γ-Butyrobetaine Is a Proatherogenic Intermediate in Gut Microbial Metabolism of L-Carnitine to TMAO

Abstract

Summary L- Carnitine, a nutrient in red meat, was recently reported to accelerate atherosclerosis via a metaorganismal pathway involving gut microbial trimethylamine (TMA) formation and host hepatic conversion into trimethylamine-N-oxide (TMAO). Herein we show that following L-carnitine ingestion, γ-butyrobetaine (γBB) is produced as an intermediary metabolite by gut microbes at a site anatomically proximal to and at a rate ~1000-fold higher than the formation of TMA. Moreover, we show γBB is the major gut microbial metabolite formed from dietary L-carnitine in mice, and like dietary L-carnitine, in a gut microbiota-dependent manner is converted into TMA and TMAO, and accelerates atherosclerosis. Gut microbial composition and functional metabolic studies reveal distinct taxa are associated with the production of γBB versus TMA/TMAO from dietary L-carnitine. Moreover, despite their close structural similarity, chronic dietary exposure to L-carnitine versus γBB promotes development of functionally distinct microbial communities optimized for the metabolism of L-carnitine versus γBB, respectively.

Trimethylamine N‐Oxide Promotes Vascular Inflammation Through Signaling of Mitogen‐Activated Protein Kinase and Nuclear Factor‐κB

“…TMAO is derived primarily from dietary choline and carnitine through the action of gut microbiota, which metabolize these constituents to trimethylamine (TMA) 1, 11, 12. TMA is absorbed in turn and travels via the portal circulation to the liver, where it is oxidized by flavin‐containing monoxygenases, primarily FMO3, to TMAO 1, 11, 12.…”

“…TMA is absorbed in turn and travels via the portal circulation to the liver, where it is oxidized by flavin‐containing monoxygenases, primarily FMO3, to TMAO 1, 11, 12. In studies in mice, supplementation with dietary choline, carnitine, precarnitine (γ‐butyrobetaine) , or even TMAO alone was sufficient to enhance macrophage cholesterol accumulation and atherogenic plaque formation, supporting a causal relationship 1, 2, 11. TMAO also has significant effects on cholesterol metabolism in the bile acid compartments 1, 11…”

Gaba-betaine modulates SIRT1 and p16INK4A expression during high-glucose induced endothelial cell senescence

“…3 Based on the relationship between GabaBet, carnitine, and TMAO, it has been hypothesized that intestinal microbiota may contribute to the wellestablished link between high levels of Lcarnitine consumption and CVD risk and that GabaBet could be related to the presence of carotid atherosclerosis and its complications linked to high levels of TMAO. 3 A study conducted on a cohort of 264 patients with carotid atherosclerosis reported increased serum levels of GabaBet and TML, but not TMAO. 23 However, a direct role of GabaBet in atherogenesis has been questioned.…”

“…A deeper characterization of the metabolism and the molecular mechanism(s) of action of this betaine is critical to understand the differences with GabaBet intermediate in gut microbial metabolism of Lcarnitine to TMAO. 3 Furthermore, future investigations might be helpful in the elucidation of the possible effect of GabaBet on SIRT6 modulation. 10 Indeed, both SIRT1 and SIRT6, showing an established role in the protection against CVD and hGluc-induced endothelial senescence, 30 could be crucial targets in the setting of natural bioactive compounds able to limit the cellular oxidative processes responsible for the onset of diabetes and its vascular complications.…”

“…1,2 GabaBet has been shown to be involved both in L-carnitine synthesis and in an alternative pathway of gut microbiota-dependent conversion of carnitine into the pro-atherogenic metabolite trimethylamine-N-oxide (TMAO). 3 At the same time, experimental data also indicate that GabaBet itself possesses cardioprotective activity. 4 Indeed, previous studies indicated that mildronate, an inhibitor of carnitine biosynthesis and uptake, induces an increase in GabaBet contents and reduces atherosclerosis in apoE/LDLR −/− mice.…”