## 4 Interaction Between the Gut Microbiota and Cardiovascular Diseases
### Short-Chain Fatty Acids
The **butyrate synthesis pathway** proceeds from acetyl-CoA through intermediates such as acetoacetyl-CoA, \(\beta\)-hydroxybutyryl-CoA, and butyryl-CoA, which is finally converted to butyrate either via the butyryl-CoA:acetate CoA-transferase route or the butyrate kinase route. The **acrylate pathway** converts lactate to propionate via lactoyl-CoA and acryloyl-CoA. The **succinate pathway** begins with the fermentation of hexoses to succinate, which is then converted to propionate through intermediates including succinyl-CoA and methylmalonyl-CoA. Finally, the **propanediol pathway** involves the conversion of deoxy sugars, such as fucose and rhamnose, into propionate via intermediate compounds like 1,2-propanediol and propionaldehyde. The representative microbial species or genera involved in each pathway are indicated, highlighting the functional diversity of the gut microbiota in SCFA production. **Abbreviations:** ACAT, Acetoacetil-CoA thiolase; ACK, acetate kinase; Acr, acryloyl-CoA reductase; BCD, butyryl-CoA dehydrogenase; BcoAT, butyryl-CoA:acetate CoA-transferase; BK, butyrate kinase; CODH/ACS, carbon monoxide dehydrogenase/acetyl-CoA synthase; ECH, enoyl-CoA hydratase (crotonase); FRD, fumarate reductase; FucA, L-fuculose-1-phosphate aldolase; FUM, fumarase; HBD, \(\beta\)-hydroxybutyryl-CoA dehydrogenase; LCD, lactoyl-CoA dehydratase; LCL, lactoyl-CoA ligase; LDH, lactate dehydrogenase; MCM, methylmalonyl-CoA mutase; MDH, malate dehydrogenase; Pct, propionate CoA-transferase; PduCDE, propenediol dehydratase complex; PduP, propionaldehyde dehydrogenase; PEPCK, phosphoenolpyruvate carboxykinase; PFOR, pyruvate:ferredoxin oxidoreductase; PK, pyruvate kinase; PTA, phosphate acetyltransferase; PTB, phosphothransbutyrylase; SCS, succinyl-CoA synthetase. Propionic acid, like butyric acid, can be synthesised via three main pathways (Figure 2). One is the propanediol pathway, which converts deoxy-hexoses into propionic acid through the action of propionaldehyde dehydrogenase (PduP)--a route commonly found in bacteria of the _Lachospiraceae_ family. The second is the succinate pathway, which is considered to be the predominant route for propionate production in the human colon. It is mainly carried out by bacteria from the _Bacteroidota_ phylum and involves the conversion of phosphoenolpyruvate into succinate, which is then metabolised into propionate through intermediate steps involving methylmalonyl-CoA and propionyl-CoA [175]. The third is the acrylate pathway, in which lactate is converted into propionate through a series of steps involving lactoyl-CoA and acryloyl-CoA intermediates, catalysed by enzymes such as acryloyl-CoA reductase (Acr), a mechanism characteristic of _Coprooccus catus_[176]. Acetate production can also occur in two ways: through the Wood-Ljungdahl pathway, by which acetogenic bacteria synthesise it from hydrogen, carbon dioxide, or formic acid, or, more predominantly, through the decarboxylation of pyruvate into acetyl-CoA, which is then hydrolys into acetate [177]. SCFAs, by binding to G-protein-coupled receptors such as free fatty acid receptors (FFAR) 2 and 3 (also known as GPR41 and GPR43, respectively), play regulatory functions in the cellular metabolism of fatty acids, glucose, and cholesterol. FFAR2 and FFAR3 are primarily expressed in intestinal epithelial cells, immune cells (such as neutrophils and macrophages), and adipose tissue, where they mediate anti-inflammatory and metabolic effects. Therefore, a dysbiotic gut microbiota, characterised by reduced SCFA production, is associated with impaired signalling through these receptors [178; 135]. These carboxylic acids also play an important role in regulating immune cell activity within the intestinal mucosa and in preserving epithelial integrity. This is achieved by reducing the pH of the colon, which inhibits the growth of pathogenic bacteria, and by the expression of tight junction proteins. In this way, butyric acid is considered to be the primary positive regulator of genes encoding these proteins.