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3,3-Dimethyl-1-Butanol and its Metabolite 3,3-Dimethylbutyrate Ameliorate Collagen-induced Arthritis Independent of Choline Trimethylamine Lyase Activity.
Fechtner, Sabrina; Allen, Brendan E; Chriswell, Meagan E; Jubair, Widian K; Robertson, Charles E; Kofonow, Jennifer N; Frank, Daniel N; Holers, V Michael; Kuhn, Kristine A.
Afiliação
  • Fechtner S; Division of Rheumatology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
  • Allen BE; Division of Rheumatology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
  • Chriswell ME; Division of Rheumatology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
  • Jubair WK; Division of Rheumatology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
  • Robertson CE; Division of Infectious Diseases, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
  • Kofonow JN; Division of Infectious Diseases, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
  • Frank DN; Division of Infectious Diseases, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
  • Holers VM; Division of Rheumatology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
  • Kuhn KA; Division of Rheumatology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. kristine.kuhn@cuanschutz.edu.
Inflammation ; 2024 Aug 17.
Article em En | MEDLINE | ID: mdl-39153148
ABSTRACT
Conflicting data exist in rheumatoid arthritis and the collagen-induced arthritis (CIA) murine model of autoimmune arthritis regarding the role of bacterial carnitine and choline metabolism into the inflammatory product trimethylamine (TMA), which is oxidized in the liver to trimethylamine-N-oxide (TMAO). Using two published inhibitors of bacterial TMA lyase, 3,3-dimethyl-1-butanol (DMB) and fluoromethylcholine (FMC), we tested if TMA/TMAO were relevant to inflammation in the development of CIA. Surprisingly, DMB-treated mice demonstrated > 50% reduction in arthritis severity compared to FMC and vehicle-treated mice, but amelioration of disease was independent of TMA/TMAO production. Given the apparent contradiction that DMB did not inhibit TMA, we then investigated the mechanism of protection by DMB. After verifying that DMB acted independently of the intestinal microbiome, we traced the metabolism of DMB within the host and identified a novel host-derived metabolite of DMB, 3,3-dimethyl-1-butyric acid (DMBut). In vivo studies of mice treated with DMB or DMBut demonstrated efficacy of both molecules in significantly reducing disease and proinflammatory cytokines in CIA, while in vitro studies suggest these molecules may act by modulating secretion of proinflammatory cytokines from macrophages. Altogether, our study suggests that DMB and/or its metabolites are protective in CIA through direct immunomodulatory effects rather than inhibition of bacterial TMA lyases.
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Texto completo: 1 Base de dados: MEDLINE Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Idioma: En Ano de publicação: 2024 Tipo de documento: Article