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When Good Germs Go Bad: "Friendly" Gut Bacteria Can Trigger Rheumatoid Arthritis in Mice

Scientists have traced the immune pathway from gut bacteria to the development of arthritis in mice



OAK RIDGE NATIONAL LABORATORY

Gut microbes deserve a lot of credit: They not only help digest our food, produce some nutrients, detoxify harmful substances, and protect us from pathogens—they are also important for the development of the immune system. Disturbances in the gut microbiota have been linked to allergies as well as disorders of the digestive and immune systems. Although intestinal organisms' impact on the digestive system's functioning is generally accepted, how they influence pathologies elsewhere in the body has remained a mystery.

New research has begun to address this enigma. Diane Mathis, professor of pathology at Harvard Medical School, and her colleagues have found that one species of naturally occurring gut bacteria can set off arthritis in mice, in part by manipulating cells of the immune system. Their study appears in the June 25 issue of the journal Immunity.

Rheumatoid arthritis (RA) is a chronic, incurable disease characterized primarily by painful joint inflammation. Although its precise cause is unknown, RA is an autoimmune disease in which the immune system mistakes the body's own substances and cells for foreign invaders and releases friendly fire on them.

To study how gut microbes affect the development of RA, the researchers made use of a specific strain of mice that naturally develop severe inflammatory arthritis. They raised the mice under germ-free conditions and found that the animals developed RA significantly more slowly than the controls that were naturally colonized with diverse, nonpathogenic microorganisms.

What's more, the colonized mice produced a much greater level of an immunoregulatory protein known as IL-17. This molecule is produced by immune cells and promotes inflammation. Blocking IL-17 function in the mice prevented disease progression, demonstrating the important role of IL-17 in arthritis.

Next, the researchers inoculated germ-free mice with a single bacterium species known as segmented filamentous bacteria (SFB), which is naturally found in the gut and has previously been shown to cause increases in IL-17. After the mice were exposed to SFB the researchers observed that the animals not only produced greater amounts of IL-17, but also developed arthritis much more rapidly suggesting that in genetically susceptible individuals gut bacteria can promote arthritis by stimulating the immune system to produce IL-17.

RA has previously been linked with infection by pathogens such as mycoplasma bacteria, Epstein-Barr virus, cytomegalovirus, parvovirus and rubella (German measles) virus, but conclusive evidence is still lacking.

"This [disease] has always been thought of in terms of pathogenic organisms," Mathis says. "People haven't really studied the effect of commensal bacteria."

Alexander Chervonsky, professor of pathology at the University of Chicago who was not involved with this study, notes that one significant outcome of this research is the finding that particular microbes, in this case SFB, can determine the outcome of an autoimmune disease. He points out, however, that even in germ-free conditions these mice still develop arthritis although they do so much more slowly. He says this suggests that the development of arthritis does not require the presence of SFB, but that exposure to the microbes may accelerate disease progression.

Evidence for microbial influence on the development of autoimmune disorders in humans comes primarily from twin studies. For example, type 1 diabetes affects both individuals in pairs of identical twins only about 50 percent of the time. If microorganisms indeed play a role in establishing this difference, there are at least two possible mechanisms at work: First, the diabetic twin could result from infection with a microbe that causes or promotes development of the disease; alternatively, the diabetes-free twin could result from colonization by germs that prevent onset of the disease. Recent studies by Chervonsky support the latter scenario, with greater diabetes incidence seen in specific strains of mice raised under germ-free conditions.

"We have to be cautious because although the mice are kept in a germ-free environment, it doesn't mean that they are not exposed to microbial products," Chervonsky says. He adds there is always concern that microbes may contaminate the feed, a possibility that could be overcome using a completely synthetic diet.

Mathis emphasized that one should not take away from these mouse studies "that mice or humans can 'catch' an autoimmune disease or arthritis," she says. She added that the better way to think about it is that individuals have varying degrees of genetic susceptibility, and when exposed to certain environmental factors may then go on to develop disease. "It's really an interaction between genetics and environment," Mathis says.

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