Send Orders for Reprints to reprints@benthamscience.net Current Medicinal Chemistry, XXXX, XX, 1-00 1 0929-8673/XX $65.00+.00 © XXXX Bentham Science Publishers REVIEW ARTICLE Gut Microbiota and Cardiovascular Disease: Symbiosis Versus Dysbiosis Antonis A. Manolis 1 , Theodora A. Manolis 2 , Helen Melita 3 and Antonis S. Manolis 4,* 1 Patras University School of Medicine, Patras, Greece; 2 Aiginiteio University Hospital, Athens, Greece; 3 Onassis Cardiac Surgery Center, Athens, Greece; 4 Athens University School of Medicine, Athens, Greece ARTICLE HISTORY Received: August 03, 2021 Revised: October 28, 2021 Accepted: October 31, 2021 DOI: 10.2174/0929867328666211213112949 Abstract: The gut microbiome interacts with host physiology through various mech- anisms, including the cardiovascular (CV) system. A healthy microbiome has the ability to process and digest complex carbohydrates into short-chain fatty acids (SCFA). These SCFA function as signaling molecules, immune-modulating molecules, and energy sources. However, when the microbiome is altered, it produces gut dysbiosis with over- growth of certain bacteria that may lead to overproduction of trimethylamine-N-oxide (T- MAO) from the metabolism of phosphatidylcholine, choline, and carnitine; dysbiosis al- so leads to increased intestinal permeability allowing the microbiome-derived lipopolysaccharide (LPS), a bacterial endotoxin, to enter the blood circulation, triggering inflammatory responses. An altered gastrointestinal (GI) tract environment and micro- biome-derived metabolites are associated with CV events. Disrupted content and func- tion of the microbiome leading to elevated TMAO and LPS levels, altered bile acid metabolism pathways, and SCFA production are associated with an increased risk of CV diseases (CVD), including atherosclerosis, myocardial infarction, thrombosis, arrhyth- mias, and stroke. Therapeutic interventions that may favorably influence a dysbiotic GI tract profile and promote a healthy microbiome may benefit the CV system and lead to a reduction of CVD incidence in certain situations. These issues are herein reviewed with a focus on the spectrum of microbiota-related CVD, the mechanisms involved, and the po- tential use of microbiome modification as a possible therapeutic intervention. Keywords: Microbiome, microbiota, cardiovascular disease, metabolic syndrome, trimethylamine-N-oxide. 1. INTRODUCTION Cardiovascular (CV) disease (CVD) is currently the leading global cause of death [1]. In addition to several other conditions known to cause CVD, alterations to the gut microbiome have recently been shown to pro- mote CVD [2-5]. The human microbiome of the gastrointestinal (GI) tract encompasses over 100 trillion microbial cells and 100 different bacterial species, a crucial symbiosis that greatly impacts host homeostasis, maintaining the phy- siological and metabolic health of the host [6]. Consid- erable knowledge of the human microbiome was ac- quired after 2007, the year the Human Microbiome Pro- ject was launched, a 5-year-long international effort *Address correspondence to this author at the First Department of Cardiology, Hippokrateio Hospital, Vas. Sofias 114, Athens 115 27, Greece; E-mail: asm@otenet.gr to characterize the microbial populations found in the human body and to identify each microorganism’s role in health and disease [7, 8]. Although the consistency of the microbiome may vary in each human GI tract, obligate anaerobes out- number facultative anaerobes and aerobes by up to 100-fold; over 90% of bacteria in a healthy adult GI tract consists of the Bacteroidetes (especially the gen- era Bacteroides and Prevotella) and Firmicutes phyla (especially members of the genus Clostridium); minor phyla include Actinobacteria, Proteobacteria, and Ver- rucomicrobia, and methanogens as the dominant amongst the Archaea; some fungi, and viruses are also present (Table 1). Specifically, 8 abundant genera, comprising Bacteroides, Eubacterium, Faecalibacteri- um, Alistipes, Ruminococcus, Clostridium, Roseburia, and Blautia, were identified in more than 1000 humans [9, 10]. These microorganisms all aid in digestion, but they can also produce valuable nutrients; lactic acid