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

细胞和全身代谢回路的变化严重影响免疫反应，可能是控制类风湿关节炎（RA）发病和进展的关键因素。在过去的资助期间，我们已经表明，滑膜成纤维细胞（SF）的代谢活化驱动炎症组织启动，这降低了关节炎期间反复炎症的组织阈值（1）。我们的初步工作现在表明，饮食干预，如营养补充微生物来源的短链脂肪酸（2）或间歇性禁食（IF），有可能改善小鼠的炎症组织引发。非靶向代谢组学研究表明，IF显著改变了SF的血清代谢产物和生物能量特征，表明IF诱导了SF的免疫代谢重编程。此外，IF诱导肠道微生物群的特征性改变。因此，在第二个资助期内，我们试图破译促进这种IF诱导的免疫代谢重新连接并导致关节炎改善的直接和间接机制（通过微生物组重塑等）。我们的长期愿景是设计一种饮食方案，用于改善关节炎的发作和预防临床前模型中的炎症组织引发，并将积极的结果转化为RA和其他形式的炎症性关节炎患者。

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.