Suppression of intestinal microbiota-dependent production of pro-atherogenic trimethylamine N-oxide by shifting L-carnitine microbial degradation

Kuka, Janis; Liepinsh, Edgars; Makrecka-Kūka, Marina; Liepiņš, Jānis; Cirule, Helena; Gustina, Daina; Loza, Einars; Zharkova-Malkova, Olga; Grı̄nberga, Solveiga; Pugovičs, Osvalds; Dambrova, Maija

doi:10.1016/j.lfs.2014.09.028

Cited by 78 publications

(63 citation statements)

References 38 publications

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“…Finally, in a recent study, Kuka et al examined the effects of meldonium, an analogue of a carnitine bioprecursor deemed to have anti-atherosclerotic effects, on the microflora-dependent production of TMAO. The study showed a significant reduction of TMA and TMAO production from L-carnitine, but not from choline [57].…”

Section: Accepted Manuscriptmentioning

confidence: 76%

New Aspects on the Metabolic role of Intestinal Microbiota in the Development of Atherosclerosis

2015

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Section: Accepted Manuscriptmentioning

confidence: 76%

New Aspects on the Metabolic role of Intestinal Microbiota in the Development of Atherosclerosis

2015

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“…It has been shown that the production of TMAO can be suppressed by shifting the microbial degradation pattern of supplemental/dietary tertiary amines (21). In addition, the cardioprotective drug meldonium, an inhibitor of L-carnitine biosynthesis and transport (22), has been shown to lower TMAO levels in both rats and humans (21,23) through inhibition of TMA production by the intestinal microbiota.…”

Section: Trimethylamine (Tma)mentioning

confidence: 99%

“…In addition, the cardioprotective drug meldonium, an inhibitor of L-carnitine biosynthesis and transport (22), has been shown to lower TMAO levels in both rats and humans (21,23) through inhibition of TMA production by the intestinal microbiota.…”

Section: Trimethylamine (Tma)mentioning

confidence: 99%

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Structure and Function of CutC Choline Lyase from Human Microbiota Bacterium Klebsiella pneumoniae

Kalnins

Kuka

Grı̄nberga

et al. 2015

Journal of Biological Chemistry

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Background:The bacterial glycyl radical enzyme CutC converts choline to trimethylamine, a metabolite involved in pathogenesis of several diseases. Results: The structures of substrate-bound and substrate-free CutC revealed significant differences. Conclusion: Choline binding to the active site triggers a conformational change from the open to closed form. Significance: A novel substrate-driven conformational mechanism and a potential target for drug design have been identified.

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“…Some intestinal bacteria can convert carnitine to trimethylamine, which is subsequently oxidized in the liver to the proatherogenic species trimethylamine-Noxide (TMAO) (Koeth et al, 2013) -a metabolic pathway we discuss in more detail below. The role of bacterial metabolism of carnitine directly promoting cardiovascular disease has been shown in multiple studies (Hartiala et al, 2014;Koeth et al, 2013;Kuka et al, 2014), but is still up for discussion in the scientific and medical communities (Johri et al, 2014). However, there is no debate that bacteria, intestinal and otherwise, utilize carnitine in many different ways for their benefit (Ussher et al, 2013).…”

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confidence: 99%

Carnitine in bacterial physiology and metabolism

2015

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Carnitine is a quaternary amine compound found at high concentration in animal tissues, particularly muscle, and is most well studied for its contribution to fatty acid transport into mitochondria. In bacteria, carnitine is an important osmoprotectant, and can also enhance thermotolerance, cryotolerance and barotolerance. Carnitine can be transported into the cell or acquired from metabolic precursors, where it can serve directly as a compatible solute for stress protection or be metabolized through one of a few distinct pathways as a nutrient source. In this review, we summarize what is known about carnitine physiology and metabolism in bacteria. In particular, recent advances in the aerobic and anaerobic metabolic pathways as well as the use of carnitine as an electron acceptor have addressed some long-standing questions in the field. Received 5 January 2015 Accepted 17 March 2015Introduction Carnitine (c-trimethylamino-b-hydroxybutyric acid) ( Fig. 1) is a quaternary amine compound that can be produced by all domains of life, and was discovered in muscle extract in 1905 by Gulewitsch & Krimberg (1905) and Kutscher (1905). It was shown to be essential for larval development of the mealworm Tenebrio molitor and was originally designated vitamin B T based on this requirement. Later, it was discovered that carnitine can be synthesized in mammals and is now considered to be a quasi-nutrient or conditionally essential nutrient (Flanagan et al., 2010), as neonates have reduced biosynthesis and rely on placental transfer of carnitine in utero and exogenous sources after birth (Combs, 2012). Fifty years after the discovery of carnitine, it was demonstrated that assorted Gram-positive and Gram-negative bacteria could use carnitine in either aerobic or anaerobic environments for a variety of cellular functions, including as an electron acceptor, as a compatible solute to survive environmental insults or as a sole carbon, nitrogen and energy source. Bacterial carnitine metabolism was most recently reviewed in 1998 (Bieber, 1988;Bremer, 1983;Kleber, 1997;Rebouche & Seim, 1998) and the field has seen important advances. This review summarizes what we knew at the time of the previous reviews and emphasizes what we have learned since, including: (i) how anaerobic bacteria synthesize and utilize crotonobetaine and carnitine as final electron acceptors, (ii) the impact of carnitine degradation by the intestinal microbiota and the genes responsible for this anaerobic conversion, (iii) the genes involved in aerobic degradation of carnitine, and (iv) how carnitine as a compatible solute impacts survival within and outside of the host. Carnitine in the environmentRecent work makes it clear that while animals represent the most readily accessible source of carnitine, carnitine is often present and sometimes abundant in soil and natural waters. Quaternary ammonium compounds are abundant in a number of soil ecosystems, including comprising a quarter of the most abundant organic nitrogen compounds in the soil water of a subalpine gras...

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Suppression of intestinal microbiota-dependent production of pro-atherogenic trimethylamine N-oxide by shifting L-carnitine microbial degradation

Cited by 78 publications

References 38 publications

New Aspects on the Metabolic role of Intestinal Microbiota in the Development of Atherosclerosis

New Aspects on the Metabolic role of Intestinal Microbiota in the Development of Atherosclerosis

Structure and Function of CutC Choline Lyase from Human Microbiota Bacterium Klebsiella pneumoniae

Carnitine in bacterial physiology and metabolism

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