## 4 Interaction Between the Gut Microbiota and Cardiovascular Diseases
### Non-Bacterial Microbiota and Atherosclerosis  
Recent research has begun to investigate how non-bacterial components of the gut microbiota, such as fungus, viruses, and bacteriophages, may affect CVD by indirect but biologically significant routes, in addition to the known functions of microbial metabolites. These organisms seem to modify the host's physiology via modifying barrier integrity, microbial community structure, and mucosal immunity, all of which are increasingly acknowledged as significant factors in the pathophysiology of atherosclerosis, rather than acting through particular circulating metabolites [16; 198]. Fungi represent a small but metabolically active component of the gut ecosystem, collectively known as the mycobiome. Although _Candida albicans_ is the most frequently detected species among the fungal elements of the gut mycobiota, other genera, including _Malssezia_, _Saccharomycesces_, and _Mucor_, have also been implicated in human disease and may play distinct roles in gut-immune-vascular interactions [199]. A preliminary study exploring the role of the gut mycobiota in subclinical atherosclerosis found that the relative abundance of _Mucor racemosus_ in the gut was negatively associated with both carotid intima-media thickness (cIMT) and the Framingham Risk Score (FRS), a clinical estimate of 10-year cardiovascular risk based on traditional factors. The results of the study point to a potential preventive effect of some fungal species in cardiovascular health, even though the underlying processes are currently unknown [200]. While _M. racemosus_ may exert a protective influence, other fungal taxa appear to have the opposite effect. A recent study suggests that _C. albicans_ is implicated in promoting pro-inflammatory responses and exacerbating atherosclerotic processes. The study showed that, in patients with dyslipidemia, elevated levels of _C. albicans_ were positively correlated with total cholesterol and LDL cholesterol, and its colonisation in murine models aggravated atherosclerosis. From a mechanistic point of view, a metabolite of _C. albicans_, formyl-methionine, activates the intestinal HIF-2\(\alpha\)-ceramide signalling pathway, leading to increased ceramide synthesis and accelerated plaque development, an effect that can be mitigated by the pharmacological inhibition of HIF-2\(\alpha\)[20]. The composition of the gut mycobiota in patients with atherosclerotic cardiovascular disease (ACVD) differs markedly from that of healthy individuals, according to a recent study. Shotgun metagenomic analyses revealed an increase in opportunistic fungal pathogens, including _C. albicans_, _Exophilata spinfifera_, and _Malssezia restricta_. Notably, network analysis revealed that the fungal-bacterial ecosystem in these individuals displayed greater dysregulation and lower interconnectivity, with species such as _Malassezia globosa, Nakasomyces glabatus_, and _Penicillium sumatranee_ emerging as central nodes [140]. Similarly, a cross-sectional study that examined the bacterial and fungal communities in patients with coronary artery disease found that the severity of the condition was correlated with increasing changes in gut fungal composition [141]. In addition to fungi, viruses and bacteriophages, collectively known as the gut virome, represent another important non-bacterial component of the intestinal microbiota with potential implications in cardiovascular health. The virome is mainly composed of bacteriophages, and has increasingly been recognised as a potential regulator of the bacterial community in the gut and can indirectly impact the cardiometabolic pathways that influence the development and progression of atherosclerosis. Phages can alter bacterial communities through lytic or lysogenic cycles, and this can result in the transmission of auxiliary metabolic genes by transduction, a horizontal gene transfer mechanism.