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. 2020 Nov 23;10:20323. doi: 10.1038/s41598-020-76346-1

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© The Author(s) 2020

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

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Proposed regulation pattern of betaine, choline, and TMAO in (A) patients with chronic kidney disease (CKD); (B) CKD-protected, hibernating, free-ranging brown bears; and (C) CKD-prone carnivorous felids, e.g. tigers. In patients with CKD (A), high levels of trimethylamine (TMA) N-oxide (TMAO) and choline are detectable, whereas betaine levels are low. Dietary intake of phosphatidyl-choline, betaine, TMA, TMAO, and L-Carnitine contribute to circulating metabolite levels. Gut microbiota can metabolize choline and L-Carnitine to TMA. After intestinal uptake of TMA, hepatic flavin-containing monooxygenases (FMOs) convert TMA into TMAO which exerts adverse cardiometabolic effects. TMAO levels in CKD are especially elevated due to an increased microbial TMA conversion (i.e. gut microbiota dysbiosis), as well as a reduced renal excretion of TMAO. In hibernating, free-ranging brown bears (B), there is no food intake and betaine, choline, and TMAO are endogenously produced. Based on our data, we propose a metabolic switch favouring betaine rather than TMAO synthesis due to increased betaine conversion from choline and reduced gut microbiota-caused TMA production. In carnivorous animals, e.g. tigers (C), dietary intake of phosphatidylcholine, betaine, TMA, TMAO, and L-Carnitine contribute to circulating metabolite levels. Similar to patients with CKD, a metabolic switch favours TMA production by gut microbiota resulting in high TMAO levels that might be involved in the high CKD prevalence of carnivorous felids. Arrow size depicts increased or decreased activation of the respective pathway.