title: The role of the short-chain fatty acid propionate and other microbiota-derived metabolites in the resolution of synovial inflammation
title: Die Rolle der kurzkettigen Fettsäure Propionate und anderer mikrobieller Metabolite in der Resolution von synovialer Entzündung
title: The role of the SCFA propionate and other microbiota-derived metabolites in the resolution of synovial inflammation
titleType: AlternativeTitle
Creators: name: Dürholz, Kerstin
Publisher: name: Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU)
Year: 0
Subjects: subject: DDC Classification::5 Naturwissenschaften und Mathematik :: 50 Naturwissenschaften :: 507 Ausbildung, Forschung, verwandte Themen

description: Rheumatoid arthritis (RA) is a highly prevalent chronic and progressive autoimmune disease. It is characterized by persistent inflammation of the synovial membrane leading to swelling, pain and destruction of the joints. Even though the pathophysiology of RA is not fully understood, a number of risk factors involved in disease development are known. Along with a significant hereditary component, smoking and a western diet have all been linked to an increased risk of getting RA. The western diet is characterized by a high fat and sugar content and low consumption of dietary fiber, resulting in changes in the gut microbiota composition and the secreted metabolites. Certain bacteria in the gut microbiota digest dietary fibers to create a variety of metabolites, including short chain fatty acids (SCFA). It has been demonstrated that SCFA have immunomodulatory function by inducing the generation of regulatory T cells and a variety of other antiinflammatory properties. This thesis aims to provide an overview over our current studies addressing the direct and indirect immunomodulatory effects dietary fiber and SCFA, with a main focus on propionate (Figure 1). We show that propionate can directly affect the development and function of different cell types in various compartments. On the one hand propionate alters the fate decision of hematopoietic stem cells in the bone marrow, leading to a lower output of megakaryocyte-erythrocyte progenitors and altered activation and function of the downstream megakaryocytes and platelets. Furthermore, propionate inhibits inflammatory priming of synovial fibroblasts in the joints, interrupting the key process leading to chronification and exacerbation of inflammation upon repeated stimuli. Unpublished data from our group demonstrates that propionate can impact inflammatory processes via indirect mechanisms, through altering the microbiota composition in the gut and, as a result, changing the released metabolites that have an impact on the host. Here, we show that propionate treatment induces bacteria-derived histamine. Histamine is able to induce resolution of paw inflammation in mice via a modulation of CNS activation. Moreover, we could also demonstrate the relevance of dietary fiber supplementation in human disease. Patients at risk for arthritis that progress over time (“progressors”) already had SCFA serum levels that were considerably lower than those of non-progressors before the onset of clinical symptoms. Dietary fiber supplementation for RA patients may enhance their overll health as well as improve a number of clinically relevant parameters. Taken together this thesis provides and summarizes new data on the relevance of dietary fiber supplementation for inflammatory diseases and shows propionate’s direct and indirect mechanisms of action in modulating inflammation and inducing resolution.