TARGETING SELECTIVE GUT MICROBIOME AND THEIR METABOLITES FOR THERAPEUTIC AND PATHOGENIC POTENTIAL IN RHEUMATOID ARTHRITIS

Project: Research project

Project Details

Description

The ability of infectious organisms to induce chronic erosive polyarthritis with similarities to Rheumatoid arthritis (RA) suggests a role of microbes in triggering disease. An extension of the infectious etiology is that the commensals, particularly in the gut, may be the causal factor. The ability of antigen-specific oral tolerance to modulate arthritis suggests a role of mucosal immune system in generating tolerance for protection from organ-specific autoimmunity. The gut microbiome is controlled by the host genotype and environmental factors; infections, geographic location, smoking, and diet. Thus, the gut provides a link for all the factors that are known to influence the development of arthritis. We will investigate this by testing our hypothesis that the gut microbes able to access the host immune system drive inflammatory response in the gut and systemically, which is manifested in the joints in genetically predisposed individuals. Our long-term goal is to generate a balanced immune system by restoring the gut community structure and use this strategy for treating inflammation.Rheumatoid arthritis is a chronic inflammatory disease that leads to deformities of joints. Predisposition to RA is associated with the presence of certain HLA class II genes. HLA polymorphism is critical for generating immune response and clearing infections. Most Veterans during their active service move to various locations due to assignments. As a result, they get exposed to various environmental factors and microbes, which impact their gut locally and consequently their immune system. It is unknown if these changes impact RA severity. Studies from the US Army and Department of Veterans Affairs have suggested that there is an increased prevalence of RA in US Veterans.Using mice carrying RA-susceptible and -resistant HLA genes, we have shown that susceptible mice show dysbiosis in gut flora, which is associated with the production of pro-inflammatory Th17 cytokines, while resistant mice produce Th1/Th2 cytokines. Our recent pilot observations suggest that RA patients harbor abundance of a rare lineage gut commensal, Eggerthella, with a decrease in one of the most abundant commensal in healthy humans, Faecalibacterium, as compared to healthy individuals. The dysbiosis in the gut microbial composition caused by an expansion of pathogenic commensals and contraction of beneficial commensals genus/species changed the microbial community structure and may modulate the immune response as well. The anti-inflammatory properties of certain gut microbes can be used to balance the immune system, thereby changing the disease phenotype. The relative abundance and richness with which these commensals are present may determine the gut immune homeostasis and systemic immune system.We may be able to harness the information obtained from our pilot studies from the human gut microbiota for biomarkers and treatment options. However, given the complexity of the gut microbiota, coupled with the relative ignorance of the pathogenesis of RA, we need to rely on an animal model to probe the mechanisms of microbial impact on development of RA and for using these commensals as biomarkers. We have generated an animal model of collagen-induced arthritis (CIA) using mice that express human RA-associated HLA genes and mimic human RA in histopathology, autoantibodies, and sex bias. We are proposing to test (1) the inflammatory ability of Eggerthella to enhance arthritis severity and the mechanism by which gut microbes become accessible to systemic immune system and (2) the anti-inflammatory properties of F. prausnitzii in an experimental model and also if F. prausnitzii can restore the gut microbial community structure and immune response caused by Eggerthella, thereby suppressing disease. Most of the drugs used for treating RA cause immune suppression and have serious side effects. Despite the many advances, there is no good way to predict the outcome of treatment or what determines a severe course of the disease. Thus, there is a need to develop novel and safe therapies that balance the immune system rather than suppressing it.The observations will be useful for treating many inflammatory conditions including RA, a Fiscal Year 2014 Peer Reviewed Medical Research Program topic area.

StatusFinished
Effective start/end date8/1/157/31/18

Funding

  • Congressionally Directed Medical Research Programs: $1,494,417.00

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