Metabolic and dietary control of mesenchymal tissue priming and persistence of arthritis

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Changes in cellular and systemic metabolic circuits heavily affect the immune response and might be critical factors controlling the onset and progression of rheumatoid arthritis (RA). In the past funding period, we have shown that metabolic invigoration of synovial fibroblasts (SFs) drives inflammatory tissue priming, which lowers the tissue threshold for repeated inflammation during arthritis (1). Our preliminary work now demonstrated that dietary interventions, such as nutritional supplementation with microbial-derived short chain fatty acids (2) or intermittent fasting (IF), have the potential to ameliorate inflammatory tissue priming in mice. Untargeted metabolomics re-vealed that IF substantially changed both the profile of serum metabolites and the bioenergetic signature of SFs, indicating IF-induced immune-metabolic reprogramming of SFs. Furthermore, IF induced characteristic alterations in the gut microbiota. During the second funding period we thus seek to decipher the direct and indirect mechanisms that promote such an IF-induced immune-metabolic rewiring and result in amelioration of arthritis (via microbiome remodeling, amongst oth-ers). Our long-term vision is to design a dietary regimen for ameliorating the onset of arthritis and for preventing inflammatory tissue priming in preclinical models and to translate positive results to patients with RA and other forms of inflammatory arthritis.