Bodkhe, Rahul

Abstract We have previously shown that treatment with a novel human commensal, Prevotella histicola, isolated from a duodenal biopsy, can protect HLA-DQ8 mice from collagen induced arthritis (CIA), a model for RA, by modulating the systemic immune response. The present study analyzed the functional and mechanistic impact of P. histicola by comparing pain, motor function, gut microbiota and metabolites in treated and non-treated arthritic DQ8 mice. P. histicola treatment reduced the arthritis-associated pain by improving the motor function when compared to control mice. Analysis of synovium showed that P. histicola treatment increased T regulatory cells and reduced the levels of IL6 in the synovium of arthritic mice which were associated with reduced pain. Treated mice showed P. histicola colonization in the duodenum, a niche from where it was isolated. Further, P. histicola treatment showed varied effects based on circadian rhythm. A longitudinal follow-up of the gut microbial profile in different gut sections suggested that dysbiosis caused due to arthritis in DQ8 is partly normalized to naïve profile after treatment with P. histicola. Treated mice showed an expansion of genus Allobaculum, a butyrate-producing Firmicutes in the guts of DQ8 arthritic mice as compared to pre-treatment. The post-treatment restoration was also reflected in short-chain fatty acids and glucose assimilation rates in T cells. The present study proposes that P. histicola treatment of arthritis in DQ8 mice leads to gut homeostasis. Normalized microbial diversity and metabolites lead to immune regulation resulting in reduced inflammation with improved physical function. The observations suggest P. histicola as a strong candidate for monoclonal bio-therapeutics.

Rheumatoid arthritis (RA) is an autoimmune disorder with multifactorial etiology; both genetic and environmental factors are known to be involved in pathogenesis. Treatment with disease-modifying antirheumatic drugs (DMARDs) plays an essential role in controlling disease progression and symptoms. DMARDs have immunomodulatory properties and suppress immune response by interfering in various pro-inflammatory pathways. Recent evidence has shown that the gut microbiota directly and indirectly modulates the host immune system. RA has been associated with dysbiosis of the gut microbiota. Patients with RA treated with DMARDs show partial restoration of eubiotic gut microbiome. Hence, it is essential to understand the impact of DMARDs on the microbial composition and its consequent influences on the host immune system to identify novel therapies for RA. In this review, we discuss the importance of antirheumatic-drug-induced host microbiota modulations and possible probiotics that can generate eubiosis.