## 4 Interaction Between the Gut Microbiota and Cardiovascular Diseases
### Short-Chain Fatty Acids  
The human digestive system cannot break down complex carbohydrates, particularly dietary fibres, which are not digested or absorbed in the small intestine. Thus, in the colon, the gut microbiota is responsible for fermenting these carbohydrates, resulting in the production of SCFAs. SCFAs consist of carboxylic acids with aliphatic chains ranging from one to six carbon atoms, with the three main ones being acetic acid (C2), propionic acid (C3), and butyric acid (C4), while valeric acid (C5) and hexanoic acid (C6) are less abundant. Bacteria belonging to the _Bacteroidata_ phylum are primarily responsible for producing acetic acid and propionic acid, whereas butyric acid mainly arises from the metabolism of bacteria of the _Bacilotta_ phylum [170; 171]. The main precursor of SCFAs is pyruvate, which is converted into acetyl-CoA. As illustrated in Figure 8, pyruvate is generated through the glycolytic pathway from hexoses and deoxy-hexoses, as well as through the pentose-phosphate pathway from pentoses. These monosaccharides are the products of the microbial hydrolysis of indigestible carbohydrates [172]. Figure 7: Bile acid modulation of farnesoid X receptor (FXR) and G-protein-coupled bile acid receptor (TGR5) signalling pathways. FXR activation in enterocytes induces FGF19, which inhibits CYPA1 expression and reduces bile acid synthesis. In hepatocytes, FXR promotes FMO3 expression, increasing TMAO production, upregulates bile acid transporters, and enhances faecal cholesterol excretion. In ECs, FXR activation upregulates eNOS, leading to NO-mediated vasodilation, and downregulates endothelin-1 and angiotensin II receptor expression, reducing vasoconstriction, vascular inflammation, and VSMC migration. TGR5 activation in ECs downregulates VCAM-1 and ICAM-2, reducing monocyte adhesion and recruitment. In macrophages, TGR5 activation inhibits the NF-kB pathway and downregulates CD36 and SR-A expression, decreasing lipid uptake, foam cell formation, and fatty streak development. **Abbreviations:** CD36/SR-A, scavenger receptors; CYPA1, cholesterol \(7\alpha\)-hydroxylase; ECs, endothelial cells; eNOS, endothelial nitric oxide synthase; FGF19, fibroblast growth factor 19; FMO3, flavin-containing monooxygenase 3; FXR, farnesoid X receptor; ICAM-2, intercellular adhesion molecule-2; NF-kB, nuclear factor kappa B; NO, nitric oxide; TGR5, G protein-coupled bile acid receptor 1; TMAO, trimethylamine-N-oxide; VCAM-1, vascular cell adhesion molecule-1; VSMC, vascular smooth muscle cell. Butyric acid is the main energy source for colonocytes and has two endogenous metabolic production pathways. The first pathway involves the phosphorylation of butyrylCoA, resulting from the reduction in acetoacetyl-CoA, a combination of two acetyl-CoA molecules, to butyryl-phosphate, which is then converted into butyrate by the action of butyrate kinase (BK), a pathway characteristic in certain _Coprooccus_ species. In the second and main pathway, the CoA fraction of butyryl-CoA is transferred to exogenous acetate via butyryl-CoA:acetate CoA transferase (BCoAT), leading to the formation of butyrate and acetyl-CoA. This pathway is utilised by bacteria such as _Faecalibacterium prausunitzii_, _Eubacterium rectale_, _Eubacterium hallii_, _Ruminococcus bromii_, and _Roseburia_ spp. (Figure 8) [173, 174]. Figure 8: Short-chain fatty acid biosynthesis by the gut microbiota: major pathways, the producing bacteria, and the enzymes involved. Non-digestible carbohydrates from the diet reach the colon, where they are metabolised by the gut microbiota into monosaccharides. These are further fermented into SCFAs, mainly acetate, butyrate, and propionate, through five major microbial pathways. The **Wood–Ljungdahl pathway** involves the fixation of CO\({}_{2}\) into acetyl-CoA and, subsequently, acetate, via a series of reactions involving folate-bound intermediates.