## 4 Interaction Between the Gut Microbiota and Cardiovascular Diseases
### Bile Acids  
Bile acids are amphipubic molecules synthesised in the liver from cholesterol and which, subsequently, are modified by the gut microbiota into secondary bile acids. They are stored in the gallbladder and are released into the small intestine after food intake, with their main functions being the emulsification of dietary fats and the promotion of intestinal absorption of lipids and fat-soluble vitamins. Bile acids can be classified into primary and secondary acids based on their structure, with primary bile acids being metabolised into secondary bile acids by enzymes derived from the gut microbiota [157, 158]. Primary bile acids, such as cholic acid and theondeoxycholic acid, result from cholesterol oxidation by cholesterol 7\(\alpha\)-hydroxylase (CYPA1), followed by conjugation with glycine or taurine by bile acid-CoA:amino acid N-acyltransferase (BAAT). Subsequently, through the action of bile salt hydrolase (BSH), primary bile acids are hydrolys and de-conjugated, ready to be metabolised by the gut microbiota through various mechanisms, including 7\(\alpha\)-dehydroxylation, dehydrogenation, and epimerisation, leading to the formation of secondary bile acids such as deoxycholic acid and lithocholic acid (Figure 6) [159, 160]. Bile acids play a protective role in the development of atherosclerosis, as they act as signalling molecules for a range of physiological processes mediated by the farnesoid X receptor (FXR) and the G-protein-coupled bile acid receptor (TGR5) [161]. FXR plays a central role in the regulation of the glucose, lipid, and bile acid metabolisms. Given its high expression in the GIT, it acts as a sensor of bile acid levels in hepatocytes and enterocytes, thus regulating the transcription of genes involved in bile acid synthesis, conjugation, and transport, including CYP7A1. The activation of FXR in ECs positively regulates endothelial nitric oxide synthase, enhancing nitric oxide production, which promotes vasodilation, reduces endothelin-1 expression, a potent vasoconstrric peptide, and modulates angiotensin II receptors, inhibiting the inflammation and migration of VSMCs, a key factor limiting the progression of atherosclerotic lesions, as these cells in the intima produce the extracellular matrix (Figure 6) [137, 160, 162]. Additionally, FXR activation also increases faecal cholesterol excretion, thereby lowering plasma cholesterol levels. This contributes to reducing the amount of circulating LDL, limiting their retention in the endothelial barrier and, subsequently, decreasing ox-LDL formation, as shown in Figure 6[163; 164]. Furthermore, there is a reduction in pro-inflammatory cytokines, such as TNF-\(\alpha\), IL-1\(\beta\), and IL-6, which initiate monocyte recruitment, inhibiting the formation of fatty streaks [165; 166; 167]. On the other hand, as illustrated in Figure 6, FXR expression in hepatocytes, which can be upregulated by bile acids, regulates FMO3, the key enzyme in TMAO synthesis, the metabolite that actively contributes to the formation and development of atherosclerotic lesions, as previously explained [168]. The activation of the bile acid membrane receptor TGR5 also plays a protective role in atherosclerosis by interfering with the crucial mechanisms underlying the formation of fatty streaks. In this context, TGR5 receptor activation can counteract this process by acting in both ECs and macrophages. In ECs, it inhibits the expression of VCAM-1 and ICAM-2, thereby limiting the recruitment and adhesion of monocytes, while in macrophages, it inhibits the NF-\(\kappa\)B inflammatory pathway, thus reducing the production of pro-inflammatory mediators (TNF-\(\alpha\), IL-1\(\beta\), IL-6) and downregulates the expression of CD36 and SR-A receptors, which are involved in lipid uptake. As a result, macrophages take up fewer lipids, limiting their accumulation in lipid droplets and ultimately preventing foam cell formation and the development of fatty streaks, as represented in Figure 7[159; 169]. Figure 6: Overview of bile acid metabolism and microbial transformation.