3,3-Dimethyl-1-Butanol and its Metabolite 3,3-Dimethylbutyrate Ameliorate Collagen-induced Arthritis Independent of Choline Trimethylamine Lyase Activity.
collagen-induced arthritis
dimethyl butyric acid
trimethylamine
microbiome
rheumatoid arthritis
Journal
Inflammation
ISSN: 1573-2576
Titre abrégé: Inflammation
Pays: United States
ID NLM: 7600105
Informations de publication
Date de publication:
17 Aug 2024
17 Aug 2024
Historique:
received:
07
03
2024
accepted:
08
08
2024
revised:
18
07
2024
medline:
17
8
2024
pubmed:
17
8
2024
entrez:
17
8
2024
Statut:
aheadofprint
Résumé
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.
Identifiants
pubmed: 39153148
doi: 10.1007/s10753-024-02126-y
pii: 10.1007/s10753-024-02126-y
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NHLBI NIH HHS
ID : U01HL152405
Pays : United States
Organisme : NHLBI NIH HHS
ID : U01HL152405
Pays : United States
Organisme : NHLBI NIH HHS
ID : U01HL152405
Pays : United States
Organisme : National Institute of Allergy and Infectious Diseases
ID : T32AI074491
Organisme : State of Colorado
ID : Office of Economic Development and International Trade Advanced Industries Accelerator Program
Organisme : State of Colorado
ID : Office of Economic Development and International Trade Advanced Industries Accelerator Program
Organisme : State of Colorado
ID : Office of Economic Development and International Trade Advanced Industries Accelerator Program
Informations de copyright
© 2024. The Author(s).
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