Authors
Thuemmler, K., Basak, S., Hulme, H., Dritsa, C., Foreman, R., Naseer, H., Salah, E., Tumber, A., Worboys, S., Douce, G., Haggarty, J. H., Williams, R., Taylor, V., Ormsby, M. J., Whitfield, P., McCullagh, J., Salt, I., Burchmore, R. J., Goodwin, R. J., Schofield, C. J., Wall, D. M.
Abstract
Background: The gut microbiota and microbiome-derived metabolites are implicated in various aspects of human health. Here we sought to determine the systemic effects, and mechanism of action, of microbiome-derived carnitine analogues in germ free and conventionally colonised mice. Results: Here we report the systemic localization of the microbiome-derived carnitine analogues, 3-methyl-4-(trimethylammonio)butanoate (3M-4-TMAB) and 5-aminovalerate betaine (5-AVAB), post-administration to germ free mice, with systemic carnitine depletion and mitochondrial dysregulation, reflected in altered acylcarnitine profiles due to incomplete carnitine-mediated fatty acid oxidation. Studies on the inhibitory potency of 3M-4-TMAB at the enzymatic, cellular, and organism levels indicate that, in part, this is a result of inhibition of gammabutyrobetaine hydroxylase, which catalyses the final step in carnitine biosynthesis. Systemic administration of 13C-labelled 3M-4-TMAB to conventionally colonised animals to further investigate the physiological relevance of this inhibition, identified a significant reduction in systemic carnitine levels due to increased excretion in urine and faeces and disruption of carnitine-mediated metabolism across ten organs. Conclusions: These results highlight the physiological relevance and significance of microbiome-derived metabolites in vivo. The depletion of carnitine and inhibition of its function have potentially long-term impacts on both mammalian energy generation and the protective, signalling and immune regulatory effects of this critical molecule.
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bioRxiv
The authors list and abstract were imported from bioRxiv on 12 Nov 2025.
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