinpoint ways to prevent the body’s inflammatory response from going awry.

When Inflammation Goes Wrong

If some inflammation is a good thing, while too much is bad, then how does the body strike the right balance? Although the mechanisms behind chronic inflammation are not fully understood, scientists do know your genes are partially responsible for regulating the immune response, acting as built-in brakes to halt inflammation after it has served its purpose.

For example, Georgia State researchers have found that a gene known as CYLD can curb certain types of inflammation. If the body’s inflammatory immune response continues unchecked, as if the brakes have been cut, an underactive CYLD gene may be to blame.

For those with defective genes, how can outof-control inflammation be stopped? That’s a puzzle researchers at the Center for Inflammation, Immunity & Infection, housed in the Institute for Biomedical Sciences, are trying to solve. Antiinflammatory medications are effective, but they can also shut down the inflammatory response entirely, essentially pulling the plug on the body’s whole immune system.

Li and his colleagues hope to develop a drug that would improve the function of CYLD, prompting it to tap the brakes on inflammation at just the right time. They are also working to identify other genes that may contribute to chronic inflammation.

“The idea is that we could adjust the dose based on exactly how much we want to tamp down inflammation,” says Li. “And we could do it with fewer side effects than existing antiinflammatory drugs.”

Georgia State researchers are also studying the environmental and lifestyle factors that can provoke prolonged, systemic inflammation. One of those factors may be components of a typical Western diet. Additives called emulsifiers give processed foods such as ice cream and yogurt their smooth, creamy texture, and prevent peanuts and oil from separating in peanut butter. Yet according to studies led by Benoit Chassaing, assistant professor in the Institute for Biomedical Sciences, and Andrew Gewirtz, professor in the Center for Inflammation, Immunity & Infection, emulsifiers also alter the makeup of bacteria in the gut, making it easier for those bacteria to break through the protective layer of mucus lining the intestines. If the bacteria reach the intestinal wall — which is normally sterile — and trigger an immune response, that can lead to chronic inflammation.

In the study, the researchers found an emulsifier-supplemented diet dramatically increased the risk of colitis — a form of chronic inflammation similar to inflammatory bowel disease (IBD) in humans — among mice who were genetically predisposed to develop the disorder. Genetically typical mice who were fed emulsifiers developed low-grade intestinal inflammation along with increased body fat, increased food intake and higher blood sugar levels — all early signs of obesity, diabetes and other metabolic problems. The feces of the emulsifier-fed mice also contained higher levels of a bacteria that can penetrate the intestines’ protective mucus and higher levels of proinflammatory bacteria in general.

Chassaing and Gewirtz are now putting together a clinical trial in partnership with the University of Pennsylvania to study the effects of emulsifiers on human gut bacteria. But Chassaing is not waiting for the results to make changes in his own diet. He sees a direct correlation between skyrocketing rates of IBD in the U.S. and our everincreasing consumption of processed foods.

To avoid emulsifiers, Chassaing and his family prepare meals from whole, raw ingredients such as fresh meats and vegetables, and buy natural peanut butter you have to stir yourself.

“And,” he notes, “you can buy emulsifier-free ice cream.”

Extinguishing the Fire Inside

As research has revealed the connection between inflammation and many major diseases, scientists have been working to identify compounds that can tamp down or block the overactive immune response. Certain types of dietary fiber may prove to be potent anti-inflammatory agents, according to Gewirtz. A study he published with colleagues in Cell Host and Microbe found that inulin — a type of fiber found in asparagus, onions, bananas, sprouted wheat and garlic — may prevent metabolic problems caused by a high-fat diet by increasing the body’s production of interleukin-22, an immune protein that regulates inflammation.

For mice whose healthy gut bacteria had been depleted by a fatty diet, adding inulin to their diet restored their good bacteria. The fiber also re-established a healthy separation between gut bacteria and the intestinal wall. Gewirtz says this points to the possibility of creating an antiinflammatory drug containing interleukin-22.

“For people who aren’t willing to change their diets, it may be possible to administer this protein pharmacologically to help prevent chronic inflammatory diseases,” he says.

Chronic inflammation is now known to drive many life-threatening diseases, yet it remains difficult to diagnose. High blood levels of C-reactive protein, a molecule produced by the liver in response to inflammation, could be a good indicator of prolonged systemic inflammation, but more sensitive tests are needed to distinguish among different types of inflammation related to various disease states. Research at the Center for Diagnostics & Therapeutics seeks to identify indicators of inflammation specific to IBD.

“Currently, the biomarkers lack specificity and, used alone, don’t hold much value,” says Emilie Viennois, a postdoctoral researcher at the center.

Identifying new biomarkers could allow doctors to distinguish more quickly between Crohn’s disease and ulcerative colitis — two different forms of IBD —  and help determine which medication would be most effective. Viennois is searching for new biomarkers in microRNA, molecules that play a key role in regulating gene activity.