For years, scientists have wondered if there was a connection between the type of bacteria in our bodies, particularly our guts, and the development of RA. Could tiny micro-organisms predict who is most susceptible to developing RA and who might be more resistant to the disease? A recent study shows some strong connections between the type of bacteria in our guts and certain genes that may predict RA development

A team of researchers from the Mayo Clinic in Rochester, Minn., and the University of Illinois at Urbana published a study in the peer-reviewed journal Public Library of Science One in April 2012 showing that the types of bacteria lurking in the guts of mice may predict which animals are more susceptible to developing RA and collagen-induced arthritis (CIA), and which mice may be more resistant to the disease. In addition, another set of scientists at the University of Illinois at Urbana have completed a study of humans to examine how consuming different types and amounts of dietary fiber could change their gut bacteria, shifting the mix toward more bacteria with potentially anti-inflammatory properties. Their study was to be published in the Journal of Nutrition in the summer of 2012.

For years, Veena Tareja, PhD, worked with RA patients at the Mayo Clinic and listened to their observations about the connection between diet and inflammation. “They would say, ‘I eat this and my arthritis gets worse.’ I always had the feeling that the gut had something to do with arthritis, because it takes most of the body’s abuse,” says Tareja, the institution’s lead researcher on the new study.

Genes and Bugs

Tareja and her colleagues knew that there were already strong correlations between mice that carry genes with particular genetic variations called alleles and the susceptibility to develop – or resist developing – RA. Mice with the gene HLA-DRB1*0401 are more susceptible to developing RA and CIA, while mice with the gene HLA-DRB1*0402 are more resistant. In addition, they knew the 0401 allele’s presence in people with arthritis was also strongly correlated to gender; three females to one male carrying that gene develop arthritis.

They suspected that the different genes must trigger different reactions in the guts of the mice that tipped the susceptibility scale one way or the other. Several recent studies, including a paper published in Arthritis & Rheumatism in 2010 by rheumatologist Jose Scher, MD, and his colleagues at the Arthritis Clinic of New York University Hospital for Joint Diseases, also established a connection between the presence of certain bacteria in the body, namely inflamed gums, and RA. 

Dr. Scher urges that finding particular bacteria in the gums of people with RA does not necessarily mean those bugs trigger RA, but is merely one step on the road to understanding possible connections. “This remains an association and causality will be difficult to prove,” he says.

Taneja and her colleagues felt that there might be some connection to the gut bacteria found in mice with the particular HLA genes. “We thought, ‘There’s got to be something this gene is doing. Our genes affect what these bugs are doing. The genes and the bugs are related somehow,’” she says. 

She also says that the gut microbiome, or the type of bacteria that are in a person’s digestive system, are affected by various factors, including diet, and more likely, our genes. “We all walk around with millions of bugs inside us, but the balance of bugs makes the difference, along with genes. Until now, nobody took it seriously, but now with new technology, we can see these bugs.” 

Scientists once had to examine bacteria in a Petri dish, says Dr. Scher, but now, they can sequence the bacteria’s DNA and analyze the bugs more accurately.
 

Meaningful Mouse Droppings

Taneja and her colleagues studied the fecal matter of 86 mice, including 41 with the 0401 allele and 45 with the 0402 allele, all given the same diet and kept in the same controlled environment. “Everything was the same except the genes they were carrying. We studied their stool samples and looked at what kind of immune response they had,” she says. What they confirmed was that the droppings of the mice with the 0401 gene were dominated by a number of Clostridium-like bacteria, especially allobaculum stercoricanis and parabacteroides distasonis. In contrast, the 0402-carrying mice were rich in two other types of bacteria, Porphyromonadaceae and Bifidobacteria.

“What we have shown is that there is an imbalance to begin with in mice with the gene,” Taneja says. These foreign organisms that we are all carrying around in our bodies may trigger the production of inflammatory cytokines, she notes. 

Altering that mix of bugs – possibly through dietary changes but more likely through targeted drug therapy someday – could help halt that RA-triggering process, she speculates. “We are trying to do something to rebalance what we already have in our guts. Scientists are realizing this more than ever before. We could treat arthritis by altering the bugs in the gut and making them in balance.”

Could dietary changes have a meaningful effect on gut bacteria? Another group of researchers at the University of Illinois’ department of animal sciences recently examined the intestinal flora in adult male humans who ate various types of dietary fiber. Twenty men were given three snack bars a day to eat in addition to their normal, controlled diets. One group of men were given bars with no dietary fiber, another group was given bars with polydextrose, and a third group was given bars with soluble corn fiber.

After examining the men’s fecal matter, the scientists found that the type of fiber the men ate had a strong effect on the levels of certain gut bacteria in their bodies. Eating more fiber significantly boosted the levels of different bacteria in the body, the researchers found. The men who ate soluble corn fiber had higher levels of Lactobacillus, a probiotic believed to be beneficial to digestive health. Both groups eating higher fiber had higher levels of Faecalibacterium prausnitzii, a bacteria believed to have anti-inflammatory properties also. Yet they also had higher levels of Clostridiaceae, the bacteria found in the guts of mice in Taneja’s study that might correlate to susceptibility to RA.

Gut bacteria’s possible connections to inflammation or the triggering of autoimmune disease is a “fascinating field of research,” says Dr. Scher. More research obviously is needed to determine how these findings may relate to the triggering of RA in humans, he says.

Guts and Gums

Dr. Scher and his colleagues examined the bacteria present in the inflamed gums of people with RA and concluded that there may be an increase in certain bugs in people with RA. Scher presented his findings at the 2011 Annual Meeting of the American College of Rheumatology in Chicago. His current research, funded by the National Institutes of Health, looks at microbiota, or bacteria living within various body cavities, and the development of diseases like RA.

“Gut bacteria have been associated to many autoimmune and rheumatic diseases. Intestinal microbiota are extremely helpful in providing humans with metabolic functions we do not have,” he says, functions like processing vitamins and complex sugars. These bugs also play a role in helping our immune systems mature. 

“Moreover, many mouse and rat models have proved that gut microbiota are sufficient to trigger joint disease,” Dr. Scher adds, including Whipple’s disease and reactive arthritis in humans. “Surveying the gut bacterial populations in different diseases such as RA is a first step into understanding whether they may act as triggering factors for joint disease.”

Despite the intriguing headlines, Dr. Scher says it is too early to firmly say whether certain gut bacteria predicts a risk for RA development in humans. “We are only looking at the tip of the iceberg,” he says. 

We don’t yet understand what processes those bacteria may kick into motion in a human body. “The association with bacteria will be by no means synonymous to causation. Understanding what are those bacteria doing, and how they differ in their metabolic and enzymatic functions will be needed,” he adds.