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Reviews in Cardiovascular Medicine  2019, Vol. 20 Issue (3): 121-128     DOI: 10.31083/j.rcm.2019.03.518
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Diet-induced chronic syndrome, metabolically transformed trimethylamine-N-oxide, and the cardiovascular functions
Shanna J. Hardin1, Mahavir Singh1, *(), Wintana Eyob1, Jack C. Molnar1, Rubens P. Homme1, Akash K. George1, Suresh C. Tyagi1
1 Department of Physiology, University of Louisville School of Medicine Louisville, Kentucky 40202, USA
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Abstract:

Recent studies have shown that the integrity of the gastrointestinal tract and its microbiome impact the functioning of various body systems by regulating immunological responses, extracting energy, remodeling intestinal epithelia, and strengthening the gut itself. The gastrointestinal tract microbiota includes bacteria, fungi, protozoa, viruses, and archaea which collectively comprise a dynamic community prone to alterations via influences such as the environment, illness, and metabolic processes. The idea that the host’s diet possesses characteristics that could potentially alter microbiota composition is a novel notion. We hypothesize that a high fat diet leads to the alteration of the gastrointestinal microbiota composition and that metabolic transformation of the compound trimethylamine into trimethylamine-N-oxide promotes vasculopathy such as atherosclerosis and affects cardiovascular functionality. Furthermore, we hypothesize that treatment with probiotics will restore the homeostatic environment (eubiosis) of the gastrointestinal tract.

Key words:  Diet      dysbiosis      eubiosis      cardiovascular disease      inflammation      phosphatidylcholine      probiotics     
Submitted:  30 June 2019      Accepted:  02 September 2019      Published:  30 September 2019     
Fund: 
  • HL74185, HL139047, AR-71789/NIH grants
*Corresponding Author(s):  Mahavir Singh     E-mail:  mahavir.singh@louisville.edu

Cite this article: 

Shanna J. Hardin, Mahavir Singh, Wintana Eyob, Jack C. Molnar, Rubens P. Homme, Akash K. George, Suresh C. Tyagi. Diet-induced chronic syndrome, metabolically transformed trimethylamine-N-oxide, and the cardiovascular functions. Reviews in Cardiovascular Medicine, 2019, 20(3): 121-128.

URL: 

https://rcm.imrpress.com/EN/10.31083/j.rcm.2019.03.518     OR     https://rcm.imrpress.com/EN/Y2019/V20/I3/121

Figure 1.  (A) A schematic illustrating the effects of diet on gut microbiome and subsequent consequences. Mice that were given a regular chow diet maintained the eubiotic gastrointestinal environment. The eubiotic environment did not promote the accumulation of TMAO or significantly alter cardiovascular functionality. (B) Mice that were fed HFD developed a dysbiotic gastrointestinal environment that supported the accumulation of TMAO and altered the cardiovascular functions. Proposed treatment with probiotic (s) supplementation may decrease some harm as caused by the HFD through mitigating deleterious effects induced by an unhealthy diet by reconstituting the microbial lining of the gut with the healthy microbes.

Figure 2.  Representation of how TMAO accumulates in the body because of the ingestion of dietary PC. The choline portion of the PC is metabolized into TMA by gastrointestinal microbes. The TMA then travels to the liver, via the bloodstream, where it is converted into TMAO by hepatic FMOs. A skeletal structure for the TMAO molecule (boxed in red color) is implicated in developing cardiovascular diseases by enhancing atherosclerotic factors. The precursor of TMAO that is TMA is produced in GIT as a byproduct of the metabolization of choline/PC by gut microbiota. The resulting gaseous TMA enters the circulatory system where it is converted into TMAO (boxed in red color) by hepatic FMOs (Eswaramoorthy et al., 2006). The FMOs are responsible for oxygenating lipophilic compounds so that they can be solubilized and rapidly excreted (FMOs selectively oxygenizes the nucleophilic nitrogen in the amine group producing the TMAO molecules) (Eswaramoorthy et al., 2006).

Figure 3.  A visual depiction of the stepwise mechanism connecting TMAO and the enhancement of atherosclerotic factors. TMAO is produced in the liver by FMOS. The increased plasma concentration of TMAO promotes the upregulation of macrophage scavenger receptors. The stimulated scavenger receptors promote inflammation and gobble-up the macrophages. Furthermore, the accumulated macrophages produce foamy cells because of their inability to properly metabolize lipids inside them. In summary, the accumulation of macrophages, foamy cells, and inflammation together promote the development of atherosclerosis.

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