Pos0002 microbiota-Derived Histamine Induces Resolution of Synovial Inflammation via Cells of the Nervous System

Abstract

BackgroundIntestinal dysbiosis has been associated with the development and progression of rheumatoid arthritis (RA) [1].Microbiota-derived metabolites such as short-chain fatty acids (SCFA) gained attention in research of inflammatory diseases as promising targets for new therapeutics. Previous work in our lab showed the potent preventive effect of SCFA on the onset of inflammatory arthritis (2, 3). Although effective potential therapeutic approaches are arising, their underlying mechanisms remain elusive [4-6].Cellular derived histamine is considered as pro-inflammatory mediator to induce acute allergic symptoms and to maintain chronicity. Interestingly, we identified an unexpected pro-resolving pathway of SCFA-induced histamine secretion by the gut microbiota. In contrast to the effective, direct Treg inducing 2-week delayed resolving effects of the SCFA propionate, we report on an indirect but ten times faster histamine-mediated pro-resolving mechanism via cells of the nervous system.ObjectivesTo understand the rapid pro-resolving effects of microbiota-derived histamine on synovial inflammation.MethodsWe used 16s rRNA sequencing, HPLC size chromatography exclusion, FMT and meta-transcriptomics to assess propionate-induced changes in microbiota composition and the secreted metabolite profile. Mice with collagen- or serum-induced arthritis (CIA/SIA) were treated orally, i.p. or intrathecally with histamine or specific receptor agonists. Cellular changes in spleen, lymph nodes and joints were assessed by Cytek spectral flow cytometry, inflammatory infiltration and bone erosion were analyzed by histology and µCT. We analyzed differences in CNS and PNS via RNAseq of the spinal cord and peripheral nerves. Effects on vessel leakiness and cell infiltration in the inflamed joints were assessed via lightsheet microscopy and in vivo PET-CT.ResultsHere, we show that therapeutic treatment of CIA mice with the SCFA propionate starting from peak of disease (30 dpi) strongly induced resolution of synovial inflammation after 14 days of treatment. We demonstrate that oral propionate-treatment causes beneficial changes in the microbiota composition and thereby alters the secreted metabolite profile. These metabolites are able to induce rapid resolution of inflammation already after 2 days. By untargeted metabolomics we were able to identify histamine as highly potent metabolite that is increased upon propionate treatment. Oral treatment of CIA mice with histamine or a histamine 3 receptor (H3R) agonist significantly improved clinical symptoms. H3R is mainly expressed on cells of the nervous system. Upon oral H3R treatment we found alterations in activation marker expression in the spinal cord. We further were able to identify changes in the composition and activation of spinal cord (CNS) and the N. plantaris (PNS) of arthritic mice induced by H3R agonist treatment through RNAseq. Moreover, lightsheet microscopy and in vivo PET-CT scans revealed alterations in vessel leakiness and cell infiltration in the inflamed joints.ConclusionIn summary, these data show that the SCFA propionate effectively regulates ongoing inflammation by promoting histamine secretion of the gut microbiota and subsequent H3R-mediated neuronal effector functions that drive the fast resolution of synovial inflammation.References[1]J. U. Scher et al., eLife 2, e01202 (2013).[2]S. Lucas et al., Nat Commun 9, 55 (2018).[3]N. Tajik et al., Nat Commun 11, 1995 (2020).[4]W. Walrabenstein et al., Rheumatology (2023).[5]J. Häger et al., Nutrients 11, (2019).[6]K. Dürholz et al., Nutrients 12, 3207 (2020).Acknowledgements:NIL.Disclosure of InterestsNone Declared.