The Role of Phytochemicals and Gut Microbiome in Atherosclerosis in Preclinical Mouse Models

Abstract

Gut microbiome alterations have recently been linked to many chronic conditions including cardiovascular disease (CVD). There is an interplay between diet and the resident gut microbiome, where the food eaten affects populations of certain microbes. This is important, as different microbes are associated with various pathologies, as they can produce compounds that are disease-promoting or disease-protecting. The Western diet negatively affects the host gut microbiome, ultimately resulting in heightened arterial inflammation and cell phenotype changes as well as plaque accumulation in the arteries. Nutritional interventions including whole foods rich in fiber and phytochemicals as well as isolated compounds including polyphenols and traditional medicinal plants show promise in positively influencing the host gut microbiome to alleviate atherosclerosis. This review investigates the efficacy of a vast array of foods and phytochemicals on host gut microbes and atherosclerotic burden in mice. Reduction in plaque by interventions was associated with increases in bacterial diversity, reduction in the Firmicutes/Bacteroidetes (F/B) ratio, and upregulation of Akkermansia. Upregulation in CYP7 isoform in the liver, ABC transporters, bile acid excretion, and the level of acetic acid, propionic acid, and butyric acid were also noted in several studies reducing plaque. These changes were also associated with attenuated inflammation and oxidative stress. In conclusion, an increase in the abundance of Akkermansia with diets rich in polyphenols, fiber, and grains is likely to reduce plaque burden in patients suffering from CVD.

Keywords: Akkermansia; ApoE; CVD; TMAO; atherosclerosis; berberine; gut; microbiome; polyphenols.

Figure 1

An overview of mechanisms and pathways via which the gut microbiome and its interaction with the host diet contribute to the pathophysiology of atherosclerosis. Intake of a westernized diet high in saturated fats and sugars instigates gut dysbiosis, which in turn triggers a cascade of various host metabolic pathways via the gut-liver-heart axis, eventually converging into atherosclerosis progression. Lack of fiber in these diets further lowers the production of microbiome-derived SCFAs leading to impaired gut epithelial permeability and translocation of microbes or their cell fragments (e.g., LPS), harmful metabolites, and PAMPs, which may provoke macrophages leading to excessive pro-inflammatory responses. On the other end, diets rich in choline/L-carnitine foster microbes harboring choline-TMA lyase enzyme leading to enhanced production of TMA and its conversion to pro-atherogenic TMAO via hepatic flavin-containing monooxygenase. TMAO impairs cholesterol metabolism by blocking reverse cholesterol transport leading to increased LDL-C. Besides, bile acid metabolism may also be perturbed by gut microbiome which is associated with dyslipidemia. Both these pathways may converge into endothelial dysfunction inducing oxidative stress by abnormal endothelial cells, activated macrophages and SMCs in the intima, and formation of foam cells via ROS-induced oxidation of LDL-C. This ultimately leads to arterial stiffness via bulging of fibrous plaque comprising of foam cells, differential SMCs, collagen, and elastin, thus marking the onset of atherosclerosis. Abbreviations: LPS: lipopolysaccharide; SCFAs: short-chain fatty acids; PAMs: pathogen-associated molecular patterns; LDL-C: low-density lipoprotein cholesterol; TMAO: trimethylamine N-oxide; FMO3: flavin-containing monooxygenase 3; FXR: farnesoid X receptor; PXR: pregnane X receptor; ROS: reactive oxygen species, SMC: smooth muscle cells. (↑): increased/higher, (↓): decreased/lower. Created with BioRender.com (accessed on 18 January 2023).

Figure 2

Structure of polyphenols and berberine. Examples of the structure of different types of polyphenols are shown for flavonols (A), phenolic acids (B), stilbenes (C), and flavonones (D). The alkaloid berberine (E) and the basic structure of protoberberines are also shown (F).

Figure 3

PRISMA flow diagram. Studies were identified through databases search in PubMed, Embase, Web of Science, and Science Direct. Of the 420 studies identified, only 62 were included in this systematic review.

Figure 4

Mechanisms regulating plaque by the microbiome. Nutritional interventions reduced plaque in the aorta of mice by modulating the microbiome. The F/B ratio was reduced while the relative abundance of Akkermansia, Bacteroides, and Prevotella was upregulated. Changes in the microbiome were associated with increases in SCFAs levels and bile acid excretion in the liver, likely mediated by upregulation of CYP7A1. Lower levels of TMA and TMAO also correlated with reduced inflammation and oxidative stress in circulation and with reduced gut barrier permeability. Red signifies upregulation and blue downregulation in expression mediated by nutritional interventions. Created with BioRender.com (accessed on 8 February 2023).