3,3-dimethyl-1-butanol and its metabolite 3,3-dimethylbutyrate ameliorate collagen-induced arthritis independent of choline trimethylamine lyase activity.

Autor:	Fechtner S; University of Colorado Anschutz Medical Campus., Allen BE; University of Colorado Anschutz Medical Campus., Chriswell ME; University of Colorado Anschutz Medical Campus., Jubair WK; University of Colorado Anschutz Medical Campus., Robertson CE; University of Colorado Anschutz Medical Campus., Kofonow JN; University of Colorado Anschutz Medical Campus., Frank DN; University of Colorado Anschutz Medical Campus., Holers VM; University of Colorado Anschutz Medical Campus., Kuhn KA; University of Colorado Anschutz Medical Campus.
Jazyk:	angličtina
Zdroj:	Research square [Res Sq] 2023 Sep 05. Date of Electronic Publication: 2023 Sep 05.
DOI:	10.21203/rs.3.rs-3297018/v1
Abstrakt:	Previous studies have identified significant alterations in intestinal carnitine metabolism in mice with collagen-induced arthritis (CIA), potentially linking bacterial dysbiosis with autoimmunity. Bacterial trimethylamine (TMA) lyases metabolize dietary carnitine to TMA, which is oxidized in the liver to trimethylamine-N-oxide (TMAO). TMAO is associated with inflammatory diseases, such as atherosclerosis, whose immunologic processes mirror that of rheumatoid arthritis (RA). Therefore, we investigated the possibility of ameliorating CIA by inhibiting TMA lyase activity using 3,3-dimethyl-1-butanol (DMB) or fluoromethylcholine (FMC). During CIA, mice were treated with 1% vol/vol DMB, 100mg/kg FMC, or vehicle. DMB-treated mice demonstrated significant (>50%) reduction in arthritis severity compared to FMC and vehicle-treated mice. However, in contrast to FMC, DMB treatment did not reduce cecal TMA nor circulating TMAO concentrations. Using gas chromatography, we confirmed the effect of DMB is independent of TMA lyase inhibition. Further, we identified a novel host-derived metabolite of DMB, 3,3-dimethyl-1-butyric acid (DMBut), which also significantly reduced disease and proinflammatory cytokines in CIA mice. Altogether, our study suggests that DMB the immunomodulatory activity of DMB and/or its metabolites are protective in CIA. Elucidating its target and mechanism of action may provide new directions for RA therapeutic development. Competing Interests: Competing interests The authors declare no competing interests.
Databáze:	MEDLINE
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