animals and microorganisms have coevolved to form a complex superorganism to benefit each other with functions they have not evolved on their own . for example , whereas microorganisms digest complex carbohydrates from plants and synthesize vitamins , the human host provides nutrients from alimentation and a protective environment . for instance , in humans , microbial cells are estimated to be 10 times more numerous than eukaryotic cells . moreover , the overall microbial genome the metagenome  has been shown to be organized in about 100 times more genes than our human genome [ 2 ] , despite a molecular complexity , in terms of base pairs , one order of magnitude lower than that of human dna . furthermore , microbial gene richness is under the control of dietary intervention , and low microbial gene diversity is prognostic of increased susceptibility to metabolic alterations [ 3 ] . for years , the role of the gut microbiota was thought to be relegated merely to digestive function . nowadays , however , the gut microbiota is widely recognized as an active organ that can modulate multiple functions of the host , from development of the intestinal immune system to hepatic and energy metabolism and to modulation of the brain in terms of behavior development and motor activity . by means of germ - free ( also called axenic ) murine models , some light has been shed on the mechanisms by which the gut microbiota modulates host metabolism with regard to diet - induced obesity , energy metabolism , and maintenance of intestinal physiology . these mice in fact are completely sterile from a microbial point of view , and their lack of gut microbiota determines a multitude of both structural and functional alterations . hence , colonization ( transplantation ) of axenic mice with gut microbiota issued from other animal models ( e.g. , obese mice ) or from human stools ( termed humanization [ 9 , 10 ] ) may allow identification of metabolic processes and the related molecular mechanisms under the control of intestinal microbes . furthermore , we and others have shown that targeting intestinal microbiota via dietary treatment , dietary fiber [ 12 ] , or antibiotics [ 13 , 14 ] ameliorated metabolic features such as glucose tolerance , insulin sensitivity , and body weight gain and reduced the associated chronic low - grade inflammation . our knowledge of the ecologic organization of the gut microbiota and its alteration  dysbiosis  has increased thanks to advances in high - throughput molecular sequencing , which obviates the need for laboratory cultivation to identify bacteria . today , the so - called holistic  -omics  approach allows very detailed analysis of the gut microbiota at the level of both taxonomy , identifying the microbiota ( phyla to species ) , and function , identifying the microbiome ( gene repertoire ) . for example , the firmicutes and bacteroidetes are recognized as the two major bacterial phyla populating gut microbiota , up to 90  % . dysbiosis of the gut microbiota has been reported for several pathologies , such as inflammatory chronic diseases of the intestine , intestinal cancer , and susceptibility to allergy , and especially for metabolic diseases , such as type 2 diabetes and obesity . for example , the obesity component appears to set the tone for gut microbial dysbiosis , because any imbalance favoring the firmicutes has been identified as the  bacterial signature  of obesity in humans   as well as in mice . on the other hand , lack of obesity in type 2 diabetic patients metabolic diseases are well - known common risk factors for development of severe cardiovascular diseases ( cvds ) , such as atherosclerosis , stroke , and myocardial infarction . in the past decade , there has been a global increase in cvd - induced death , mainly as the result of coronary heart disease ( 7.6 million ) and stroke ( 5.7 million ) . the world health organization estimates about 20 million cvd deaths in 2015 , rendering cvd as the major contributor to mortality worldwide . if we take into account only the data relative to the usa , the situation resembles a war bulletin . in fact , it is estimated that 3.88  % of the us population older than 18  years will have a stroke by 2030 . from 2010 to 2030 , the total direct annual medical cost attributable to stroke is expected to increase from $ 71.55 billion to $ 183.13 billion , with an overall estimated increase of 129  % . recent evidence from the literature provides a link between microbial activity and the modulation of overall cardiometabolism . these experimental results were obtained through metabolomics , the overall analysis of plasma metabolites ( metabolome ) , which enabled identification of key atherogenic microbial products , such as trimethylamine ( tma ) and its hepatic - generated metabolite tma - n - oxide ( tmao ) , resulting from microbial metabolism of dietary nutrients such as choline and l - carnitine [ 28 ] . however , the impact of gut microbiota and its dysbiosis on the induction of cvd remains a subject for debate because of some controversial aspects of the molecular mechanisms underlying this relationship , which are discussed in this review . at the end of the 1990s , the link between gut microbiota and cvd had not yet been discovered , and the first article to focus on this relationship failed to demonstrate any interaction . in this context , wright et al .   reported that axenic ( germ - free ) apoe knock - out mice were not protected from the development of atherosclerotic plaque , suggesting that the gut microbiota is not mandatory for the etiology of atherosclerosis . in addition , a meta - analysis of clinical trials of antibiotic therapy in patients with coronary artery disease ( cad ) failed to demonstrate any benefit with regard to the mortality or cardiovascular events in cad patients . this result suggests that gut microbiota modification by antibiotics does not modify the evolution of cad . in another study , 4,012 patients with documented stable cad received either 600  mg of azithromycin or placebo weekly for 1  year , with no effect on the risk of cardiac events among patients with stable cad . nevertheless , in a dahl s rat model of ischemia / reperfusion injury of the heart , microbiota was shown to increase the severity of myocardial infarction . in fact , the authors showed that treatment with vancomycin , a very poorly absorbable antibiotic , led to a 27  % reduction in myocardial infarction and a 35  % increase in postischemic mechanical function recovery . this effect was associated with a change in the gut microbiota at both the bacterial and fungal levels and to reduced plasma levels of leptin . the latter datum was confirmed mechanistically by administration of the leptin - suppressing probiotic lactobacillus plantarum 299v , which resulted in a 29  % reduction in myocardial infarction . these first two contradictory examples of antibiotic utilization ( azithromycin vs vancomycin ) clarify the complexity of gut microbiota - based intervention in terms of efficacy and properties of the applied protocol . interestingly , l. plantarum ph04 ( another strain of the aforementioned probiotic ) also was described as a cholesterol - lowering probiotic in hypercholesterolemic mice , in which administration of this probiotic was associated with a 10-fold increase in fecal lactic acid bacteria . recently , several works highlighted a new mechanism by which the intestinal microbiota seems to participate in the etiology of cvd . this discovery is based on metabolomic studies of plasma samples from patients with atherosclerotic plaque formation . the authors found that the concentration of the metabolite tmao was elevated in patients with atherosclerosis and was correlated directly with this pathology . moreover , the authors demonstrated that the gut microbiota is responsible for tmao synthesis by converting choline , an essential nutrient , into tma . for example , bacteria from the class erysipelotrichia ( phylum firmicutes ) reportedly can metabolize choline to tma , hence mimicking a choline deficiency . next , tma is absorbed and rapidly oxidized by hepatic cells to form tmao , which is responsible for macrophage foam cell formation , as reported in fig .  1 , by reducing reverse cholesterol transport in vivo , and consequently promotes cholesterol accumulation in the foam cells of atheroma [ 28 ] . however , the molecular mechanisms by which tmao reduces reverse cholesterol transport are not well understood.fig . products from a protein - rich diet , such as l - carnitine and phosphatidylcholine , may be metabolized into choline , which is converted to trimethylamine ( tma ) by the gut microbiota . tma may be oxidized into the liver to form tma - n - oxide ( tmao ) , which can promote the formation of atherosclerotic plaque [ 28 ] . on the other hand , diet - induced gut microbiota dysbiosis may result in bacterial translocation into the systemic blood flow , where a blood microbiota ( almost 90  % gram - negative bacteria ) may become established [ 40 ] . interestingly , a plaque - specific blood - like microbiota exists , and it is dominated by gram - negative bacteria ( proteobacteria phylum ) as well   gut microbiota and its impact on the cardiovascular system . products from a protein - rich diet , such as l - carnitine and phosphatidylcholine , may be metabolized into choline , which is converted to trimethylamine ( tma ) by the gut microbiota . tma may be oxidized into the liver to form tma - n - oxide ( tmao ) , which can promote the formation of atherosclerotic plaque [ 28 ] . on the other hand , diet - induced gut microbiota dysbiosis may result in bacterial translocation into the systemic blood flow , where a blood microbiota ( almost 90  % gram - negative bacteria ) may become established [ 40 ] . interestingly , a plaque - specific blood - like microbiota exists , and it is dominated by gram - negative bacteria ( proteobacteria phylum ) as well   therefore , on one hand , bacteria from the class erysipelotrichia may promote atherosclerosis via tma  tmao production . on the other hand , these bacteria may promote nonalcoholic fatty liver disease ( nafld ) by reducing choline availability for the synthesis of very low - density lipoprotein in the liver , resulting in triglyceride accumulation in the hepatocytes . it is noteworthy that the abundance of bacteria from the class erysipelotrichia also increases with an iron - rich diet , which promotes gut epithelial cell stress via iron accumulation in the enterocytes and , consequently , inflammation - induced dysbiosis of the gut microbiota . hence , an iron - rich diet may be directly responsible for the development of nafld and atherosclerosis via alteration of the gut microbiota . besides the intestine , several other organs of the body , such as the mouth , skin , vagina , and airways , harbor their own microbiota , each with a specific bacterial proportion . interestingly , atherosclerotic plaque also has been shown to harbor its own microbiota , dominated by members of the phylum proteobacteria ( e.g. , escherichia coli ) . remarkably , this phylum is also the most abundant of the newly identified blood microbiota we discovered recently in diabetic patients in the epidemiological study on the insulin resistance syndrome ( desir ) cohort [ 40 ] . therefore , it may be speculated that the establishment of blood microbiota might represent the first step in the kinetics of atherosclerotic plaque formation . bacteria from the genus collinsella also were found to be enriched in patients with symptomatic atherosclerosis , defined as the presence of stenotic atherosclerotic plaques at the level of the carotid artery and leading to cerebrovascular events . by contrast , bacteria belonging to roseburia and eubacterium were augmented in the gut microbiota of healthy controls . in this study , by karlsson et al . , the microbiome ( functional gene level ) also was investigated , revealing enrichment of genes encoding for peptidoglycan , among others , in the metagenome from patients . among the strategies to target the gut microbiota , prebiotics [ 42 , 43 ] and probiotics   are those used most often . in an article published in 2014 , gan et al . proposed using lactobacillus rhamnosus gr-1 as a probiotic for treating heart failure in rats the authors showed that the probiotic treatment could delay heart failure development after coronary occlusion in rats . however , the probiotic treatment did not affect the cecal microbiome profile . in another article , the authors showed that methanomassiliicoccus luminyensis b10 , a methanogen bacterium , can deplete tma by reducing it with h2 for methanogenesis . therefore , they suggest that bacteria from this group may be used as probiotics to treat metabolic disease as well as cvd by reducing tma and , hence , tmao plasma levels . in this context , plasma levels of choline , as well as betaine , may be used as a prognostic value to determine the risk of developing a major adverse cardiac event ( mace ) , such as death , myocardial infarction , or stroke . in this study , wang et al .   examined a 3-year survey of 3,903 sequential stable subjects who underwent elective diagnostic coronary angiography . however , the authors reported that values of choline and betaine are prognostic of mace only in association with increased tmao plasma levels . besides cvd in adulthood , this disease also represents a serious health challenge in term infants . congenital heart disease ( chd ) chd also is one of the most important risk factors for necrotizing enterocolitis ( nec ) in term infants . infantis is reported to be effective in terms of reducing inflammation in nec , even if the gut microbiota appears not to be significantly affected by the probiotic . interestingly , chd also is associated with dysbiosis of the gut microbiota , such as reduced total bacteria , bacteroidetes , and bifidobacteria , when healthy infants are compared with chd infants . nevertheless , administration of the probiotic bifidobacterium infantis again did not show a significant change in plasma cytokines or in the microbial stool profiles of chd infants compared with the placebo group . periodontitis ( also known as periodontal disease [ pd ] ) is an inflammatory disease of the oral cavity defined as a chronic bacterial infection of the soft and hard tissues supporting and surrounding the teeth and caused by gram - negative capnophilic bacteria [ 50 , 51 ] . besides metabolic diseases such as type 2 diabetes and obesity , pd in fact , pd has been associated with cvd and atherosclerosis , suggesting that the oral microbiota may be causal in the etiology of atherosclerosis . in this context , we recently reported that 1-month colonization with periodontal pathogens such as porphyromonas gingivalis , prevotella intermedia , and fusobacterium nucleatum aggravated high - fat diet ( hfd)-induced metabolic alteration ( glucose intolerance ) as well as systolic and diastolic arterial pressure in diabetic mice . the molecular mechanism underlying this phenotype is associated with gram bacterial lipopolysaccharide ( lps ) , because we also showed that cd14 knock - out mice were protected from hfd - induced periodontal defects . the possibility that lps might bridge pd and cvd also was suggested by another paper showing that lps from porphyromonas gingivalis was responsible for inflammation - induced cvd via increased oxidative stress and mitochondrial dysfunction . oral bacterial spread into the bloodstream ( bacterial translocation ) also may be the origin of pd - induced endocarditis and myocardial and/or cerebral infarction , especially in patients with heart valve dysfunction , as the result of uncontrolled bacteremia . for example , oral streptococci have been found to dominate infective endocarditis . following bacterial translocation , calandrini et al .   detected the periopathogen aggregatibacter actinomycetemcomitans in 20  % of endarterectomy ( the surgical removal of atherosclerotic plaque from an artery ) specimens from patients with myocardial infarction , followed by pseudomonas species . however , metagenomic analysis of the oral microbiota from 15 patients with clinical atherosclerosis failed to show differences when compared with control subjects . in addition , the same study failed to demonstrate that atherosclerosis patients harbor a gut microbiota different from that of control subjects . currently , the worldwide scientific community is paying more attention to the putative consequences of alterations in the gut microbiota and the progression of cardiometabolic disease , given the pleiotropic range of host functions that may be affected by gut microbiota dysbiosis [ 59 , 60 , 16 ] . despite convincing studies showing the deleterious effects of gut microbiota metabolism of a protein - rich diet , gut microbiota metabolism of l - carnitine , and the association with cardiovascular risk , in fact , it also has been shown that l - carnitine may ameliorate metabolic diseases by increasing insulin sensitivity of the skeletal muscle and may reduce ischemic heart disease . moreover , dietary fish is rich in tmao , despite the beneficial effects of fish oil on cardiovascular events . these results demonstrate that the complex ecology of the gut microbiota and its metabolic behavior must be considered as being associated with specific metabolic conditions , rather than generalized as a common mechanism of etiology . therefore , uncertainty remains as to whether the gut microbiota should be considered a cause or consequence of a given pathology . the path to finding and developing microbe - based therapies passes ineluctably through the elucidation of this relevant dilemma .
these days , the gut microbiota is universally recognized as an active organ that can modulate the overall host metabolism by promoting multiple functions , from digestion to the systemic maintenance of overall host physiology . 
 dysbiosis , the alteration of the complex ecologic system of gut microbes , is associated with and causally responsible for multiple types of pathologies . among the latters , metabolic diseases such as type 2 diabetes and obesity 
 are each distinguishable by a unique gut microbiota profile . 
 interestingly , the specific microbiota typically found in the blood of diabetic patients also has been observed at the level of atherosclerotic plaque . here , 
 we report evidence from the literature , as well as a few controversial reports , regarding the putative role of gut microbiota dysbiosis - induced cardiovascular diseases , such as atherosclerosis , which are common comorbidities of metabolic dysfunction .