Unraveling the metabolic pathway of choline-TMA-TMAO: Effects of gypenosides and implications for the therapy of TMAO related diseases

Sep 16, 2021Pharmacological research

How gypenosides affect the breakdown of choline into TMA and TMAO and their potential for treating TMAO-related diseases

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Abstract

Gynostemma pentaphyllum can reduce plasma TMAO levels, which is associated with lipid metabolism and nervous system protection.

Trimethylamine (TMA) penetrates the blood-brain barrier more easily than trimethylamine-N-oxide (TMAO).
The enzyme MAO is partially involved in converting TMA in the brain, contributing to the choline-TMA-TMAO pathway.
Gypenosides remodel the gut microbiota and influence the enzyme trimethylamine lyase, which is crucial for converting choline to TMA.
Gypenosides also interfere with enzymes linked to the tricarboxylic acid (TCA) cycle and lipid metabolism, impacting both TMAO and lipid levels.
There is a bidirectional relationship between lipid metabolism and TMAO metabolism, indicating they may influence each other.

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Trimethylamine-N-oxide (TMAO) has emerged as a promising new therapeutic target for the treatment of central nervous system diseases, atherosclerosis and other diseases. However, its origin in the brain is unclear. Gynostemma pentaphyllum (Thunb.) Makino can reduce the increase of TMAO level caused by a high fat diet. But its effective chemical composition and specific mechanism have not been reported. The study confirmed that TMA was more easily to penetrate blood brain barrier than TMAO, the MAO enzyme was partly involved in the transformation of the TMA in brain, which further supplemented the choline-TMA-TMAO pathway. Based on the above metabolic pathway, using multi-omics approaches, such as microbiodiversity, metagenomics and lipidomics, it was demonstrated that the reduction of plasma TMAO levels by gypenosides did not act on FMO3 and MAO in the pathway, but remodeled the microbiota and affected the trimethylamine lyase needed in the conversion of choline to TMA in intestinal flora. At the same time, gypenosides interfered with enzymes associated with TCA and lipid metabolism, thus affecting TMAO and lipid metabolism. Considering the bidirectional transformation of phosphatidycholine and choline, lipid metabolism and TMAO metabolism could affected each other to some extent. In conclusion, our study revealed the intrinsic correlation between long-term application of gypenosides to lipid reduction and nervous system protection, and explained why gypenosides were used to treat brain diseases, even though they had a poor ability to enter the brain. Besides, it provided a theoretical basis for clinical application of gypenosides and the development of new drugs.

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Unraveling the metabolic pathway of choline-TMA-TMAO: Effects of gypenosides and implications for the therapy of TMAO related diseases

Abstract

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