Targeting Selective Gut Microbiome and Their Metabolites for Therapeutic and Pathogenic Potential in Rheumatoid Arthritis

Incidence of autoimmune diseases like rheumatoid arthritis (RA) is increasing in developed countries. One reason for this increase has been suggested to be due to extra hygiene habits. This limits the variability in good bacteria we harbor in our guts. Although we are all scared of bugs (bacteria), not all of them are bad for our health. Our gut harbors a number of bacteria (commensal), and recent studies suggest that some of these bugs might be beneficial to our health. Actually, the good bacteria help us digest some foods that our body cannot digest, thus providing energy. Thus, we live in harmony with bacteria in our gut. We recently studied bacteria in stool samples of RA patients. Bacteria live in colonies like we do. In RA patients, a bad bug can change the nature of that colony. RA is an autoimmune disease that is associated with the presence of certain genes called histocompatibility leukocyte antigen (HLA) genes. These genes are required for generating immune response to infections and clear infectious agents. Some studies suggest that infections are the cause for onset of RA, suggesting a role of environmental factors. Since we have bacteria residing in our gut, it is possible that some of these bacteria may be pathogenic, which are kept in check by good bugs. Thus, bacteria can impact RA onset. Veterans when on active duty move to different places and also are deployed outside the United States. They are exposed to different microbes at various places and other environmental factors that can change the bacterial colonies residing in their guts.

Our recent data showed that certain bugs that are present with very few numbers in healthy adults expand in RA patients. We will test disease-causing properties of one bug that we observed in RA patients. In addition, we will test bugs present in abundance in healthy individuals but decreased in numbers in patients for treating RA. The experiments proposed here will test a new concept for treating arthritis. We will evaluate whether good bugs found in our gut can be used to alter the extent and severity of disease in humans, using experimental model of RA. To test any therapy, we need a suitable animal model that can recapitulate human disease. Therefore, we have developed unique mice that express human MHC class II genes associated with disease and also those that provide resistance. An attractive aspect of the model is that all immune cells responsible for disease are specific for the human MHC class II molecules. Recently, we have shown that mice expressing RA-susceptible human gene differ in their gut flora from the mice that express RA-resistant human gene. Mice expressing RA-associated gene have inflammatory conditions in the gut, as these bugs produce chemicals. We will use our animal model of arthritis to delineate if giving good bugs (that we have identified from healthy individuals) to mice carrying disease-causing bugs will alter their gut microbiota and lead to change in inflammatory conditions and prevent arthritis development in mice. Since the bacteria are native to the gut, they are less likely to be causing any serious side effects. The proposed experiments will provide new insights into how our gut can control disease development and also provide clues to treatment. It is said, 'You are what you eat.' We want to bring in the novel aspect of changing the colonies of bacteria in such a way that it is good for health of an individual. This treatment will be applicable to many other conditions.