## 4 Interaction Between the Gut Microbiota and Cardiovascular Diseases
### Tryptophan Metabolites  
Tryptophan is an essential amino acid that cannot be synthesised endogenously and must, therefore, be acquired through dietary protein intake [187]. The conversion of tryptophan to indole is an important metabolic process, mediated mainly by the enzyme tryptophanase, which is expressed in many Gram-negative, as well as Gram-positive, bacterial species, including _E. coli_, _Clostridium_ spp., and _Bacteroides_ spp. [188]. While this section focuses on the microbiota-dependent tryptophan metabolism, it is important to acknowledge that host-mediated pathways, such as the kynure pathway, also contribute to the pathogenesis of atherosclerosis. The enzyme indoleamine 2,3-dioxygenase (IDO1), which catalyses the first step in this pathway, is induced by inflammation and has been implicated in both pro- and anti-atherogenic processes. Although the microbiota may influence systemic tryptophan availability and thus indirectly affect the kynure metabolism, the mechanistic interactions between these axes remain incompletely understood and lie beyond the scope of the present discussion [189]. In this context, several studies have demonstrated that, through several other metabolic pathways, intestinal microbial species produce not only indole, but also other tryptophan catalogues. For instance, _Clostridium sporogenes_ converts tryptophan into tryptamine, indoleactic acid (ILA), and indolepropionic acid (IPA). Similarly, some species of the genus _Peptostreptococcus_, including _P. russellii_, _P. anaerobius_, and _P. stomatis_, are able to convert tryptophan into indoleacrylic acid (IA) and IPA. Additionally, _Lactobacillus_ species convert tryptophan into indole-3-aldehyde (IAId) and ILA via the action of aromatic amino acid aminotransferase and indoleactic acid dehydrogenase. _Ruminococcus gnavus_ also metabolises tryptophan, producing tryptamine through the enzyme tryptophan decarboxylase. Several _Bacteroides_ species, along with _Clostridium brattetti_, are capable of producing ILA and indole-3-acetic acid (IAA), whereas _Bifidobacterium_ species primarily generate ILA. Moreover, the metabolite 3-methylindole (skatole), known for its strong odour, is produced by _Bacteroides_ and _Clostridium_ species via the decarboxylation of IAA [187; 190]. These compounds have emerged as key modulators of vascular inflammation, oxidative stress, and endothelial function [189], primarily through their interaction with host receptors such as the AhR, by modulating the expression of genes involved in xenobiotic metabolism, inflammation, and barrier integrity [191]. AhR is a ligand-dependent transcription factor expressed in a variety of cell types, including endothelial cells, epithelial cells, and several subsets of immune cells, that binds a variety of endogenous and exogenous compounds, including indole metabolites produced by the gut microbiota. In the context of atherosclerosis, AhR activation by tryptophan metabolites can have both positive and negative effects, depending on the specific metabolite, its concentration, and the cells or tissue involved [136]. Therefore, tryptophan metabolites, such as IAId, ILA, and IPA, have been shown to have atheoprotective effects, contributing to the maintenance of vascular homeostasis, since they seem to promote anti-inflammatory responses, preserve endothelial barrier function, and supress the production of ROS [189; 192; 193]. Conversely, other compounds derived from tryptophan, namely indoxyl sulphate (IS), a hepatic metabolite derived from microbial indole, act as uremic toxins and have been associated with vascular calcification, endothelial dysfunction, and pro-inflammatory signalling through the AhR and other pathways [194]. Since its clearance is impaired in patients with chronic renal disease, IS accumulation is especially significant in these patients, aggravating atherosclerotic processes [195; 196]. The dual role of AhR ligands derived from microbiota is supported by data from animal models of atherosclerosis.