Inhibition of systemic mammalian metabolism by carnitine mimics from the gut microbiota

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.

doi:10.1101/2025.11.11.687811

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bioRxiv · 10.1101/2025.11.11.687811

Inhibition of systemic mammalian metabolism by carnitine mimics from the gut microbiota

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Abstract

BackgroundThe 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. ResultsHere 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. ConclusionsThese 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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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.. 2025-11-11. Inhibition of systemic mammalian metabolism by carnitine mimics from the gut microbiota. https://doi.org/10.1101/2025.11.11.687811

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