**5. Targeting the TMA/TMAO pathway as a therapeutic strategy to combat CVD risk-current research and future directions**

The gut microbiome is a growing area of research in metabolic health and its link to CVD risk. The development of high-throughput metagenomic tools has aided a new understanding of the gut microbiome's role in CVD risk [113]. The gut microbiome can be targeted to modify TMAO synthesis, according to recent fecal microbial transplant research [114] and as a result TMA/TMAO levels can be regulated. Based on research by Maisto et al., in healthy subjects, grape pomace polyphenolic extract has been found to lower serum levels of TMAO [115]. Resveratrol (RSV) reduces TMAO- induced atherosclerosis by lowering TMAO levels and enhancing hepatic bile acid synthesis through gut microbiota remodeling [116]. Antimicrobial phytochemicals, such as allicin, a dietary dosage derived from garlic, effectively neutralize the metabolic ability of gut microbiota to produce TMAO- induced by L-carnitine intake [117]. Luhong granules, a complex blend of herbs, flowers, animal parts, seeds, and roots, prolong ventricular remodeling after myocardial infarction by lowering TMAO and LPS levels in the bloodstream by increasing the gut microflora and intestinal barrier function [118]. A single oral dosage of a cutC/D inhibitor lowers plasma TMAO levels for up to three days and reverses diet-induced platelet reactivity and thrombus formation as studied in animal models, with no toxicity or increased bleeding risk [119]. In experiments with mice models, *Lactobacillus plantarum* ZDY04 significantly reduced serum TMAO and cecal TMA levels in mice by modulating the relative abundance of specific bacterial species, including *Bacteroids* and significantly inhibiting the development of TMAO-induced atherosclerosis in choline fed mice [120]. In high-fat diet-induced obese mice, capsanthin extract prevents obesity, lowers serum TMAO levels, and modifies the gut microbiota composition by decreasing serum triglycerides, total cholesterol, and TMAO levels and markedly increasing microbial diversity [121]. The ability of several oral probiotics to modify circulating TMAO levels in different cohorts, including healthy participants and patients with a CVDrelated disease, has been investigated [122–125]. None of them, however, appeared to have a significant effect on TMAO levels in the treatment groups as compared to the placebo groups. In another study, TMA-degrading microorganisms were used by Qiu et al. (2017) to investigate another promising technique for lowering TMA levels in the gut where oral administration of a TMA-metabolizing strain (*Enterobacter aerogenes* ZDY01) reduced TMA in the cecum and TMAO in the serum, as well as changing the microbial community composition in mice, according to their findings [126]. In human studies, changes in urine TMAO levels have been discovered in untargeted metabolomics investigations following supplementation with *Origanum dictamus* tea and *Curcuma longa* extract [127, 128].

## **6. Conclusions**

Diet has been shown to have an important role in the formation of TMAO because it offers the nutritional precursors needed to create TMA and TMAO. There is a positive correlation between circulating TMAO levels and the consumption of food rich in dietary precursors of TMAO like seafood, meat, eggs etc. Targeting the TMA/TMAO metabolism has emerged as a promising tool for cardiovascular disease prevention and treatment in recent years. Targeting the microbiota and host metabolic systems implicated in TMA and TMAO production shows potential for future intervention.

*Gut Microbial Metabolite Trimethylamine-N-Oxide and Its Role in Cardiovascular Diseases DOI: http://dx.doi.org/10.5772/intechopen.107976*

Animal models have largely established the capacity of specific diets, food ingredients, and phytochemicals found in herbs to reduce circulation of TMAO levels. The link between changes in TMAO levels and gut microbiota has only been shown in a few cases, and the exact processes behind the impacts of the dietary items under investigation are yet unknown. More importantly, there are few studies that suggest that lowering circulating TMAO levels has a favorable effect in humans. Because the majority of the studies have been conducted on animal models, the results are difficult to apply to humans. Future research in this area should address conventional microbial research obstacles as well as those more specific to the study of TMA/ TMAO metabolism, such as the substantial intra-individual variability of plasma TMAO levels observed in some humans. With the advancement and availability of next-generation sequencing and other omics technologies, a change from studies focusing on defining microbial community composition to more function-oriented research on the gut microbiota is envisaged. Bioinformatic approaches, shotgun metagenomics, meta-transcriptomics, meta-proteomics, and metabolomics, are all expected to be crucial in unraveling the intricate relationships between nutrition, microbial metabolism, and host health.

## **Acknowledgements**

All images in this manuscript were made using BioRender.
