## 4 Interaction Between the Gut Microbiota and Cardiovascular Diseases
### Microbiota-Induced Immune and Inflammatory Pathways in Atherosclerosis  
The continuous communication between the gut microbiota and the immune system is essential for maintaining systemic homeostasis. However, under conditions of intestinal dysbiosis, this balance is disrupted, triggering chronic low-grade inflammation, characterised by elevated levels of pro-inflammatory cytokines such as TNF-\(\alpha\) and IL-6, implicated in the pathophysiology of atherosclerosis, since they promote an inflammatory state that damages the endothelium and facilitates the formation of atherosclerotic plaques [201; 202].  
In parallel, increased intestinal permeability, also known as \"leaky gut\", another common alteration associated with dysbiosis, allows for the translocation of bacterial products, such as LPS, into the systemic circulation [203]. These components, in turn, activate Toll-like receptors, notably TLR, present on endothelial and immune cells, thereby promoting a systemic inflammatory response. This process contributes to atherosclerosis progression by stimulating monocyte adhesion to the endothelium and promoting foam cell formation within atherosclerotic plaques [204; 205]. Bacterial translocation is also associated with the activation of the NF-kB signalling pathway, which is crucial in regulating vascular inflammation [206].  
In addition, the activation of TLR4 and TLR2 receptors, which recognise pathogen-associated molecular patterns (PAMPs) such as LPS, peptidoglycancans, and bacterial lipoproteins, leads to the activation of pro-inflammatory intracellular signalling pathways, including the NF-kB pathway. This promotes the expression of inflammatory cytokines and endothelial adhesion molecules, facilitating the infiltration of monocytes and T lymphocytes into atherosclerotic plaques, which aggravates inflammation and accelerates the progression of the disease. These alterations also contribute to endothelial dysfunction, a critical step in the pathophysiology of atherosclerosis, as previously discussed [207; 208; 209; 201].  
On the other hand, dysbiosis favours the proliferation of pathologists, such as members of the _Enterobacteriaceae_ family, which have the ability to proliferate in inflammatory intestinal environments [88]. These microorganisms utilise nitrates as final electron acceptors in anaerobic respiration, giving them a competitive advantage under inflammatory conditions [88; 210]. This process is associated with increased production of TMA, as discussed in Section 4.1, and contributes to alterations in the lipid composition of endothelial cells, promoting the formation of atherosclerotic plaque [211].  
Beyond the innate immune response mediated by TLRs, the gut microbiota can also influence the adaptive immune response, namely the expansion of Th17 lymphocytes, which play a central role in the chronic inflammation associated with atherosclerosis [212]. Studies have shown that intestinal dysbiosis can favour the differentiation of Th17 cells, which secrete cytokines such as IL-17 that promote vascular inflammation and plaque instability. This mechanism is particularly relevant, given that Th17 lymphocytes are associated with autoimmune and chronic inflammatory processes [212; 213]. Nonetheless, a study has suggested that IL-17 might also exert stabilising effects on atherosclerotic plaques by downregulating VCAM-1 expression on endothelial cells [214], highlighting the complex and context-dependent role of IL-17 in atherosclerosis. The increase in Th17 cells in atherosclerosis enhances the activation of the NF-kB pathway and the production of matrix MMPs, which degrade the extracellular matrix and weaken plaque structure, increasing the risk of rupture and thrombosis [215; 216].