## 5 Gut Microbiota-Targeted Interventions in the Prevention and Progression of Atherosclerosis
### Probiotics  
The term \"probiotic\", derived from the Greek meaning \"promotion of life\", refers to \"live microorganisms which, when administered in adequate amounts, confer a health benefit on the host\". Ideally, these microorganisms should be of human origin, safe, and free from genes conferring antibiotic resistance, virulence, pathogenicity, or toxicity, and should not exhibit haemolytic activity [228,229]. Functionally, probiotics can be divided into three main groups: lactic acid bacteria, with bacteria belonging to the genera _Lactobacillus_ and _Bifidobacterium_; non-lactic acid bacteria, such as _Bacillus_ spp., _Escherichia_ spp., and _Propionibacterium_ spp. ; and yeasts and fungi, mainly _Saccharomyces_ spp. and _Apergillus_ spp. Nevertheless, Lactobacillus spp. and _Bifidobacterium_ spp. have been most extensively used as probiotics in recent decades [230]. To be suitable for human use, probiotics must tolerate gastric acid and bile salts to reach the intestine in a viable and stable form. Once this chemical barrier is overcome, they must adhere to the intestinal ECs, where they exert their functions. In addition, they should exhibit antimicrobial activity to inhibit the growth of pathogenic bacteria. Probiotics should also benefit the host by strengthening the immune system, preventing infections, promoting intestinal homeostasis, and reducing plasma cholesterol levels [230,231]. Considering the benefits associated with lowering plasma cholesterol in the context of atherosclerosis, the hypocholesterolaemic and anti-atherosclerotic effects of probiotics may be explained through different mechanisms. These include the activity of bile salt hydrolase (BSH), the production of SCFAs, the co-precipitation of cholesterol with deconjugated bile salts, and the assimilation of cholesterol during bacterial growth, with the subsequent incorporation into the cell membrane [232]. Several studies have shown that many _Bifidobacterium_ and _Lactobacillus_ species produce BSH, an enzyme whose activation may reduce cholesterol levels by increasing the excretion of free bile acids and, consequently, decreasing their intestinal reabsorption. In response, the liver increases cholesterol uptake to synthesise new bile acids, ultimately contributing to reduced circulating cholesterol levels. In addition, certain strains of these bacteria have the capacity to bind cholesterol and either incorporate it into their cell membranes or sequester it on their surface, further contributing to plasma cholesterol reduction. Another important metabolic pathway involves SCFAs, which lower cholesterol via two different mechanisms: the inhibition of the enzyme HMG-CoA reductase, the rate-limiting enzyme for hepatic cholesterol synthesis; and the stimulation of 7\(\alpha\)-hydroxylase activity by propionic acid, thereby enhancing hepatic bile acid synthesis via cholesterol oxidation [217; 233; 234; 235]. Probiotics also contribute to intestinal homeostasis by improving epithelial barrier integrity through the promotion and maintenance of tight junctions. This provides an additional mechanism of protection against atherosclerosis by preventing the absorption of microbial metabolites and components such as TMAO and LPS, which are key contributors to its pathogenesis [236]. In this context, _Lactobacillus plantarum_ ZDY04 has been shown to reduce plasma TMAO levels through the modulation of the gut microbiota [237]. In addition, _E. ficeum_ GEFA01 shows potential as a probiotic for atherosclerosis by lowering cholesterol and modulating gut microbiota in hyperlipidaemic mice [154]. Finally, by inhibiting NF-kB activation, as observed in a study with _Lactobacillus acidophilus_ ATCC 4356, probiotics have a proactive role in preventing atherosclerosis by promoting an anti-inflammatory action. This is demonstrated by their capacity to decrease levels of the pro-inflammatory cytokine TNF-\(\alpha\) and increase expression of the anti-inflammatory cytokine IL-10 [238].