Atherosclerosis is a chronic inflammatory disease characterized by the formation of plaque in arteries, which consists of necrotic cores, calcified regions, and an accumulation of lipids and cells such as leukocytes, foam cells, and endothelial cells (ECs) [ 29 30 ]. Gut dysbiosis can contribute to the development and progression of atherosclerosis through two major pathways—the metabolism-independent pathway and the metabolism-dependent pathway [ 32 ].

2.1. Metabolism-Independent Pathway

Gut dysbiosis can be involved in the pathogenesis of atherosclerosis directly through the metabolism-independent pathway [ 32 ]. Specifically, bacterial components such as lipopolysaccharides (LPS) found on the outer membrane of Gram-negative bacteria can promote the formation of foam cells, which are a major component of atherosclerotic plaque [ 33 ].

Foam cells are macrophages, phagocytic immune cells, that have engulfed excessive amounts of modified low density lipoprotein (LDL) cholesterol in an attempt to remove it from the bloodstream [ 34 35 ]. LDLs are responsible for the transport of cholesterol within the bloodstream [ 36 ]. The formation of foam cells is initiated when apolipoprotein B on the surface of circulating LDLs binds to LDL receptors on the endothelium, initiating endocytosis of the LDL into the tunica intima [ 34 ]. The LDL then undergoes oxidation through enzymatic attack or reaction with reactive oxygen species to produce oxidized, low density lipoproteins (oxLDLs) [ 37 ]. The accumulation of oxLDLs within the arterial wall stimulates ECs to express cell adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1) and chemokines such as monocyte chemoattractant protein-1 (MCP-1), that cause monocytes to adhere to the endothelium and migrate into the tunica intima respectively [ 34 ]. The oxLDLs also stimulate the production of macrophage-colony-stimulating factor (M-CSF) that induces differentiation of the incoming monocytes into mature macrophages [ 34 ]. Scavenger receptors (ScRs), such as cluster of differentiation 36 (CD36) that are expressed on the surface of macrophages, then mediate the uptake of oxLDL into the macrophage [ 34 38 ]. The accumulation of modified cholesterol within the macrophages leads to foam cell formation [ 34 ]. The foam cells deposit in arterial plaque, further contributing to atherosclerosis [ 34 ].

40,40, The body has internal homeostatic mechanisms such as reverse cholesterol transport (RCT), to counteract the accumulation of excess cholesterol in peripheral tissues. RCT is a process by which excess cholesterol is brought to the liver to be converted into bile acids (BAs) [ 39 41 ]. This transport is specifically mediated by the apolipoprotein A1 (ApoA-1) on high density lipoproteins (HDLs) which bind to cholesterol to facilitate transport to the liver [ 39 41 ]. Inside the macrophages, this process is mediated by a variety of receptors, specifically the liver X receptors (LXRs) α and β, and the cholesterol transporters adenosine triphosphate (ATP)-binding cassette transporter A1 (ABCA1) and ATP-binding cassette transporter G1 (ABCG1) [ 41 42 ]. When macrophages uptake oxLDLs, LXRs are stimulated and bind to LXR response elements on DNA to increase the expression of cholesterol transporters such as ABCA1 and ABCG1 [ 41 42 ]. The end result of this transcriptional cascade is oxLDL being removed from the cell, transported to the liver, and subsequently excreted through BAs [ 41 42 ]. This efflux of cholesterol from foam cells is a critical step in preventing the development of atherosclerotic plaque.

43,44,47,48, Gut dysbiosis can overwhelm mechanisms such as RCT and promote the formation of foam cells, specifically by inducing metabolic endotoxemia [ 41 45 ]. Metabolic endotoxemia is a condition characterized by an increased presence of LPS in circulation [ 33 46 ]. High-fat (HF) diet-induced dysbiosis is associated with reduced presence of bifidobacteria, which normally promote intestinal barrier function and prevent bacterial translocation [ 33 ]. Dysbiosis also results in the reduced expression of intestinal tight junction proteins, further increasing intestinal permeability [ 46 ]. This allows for increased levels of LPS to enter circulation, which goes on to promote inflammation and foam cell formation, by acting on TLR4 [ 33 ]. TLR4 is a PRR expressed on cells such as macrophages, ECs, enterocytes, and DCs [ 33 ]. Circulating LPS are sensed by a cell-surface-receptor complex that contains TLR4 and its co-receptors cluster of differentiation 14 (CD14) and myeloid differentiation protein-2(MD-2) [ 47 ]. In response to LPS-binding, the intracellular domain of TLR4 activates several signal transduction responses that lead to the production of pro-inflammatory cytokines, chemokines, and cell-adhesion molecules [ 33 49 ]. One of these complex transduction responses involves the molecule myeloid differentiation primary response gene 88 (MYD88) and will be explored in detail below.