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

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.