The role of the gut microbiota in systemic immune responses and autoimmune arthritis (360G-Wellcome-201483_Z_16_Z)

Alterations in gut microbial composition, termed dysbiosis, are associated with the development of autoimmune arthritis. However, the mechanisms by which intestinal bacteria influence immune responses at distal sites have not been identified. Recent studies showed that bacterial metabolites, retinoic acid and short-chain fatty acids, modify CD4 T-cell fate through epigenetic mechanisms. Based on these findings I propose that bacterial species produce key microbial products that act on cis-regulatory elements to alter the differentiation potential of immune cells as they migrate through the gut. My project will address whether transient dysbiosis can permanently influence the differentiation potential of mature CD4 T cells and their precursors, favouring a pro-inflammatory phenotype during subsequent antigen encounters. My experiments will use state-of-the-art techniques and sophisticated animal models to address three key goals: 1. To assess the effects of transient dysbiosis on CD4 T-cell regulatory elements, their lineage potential and pathogenicity 2. To explore the mechanisms by which commensals regulate CD4 T-cell fate 3. To translate my findings into a causal link between dysbiosis and human autoimmune arthritis. Understanding how variation in gut microbial composition influences CD4 T-cell pathogenicity will provide the rationale for therapeutic targeting of the microbiota to modulate immune-mediated inflammation.