DMB-treated mice demonstrated > 50% reduction in arthritis severity compared to FMC and vehicle-treated mice.
The reduction in arthritis severity was not linked to the production of TMA or TMAO.
DMB acted independently of the intestinal microbiome, indicating alternative pathways of action.
A novel metabolite of DMB, 3,3-dimethyl-1-butyric acid (DMBut), was identified as potentially protective.
Both DMB and DMBut significantly reduced disease severity and proinflammatory cytokines in murine models.
In vitro studies indicate that these compounds may modulate the secretion of proinflammatory cytokines from macrophages.
Simplified
Conflicting data exist in rheumatoid arthritis and the (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.
Key numbers
> 50%
Reduction in Arthritis Severity
DMB-treated mice showed over 50% reduction in arthritis severity compared to controls.
Significantly reduced IL-1β and IL-6 levels
Cytokine Reduction
Both DMB and DMBut treatments significantly lowered IL-1β and IL-6 in mice.
Full Text
We can’t show the full text here under this license.
