An increased incidence of autoimmune and allergic diseases in developed countries has been suggested to be due to extra hygiene habits. This limits the gut flora, which includes good bacteria. 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. Recent findings have shown that levels of certain good bugs, such as Prevotella and bifidobacterium species, are decreased in the stool of patients of rheumatoid arthritis and Crohn's disease. Rheumatoid arthritis and multiple sclerosis (MS) are both autoimmune diseases that are associated with the presence of certain genes called histocompatibility leukocyte antigen (HLA) genes. However, it is difficult to study these genes in humans due to the presence of multiple MHC genes. The experiments proposed here will test a new concept whether good bugs found in our gut can be used to alter the extent and severity of disease in autoimmunity in humans using an experimental model of Rheumatoid Arthritis (RA) and Multiple Sclerosis (MS). 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. Our experiments use a relevant autoantigen to induce a disease similar to RA and MS in these humanized animals of specific genetic backgrounds. 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 isolated a gut friendly commensal bacterium from the bowel of human that showed anti-inflammatory properties in HLA class-II transgenic mice. We will use our humanized animal model of arthritis and MS to identify whether these bugs can ameliorate disease. If successful, this novel treatment option will offer new hope not only to patients with RA and MS but other inflammatory autoimmune diseases, too. Since the bacterium is commensal (good bug from our gut), they are less likely to cause any serious side effects. Thus, the proposed experiments will provide new insights into the use of commensal bacteria as a novel therapeutic option, which might be relevant to human inflammatory and autoimmune diseases.