The complex and highly dynamic relationship between the gut microbiome and the immune system has been identified as a pivotal factor in the pathogenesis of rheumatoid arthritis (RA), during remission and relapse. Nevertheless, the mechanisms that maintain this communication equilibrium and the factors that disrupt it, remain incompletely understood. Our preliminary data indicate that bacterial extracellular vesicles (bEVs), released by a dysbiotic gut microbiota, cross the intestinal barrier, enter the systemic circulation and peripheral tissues to modulate immune responses by influencing myeloid cell function. Notably, macrophages exposed to pathogenic bEVs adopt a pro-inflammatory phenotype, exacerbating inflammation. A key regulator in this metabolic switch is ACOD1 (aconitate decarboxylase 1), which synthesizes the anti-inflammatory metabolite itaconate. Itaconate regulates metabolic response and transcription factors such as the nuclear factor-κB (NF-κB) and HIF1α signalling. Our findings show that bEVs trigger an HIF1α dependent ACOD1-mediated response in macrophages, and that the disruption of this pathway may drive arthritis relapse by tipping the immune balance toward inflammation. Based on these preliminary data, we hypothesise that bEVs released by the dysbiotic gut microbiota play a pivotal role in driving arthritis relapse by modulating myeloid effector function through ACOD1-dependent pathways. To test this hypothesis, we will investigate the biodistribution and immune-modulatory properties of bEVs in murine models of arthritis and RA patient samples. The long-term objective is to define how the gut microbiome and its associated soluble mediators influence immune homeostasis and disease progression/relapse in RA, ultimately identifying novel therapeutic approaches to foster long-term remission and reducing the risk of disease relapse in RA patients.
Principal Investigators
Prof. Dr. rer. nat. Claudia Günther