Cardiovascular diseases (CVDs) are major outcomes of metabolic impairments in humans, which result from several genetic and environmental factors. In recent years, a ‘microbiome hypothesis’ has been proposed as a result of several studies that have attempted to understand underlying mechanisms of CVDs. Similar to CVDs, both genetic and environmental factors, especially diets, have a major impact on shaping gut microbiota and their functions. In the past decade, strong evidence has emerged to confirm the role of gut microbiota in contributing to the onset of CVDs. However, a comprehensive understanding of interactions among diet, host genotype, gut microbiota and CVDs is still facing challenges due to the complicated nature of CVDs. In this chapter, we review the present state of our knowledge about the contributory role of gut microbiota in CVDs and discuss the knowledge gaps that warrant further investigations. Moreover, we review the potential intervention strategies that may target the microbiota-driven pathology in CVDs and discuss the strength and weakness of animal models in studying the roles of gut microbiota in CVDs.
- gut microbiome
- cardiovascular disease
- host genotype
Cardiovascular disease (CVD) is a leading cause of death in industrialized societies, with increasing incidence in developing countries . A combination of genetic and environmental factors contributes to risk for developing CVD . A significant portion of CVDs can be attributed to ischemic heart disease, often a result of underlying coronary arterial diseases such as atherosclerosis. Risk factors for atherosclerosis include dyslipidaemia, hypertension, obesity, smoking, and diabetes [3, 4]. Extensive searching in recent years for causal genetic variants found less than one-fifth of CVD risk is accounted for by genetic determinants [5, 6]. Excluding tobacco exposure, dietary intake is our largest environmental risk, as we consume kilogram quantities into our bodies daily. However, specific dietary composition and precise quantification of dietary intake of a given individual are often difficult to assess.
Over the past decade, there has been a growing body of knowledge on the ecological diversity of microbes living symbiotically within us, especially in our gastrointestinal tract. More than 100 trillion microbial cells reside in the human gut, which is far outnumbering the host cells of the human body . Microbial symbionts in our gastrointestinal system have coevolved with us and critically contribute to a variety of physiologic and metabolic processes of our body. Undeniably, human DNA is estimated to represent less than one-tenth of the total DNA within our bodies due to the remarkably large number of microorganisms in and on us, mainly within our gastrointestinal tract . The composition of the microbial community in our gut can be largely affected not only by dietary exposures but also by genetic variants of the host, as well as any changes that impaired host’s physiology and homeostasis. In recent years, although there is increasing evidence supporting an association between gut microbiota and diseases in human and animals [9, 10], the participatory roles of gut microbiota in our health, immune function, and disease initiation and progression have just begun to be explored. There has been an established understating of the role of microbial dysbiosis in the pathogenesis of some diseases of altered intestinal health . The alteration of gut microbiota may contribute enormously to the digestion of food and absorption of metabolites, which further contribute to the development of a range of CVDs from atherosclerosis to cardiorenal dysfunction .
The gastrointestinal ecosystem is arguably the largest endocrine as well as paracrine organ in the body, producing a variety of biologically active compounds that may be transported in the systemic circulation and distributed to other organ systems within the host, thereby influencing diverse essential biochemical processes . This chapter summarizes recent developments in our knowledge of the contributory role of gut microbiota on the initial onset and development of CVDs, and how diets and genetics of the host participate in their development. Potential strategies that can modulate gut microbiota for prevention and therapeutic interventions for CVDs will also be discussed.
2. Intestinal microbiota in cardiovascular disease—the good, the bad, and the ugly
The understanding of the link between gut microbiota and CVD was limited until the late 1990s. The fact that axenic (germ-free) ApoE knockout mice were not protected from the development of atherosclerosis suggested that the gut microbiota is not important in the pathogenesis of atherosclerosis . A meta-analysis of clinical trials revealed that the modification of gut microbiota by antibiotics failed to demonstrate any benefit with regard to mortality due to cardiovascular events in coronary artery disease patients . Furthermore, in an extensive study involving 4012 patients with stable coronary artery disease, the administration of azithromycin showed no effect on the risk of cardiac events . However, the composition of the microbiota was shown to increase the severity of myocardial infarction in a Dahl S rat model of ischaemia/reperfusion injury of the heart, in which the authors indicated that vancomycin, a poorly absorbable antibiotic, reduced 27% of myocardial infarctions and increased 35% postischaemic mechanical function recovery . This effect was associated with a change in the gut microbiota (both bacteria and fungi) and a reduction of plasma leptin, which was later confirmed by administration of the leptin-suppressing probiotic
Invasion of indigenous and/or pathogenic oral and intestinal bacteria, as well as their metabolites and toxins into the vascular system, has been demonstrated in association with several CVD events [17, 18], although a causal association between periodontal infection and atherosclerotic CVD or its sequel has not been demonstrated. Periodontitis, also known as periodontal disease (PD), is an inflammatory disease of the oral cavity due to chronic bacterial infection of soft and hard tissues of the gum, mainly by Gram-negative bacteria . A high-fat diet can induce not only metabolic alteration but also increased systolic and diastolic pressure in diabetic mice after longer term colonization with periodontal pathogens, such as
In recent years, more studies have highlighted the contributory role of gut microbiota in CVD. Initial hypothesis-generating studies using untargeted metabolomics analyses of plasma samples identified three metabolites, including phosphatidylcholine (PC; lecithin) metabolism-choline, betaine, and trimethylamine-N-oxide (TMAO) that are potentially associated with cardiovascular risk . Another study also found increased concentration of the metabolite TMAO in patients with atherosclerosis and their correlation with this pathology . Gut microbiota has been demonstrated to be responsible for TMAO synthesis by converting choline, an essential nutrient, into TMA. Subsequent oxidation of TMA through flavin monooxygenase 3 (FMO3) from the liver formed TMAO [25–27]. As an example, the bacteria belonging to
In addition to the three bacterial metabolites described previously, l-carnitine has also been shown to accelerate atherosclerosis in mouse models, but only in the presence of intact gut microbiota and TMA/TMAO generation. High carnitine levels significantly increased the risk of myocardial infarction (MI), stroke, or death in experimental subjects with concurrently high TMAO levels. Similar to PC/choline, l-carnitine is a TMA-containing compound that releases TMA through the gut microbiota and consequently converted into TMAO by hepatic FMO (Figure 1) . Thus, intestinal microbiota may play an obligatory role in generating TMAO from multiple dietary nutrients, and TMAO is the proatherogenic species probably promoting the associations noted between plasma levels and both prevalent and incident CVD risks.
Recent studies reveal that the potential pathogenic contribution of gut microbiota-dependent generation of TMAO may extend beyond the development of progression of atherosclerosis and its adverse complications (MI, stroke, or death). A recent observation also indicated increased TMAO levels in heart failure patients . In these patients, intestinal ischaemia can be demonstrated by a decrease in intestinal mucosal pH  or reduced passive carrier-mediated transport of d-xylose . Due to the consequences of intestinal ischaemia and congestion, the morphology, permeability, and function of the intestinal mucosa may substantially altered in congestive heart failure (CHF), especially in advanced stages with cardiac cachexia . Our knowledge on the mechanistic associations between gut microbiota and CHF is improving. Although evidence is still accruing, higher concentrations of adherent bacteria have been identified in the intestinal mucosal biofilm of patients with CHF . The composition of intestinal microbiota may alter rapidly during intestinal ischaemia and reperfusion or following an increase in portal vein pressure because of the activation on bacterial virulence in microbiota by gut liminal hypoxia, hypercapnia, changes in local pH, redox state, and norepinephrine . Hypoperfusion and congestion in the intestine may reduce cardiac output and further disrupt the barrier function of the intestine and promote systemic inflammation through bacterial translocation, potentially leading to further CHF exacerbations (Figure 2). However, major changes in the gut microbial composition have not been observed in a rat model of CHF induced by coronary artery ligation . In this regard, the role of gut microbiota is possibly unique to human CHF.
The microbial analysis of atherosclerotic plaque has shown that the embedded microbiota is dominated by bacteria of the phylum
3. Role of diet and host genotype in shaping intestinal microbiota profile associated with cardiovascular diseases
Dietary cholesterol has major effects on gastrointestinal microbiota, which is consequently associated with the onset of CVD. In our recent study, we tested the effect of diet and host genotype on intestinal microbiota using two Japanese quail strains that are atherosclerosis-susceptible (SUS) and atherosclerosis-resistant (RES) . In that study, dietary cholesterol reduced the abundance of
When mice were fed a ‘Western diet’, which was high in fat and cholesterol, the overall diversity of their gut microbiota dropped significantly due to a bloom of a class of
In the past decade, numerous studies have been published on the relationship between gut microbiota and cardiovascular diseases in human and in animal models. In humans, about 50% of dietary cholesterol is absorbed in the duodenum; consequently, the rest can be metabolized by
A number of studies including our quail model highlighted the importance of host genotype in responding to diet-induced atherosclerosis. However, further research effort is need to address the underlying biochemical pathways by which host genetics interplay with diets to influence the CVD events through alteration of gut microbiota.
4. Animal models for studying gut microbiome in cardiovascular disease
Cardiovascular diseases (CVDs) involve complicated multifactorial pathologies, in which both genetic and environmental factors are involved. In order to provide us with important insights into the pathophysiology of CVD events, the development of animal models of CVD is essential as tools to evaluate novel therapeutic strategies to predict and to prevent these complications. Until now, there have been numbers of animal models used for CVD, including those implemented in both large (pig and dog) and small (mice and rat) animals, designed for enhancing scope with more precision and to better represent human pathologies. With or without genetic modifications, mouse, rat and rabbit models are more commonly used and less expensive animal models for studying CVDs compared to porcine and canine models, which better represent the human pathology, but are less popular due to the cost and difficulties in handling. For atherosclerosis, mouse models have proven to be useful to study development and progression of atherosclerotic lesions. In particular, knockout and transgenic mouse models have been well developed to study the molecular and cellular mechanisms involved in atherogenesis and to evaluate the effectiveness of new and existing drugs for the prevention and/or treatment of atherosclerosis. The most widely used knockout mouse models include low-density lipoprotein receptor-deficient mice (LDLR−/− mice) and apolipoprotein E-deficient mice (ApoE−/− mice). Mice carrying ApoE mutations such as ApoE3Leiden (E3L) and ApoE (Arg 112→Cys→142) transgenic mice are very useful mouse models to study hyperlipidaemia and atherosclerosis. The high-cholesterol diet rabbit model has been widely used for experimental atherosclerosis . Several porcine models have been employed for closer representation to pathologies in humans [53–56]. However, the extensive application of porcine models is still limited. In heart failure, dog models of myocardial infarction and serial microembolization of the coronary artery were developed . Like the pig models, dog models are very restricted due to their cost, ethical complications, and difficulties in handling.
Since the ‘microbiome hypothesis’ has been applied to CVDs and other metabolic diseases, the most common and feasible animal model is the mouse model. As we know, murine models have been extensively applied in biomedical research due to similarities in anatomy, physiology, and genetics, which have allowed numerous inferences about human pathology to be drawn from murine experimentation. In gut microbiota research, mouse models are being increasingly used to study the role and functioning of the gut microbiota and its association with diseases. However, application and direct translation of results obtained from traditional CVD mouse models to study the role of the gut microbiome and its interaction with the host have their limitations for the following reasons:  the variation of the gut microbiota of laboratory mice relates to genetic, physiologic, and environmental factors, and those factors also trigger the pathologies of CVD;  cross-talk between the gut microbiota and the host is host-specific so observations in mouse models might not be applicable to humans;  the inherent genetic variations in the human population cannot be captured by the inbred mouse strains that have genetic homogeneity; and finally  differences in multiple factors between mice and humans, such as genetic background, birth mode (caesarean or vaginal), mode of feeding (breast or bottle), diet, age, medical history, and social activities, which all contribute in shaping the gut microbiota of humans.
Existing animal models for CVDs have not yet been fully evaluated in studying the role of the gut microbiome in developing pathologies of CVD events. This should be considered in future investigations, and the most appropriate animal model to study the links between gut microbiota and CVD should be proposed and recommended. Rabbits , guinea pig , pigeon , and quail  have been used as models for studying atherosclerosis but not in association with gut microbiota. Recently, we proposed a new quail model that would be useful for studying the interaction of host genotype and diet in affecting the gut flora in association with the development of atherosclerosis . We proposed that our Japanese quail model may have advantages over others because quail are naturally deficient in apolipoprotein E. When we fed a high cholesterol diet, males of the SUS quail developed lesions exhibiting structural features (e.g. focal haemorrhage, calcification, and fibrosis) that closely similar those in the human atherosclerosis [62, 63]. In addition, quail model is easier to be handled, lower costs for larger sample size, and require less laboratory space compared to other porcine or canine models. As a further incentive, our recent microbiome study has provided the baseline understanding for the association between the gut microbiome and the development of atherosclerosis in quail model.
5. The potential of modulation of gut microbiota as novel preventive and therapeutic strategies for cardiovascular disease
During these past few years, several research efforts aimed to modulate both structure and function aspects of the gut microbiome were reported [64, 65]. Faecal transplantation is one of the successful stories for restoring impaired gut microbiome into normal gut microbiome, which has shown certain success in applications of certain human diseases especially in
5.1. Dietary intervention
As choline, PC, and carnitine are primary sources of gut microbiota-associated TMAO production, dietary modulation is a logical intervention strategy . It has been shown that vegetarians and vegans have markedly reduced production of TMA and TMAO from dietary l-carnitine and have lower plasma TMAO levels than omnivores . Similarly, studies have shown that different gut microbial communities were found in vegetarians and vegans compared with omnivores [29, 67]. In animal model studies, long-term exposure to dietary l-carnitine increased TMA synthetic capacity by 10-fold with a concurrent shift in gut microbial composition . Thus, chronic dietary exposure (e.g., omnivore vs. vegan/vegetarian among humans or normal chow vs. chow plus l-carnitine in mouse studies) shifts gut microbiota, with a selective advantage for certain bacterial species that prefer l-carnitine as a carbon fuel source to increase in proportion within the community and amplify the potential to produce TMA .
The elimination of l-carnitine from the diet is a potentially achievable goal that may reduce some TMAO production. But, choline is an essential nutrient and its complete elimination from the diet is unwise. Furthermore, bile has a very high total choline (PC) content, and the rapid turnover and sloughing of intestinal epithelial cells results in significant exposure of distal gut segments (and hence microbes) to choline, independent of dietary intake. Absorbent removal of TMA from the intestines by specific oral binding agents is a challenging but potentially feasible therapeutic approach for reducing TMA and TMAO levels. The details of application of binding reagents will be discussed in the following specific section.
5.2. Antibiotic intervention
The association between certain groups of bacteria and CVD such as atherosclerosis has previously been postulated. However, a number of randomized controlled studies have failed to demonstrate a benefit of antibiotic therapy for secondary prevention of cardiovascular events [15, 68]. On the other hand, antibiotics can influence the pathophysiological outcomes driven by changing the abundance or composition of the gut microbiota. A well-known antibiotic, vancomycin, presented a reduction of myocardial infarct size in a rat model of ischaemia-reperfusion . Interestingly, there was no effect on severity of myocardial infarction by direct infusion of vancomycin into the coronary circulation. Furthermore, the oral administration of the antibiotic polymyxin B reduced monocyte production of certain proinflammatory cytokines in patients with HF and improved flow-medicated dilation . Although the previous findings reflect the effect of antibiotics in the modulation of gut microbiota on the pathophysiology of various CVD events including HF, the potential adverse effects of antibiotics, such as microbial substitution and generation of antibiotic-resistant microbes, commonly occur in clinical practices. Hence, the extensive application of this strategy is arguable and challenging. Careful considerations are needed to minimize the adverse effects of antibiotic agents. Additional investigations are needed to determine the benefits of proper application of antibiotics in specific circumstances in clinical practices.
5.3. Prebiotic/probiotic intervention
Prebiotics are non-digestible food ingredients, mainly fibres that beneficially affect the host’s health by selectively stimulating the growth and/or activity of some genera of gut microorganisms especially in the hindgut. Probiotics are live microorganisms that confer a health benefit to the host when administered in adequate amounts through improving the intestinal microbial balance . However, the effectiveness of both prebiotics and probiotics varies on their sources, methods of preparation and administration, and the dosage. They have been extensively applied in most gastrointestinal disorders, and recently their applications in metabolic and cardiovascular diseases have been studied due to their potential role to modulate gut microbiota that consequently may diminish the pathophysiology of those diseases. In a study, done in a ‘humanized’ mouse model (germ-free mice colonized with human gut flora), the probiotic administration alters the production of several metabolites including TMAO through modulation of symbiotic gut microbial-host interactions . Evidence has been provided that demonstrates that intervention with a probiotic product can favourably affect cardiac morphology and function in animal models . A leptin suppressing probiotic bacteria,
5.4. Binding agents of key mediators
As the metabolites (e.g. TMAO) and their precursors (e.g. TMA) play important roles in the pathogenesis of CVD, a promising intervention would be to remove such metabolites and their precursors from the gut by oral administration of specific non-absorbent binding agents. Oral charcoal absorbent (AST-120) has been clinically applied to remove uremic toxins, such as indoxyl sulphate, in patients with advanced renal failure . AST-120 has been shown to prevent progression of LV hypertrophy and cardiac fibrosis in rats with chronic kidney disease (CKD)  and in a combination model with CKD plus HF  without affecting blood pressure. However, the efficacy of binding agents has not yet been demonstrated in human, and more research should explore the potential use of such strategies.
Coevolution over millions of years between human and microorganism has led to a mutualistic relationship, in which diverse ecosystems of gastrointestinal microbiota and its metabolic functions contribute to the maintenance of our metabolic homeostasis. The interaction between heart and gut, or the heart-intestine axis, has emerged as a novel concept to provide new insights into the complex mechanisms of CVD. Gut microbiota function as a filter for our largest environmental exposure, our dietary intake, and the microbial community within each of us obviously influences how we experience a diet. We need to appreciate that our gut microbial ecosystem makes up a large and plastic endocrine organ that influences numerous metabolic and physiological processes. Although recent sequencing efforts of gut microbiota provide multiple evidences of its associations with CVD events, simply cataloguing the microbes within is not sufficient and further studies should focus on discovery of the functional aspects of microbiota and its metabolites that contribute to the pathophysiology of CVD and other metabolic diseases that trigger CVD events. Not all currently available animal models are suitable for discovering the role of gut microbiota on CVD and associated diseases, thus, new
We thank the support of the British Columbia Ministry of Agriculture Specialty Birds Research Fund.
Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Blaha MJ, et al. Heart disease and stroke statistics—2014 update: a report from the American Heart Association. Circulation. 2014;129(3):e28-e292.
Nabel EG. Cardiovascular disease. The New England Journal of Medicine. 2003;349(1):60-72.
Davignon J, Ganz P. Role of endothelial dysfunction in atherosclerosis. Circulation. 2004;109(23 Suppl 1):III27-III32.
Mulvihill EE, Huff MW. Citrus flavonoids and the prevention of atherosclerosis. Cardiovascular & Hematological Disorders Drug Targets. 2012;12(2):84-91.
Ardissino D, Berzuini C, Merlini PA, Mannuccio Mannucci P, Surti A, Burtt N, et al. Influence of 9p21.3 genetic variants on clinical and angiographic outcomes in early-onset myocardial infarction. Journal of the American College of Cardiology. 2011;58(4):426-434.
Ripatti S, Tikkanen E, Orho-Melander M, Havulinna AS, Silander K, Sharma A, et al. A multilocus genetic risk score for coronary heart disease: case-control and prospective cohort analyses. Lancet. 2010;376(9750):1393-1400.
Lozupone CA, Stombaugh JI, Gordon JI, Jansson JK, Knight R. Diversity, stability and resilience of the human gut microbiota. Nature. 2012;489(7415):220-230.
Human Microbiome Project C. Structure, function and diversity of the healthy human microbiome. Nature. 2012;486(7402):207-214.
Cenit MC, Matzaraki V, Tigchelaar EF, Zhernakova A. Rapidly expanding knowledge on the role of the gut microbiome in health and disease. Biochimica et Biophysica Acta. 2014;1842(10):1981-1992.
Lee WJ, Hase K. Gut microbiota-generated metabolites in animal health and disease. Nature Chemical Biology. 2014;10(6):416-424.
Carding S, Verbeke K, Vipond DT, Corfe BM, Owen LJ. Dysbiosis of the gut microbiota in disease. Microbial Ecology in Health and Disease. 2015;26:26191.
Tang WH, Hazen SL. The contributory role of gut microbiota in cardiovascular disease. The Journal of Clinical Investigation. 2014;124(10):4204-4211.
Wright SD, Burton C, Hernandez M, Hassing H, Montenegro J, Mundt S, et al. Infectious agents are not necessary for murine atherogenesis. The Journal of Experimental Medicine. 2000;191(8):1437-1442.
Andraws R, Berger JS, Brown DL. Effects of antibiotic therapy on outcomes of patients with coronary artery disease: a meta-analysis of randomized controlled trials. JAMA. 2005;293(21):2641-2647.
Grayston JT, Kronmal RA, Jackson LA, Parisi AF, Muhlestein JB, Cohen JD, et al. Azithromycin for the secondary prevention of coronary events. The New England Journal of Medicine. 2005;352(16):1637-1645.
Lam V, Su J, Koprowski S, Hsu A, Tweddell JS, Rafiee P, et al. Intestinal microbiota determine severity of myocardial infarction in rats. FASEB Journal: official publication of the Federation of American Societies for Experimental Biology. 2012;26(4):1727-1735.
McIntyre CW, Harrison LE, Eldehni MT, Jefferies HJ, Szeto CC, John SG, et al. Circulating endotoxemia: a novel factor in systemic inflammation and cardiovascular disease in chronic kidney disease. Clinical Journal of the American Society of Nephrology: CJASN. 2011;6(1):133-141.
Szeto CC, Kwan BC, Chow KM, Lai KB, Chung KY, Leung CB, et al. Endotoxemia is related to systemic inflammation and atherosclerosis in peritoneal dialysis patients. Clinical Journal of the American Society of Nephrology: CJASN. 2008;3(2):431-436.
Loesche WJ, Grossman NS. Periodontal disease as a specific, albeit chronic, infection: diagnosis and treatment. Clinical Microbiology Reviews. 2001;14(4):727-752, Table of contents.
Blasco-Baque V, Kemoun P, Loubieres P, Roumieux M, Heymes C, Serino M, et al. Impact of periodontal disease on arterial pressure in diabetic mice. Ann Cardiol Angeiol (Paris). 2012;61(3):173-177.
Bullon P, Cordero MD, Quiles JL, Morillo JM, del Carmen Ramirez-Tortosa M, Battino M. Mitochondrial dysfunction promoted by Porphyromonas gingivalislipopolysaccharide as a possible link between cardiovascular disease and periodontitis. Free Radical Biology & Medicine. 2011;50(10):1336-1343.
Peschel T, Schonauer M, Thiele H, Anker SD, Schuler G, Niebauer J. Invasive assessment of bacterial endotoxin and inflammatory cytokines in patients with acute heart failure. European Journal of Heart Failure. 2003;5(5):609-614.
Wang Z, Klipfell E, Bennett BJ, Koeth R, Levison BS, Dugar B, et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature. 2011;472(7341):57-63.
Spencer MD, Hamp TJ, Reid RW, Fischer LM, Zeisel SH, Fodor AA. Association between composition of the human gastrointestinal microbiome and development of fatty liver with choline deficiency. Gastroenterology. 2011;140(3):976-986.
Barrett EL, Kwan HS. Bacterial reduction of trimethylamine oxide. Annual Review of Microbiology. 1985;39:131-149.
Zhang AQ, Mitchell SC, Smith RL. Dietary precursors of trimethylamine in man: a pilot study. Food and Chemical Toxicology: an International Journal published for the British Industrial Biological Research Association. 1999;37(5):515-520.
Bain MA, Fornasini G, Evans AM. Trimethylamine: metabolic, pharmacokinetic and safety aspects. Current Drug Metabolism. 2005;6(3):227-240.
Tang WH, Wang Z, Levison BS, Koeth RA, Britt EB, Fu X, et al. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. The New England Journal of Medicine. 2013;368(17):1575-1584.
Koeth RA, Wang Z, Levison BS, Buffa JA, Org E, Sheehy BT, et al. Intestinal microbiota metabolism of l-carnitine, a nutrient in red meat, promotes atherosclerosis. Nature Medicine. 2013;19(5):576-585.
Dumas ME, Barton RH, Toye A, Cloarec O, Blancher C, Rothwell A, et al. Metabolic profiling reveals a contribution of gut microbiota to fatty liver phenotype in insulin-resistant mice. Proceedings of the National Academy of Sciences of the United States of America. 2006;103(33):12511-12516.
Goldsmith JR, Sartor RB. The role of diet on intestinal microbiota metabolism: downstream impacts on host immune function and health, and therapeutic implications. Journal of Gastroenterology. 2014;49(5):785-798.
Simbaqueba C, Shrestha K, Patarroyo M, Troughton RW, Borowski AG, Klein AL, et al. Prognostic implications of relative hypochromia in ambulatory patients with chronic systolic heart failure. Congestive Heart Failure. 2013;19(4):180-185.
Krack A, Richartz BM, Gastmann A, Greim K, Lotze U, Anker SD, et al. Studies on intragastric PCO2 at rest and during exercise as a marker of intestinal perfusion in patients with chronic heart failure. European Journal of Heart Failure. 2004;6(4):403-407.
Sandek A, Bjarnason I, Volk HD, Crane R, Meddings JB, Niebauer J, et al. Studies on bacterial endotoxin and intestinal absorption function in patients with chronic heart failure. International Journal of Cardiology. 2012;157(1):80-85.
Sandek A, Bauditz J, Swidsinski A, Buhner S, Weber-Eibel J, von Haehling S, et al. Altered intestinal function in patients with chronic heart failure. Journal of the American College of Cardiology. 2007;50(16):1561-1569.
Alverdy J, Zaborina O, Wu L. The impact of stress and nutrition on bacterial-host interactions at the intestinal epithelial surface. Current Opinion in Clinical Nutrition and Metabolic Care. 2005;8(2):205-209.
Gan XT, Ettinger G, Huang CX, Burton JP, Haist JV, Rajapurohitam V, et al. Probiotic administration attenuates myocardial hypertrophy and heart failure after myocardial infarction in the rat. Circulation Heart Failure. 2014;7(3):491-499.
Koren O, Spor A, Felin J, Fak F, Stombaugh J, Tremaroli V, et al. Human oral, gut, and plaque microbiota in patients with atherosclerosis. Proceedings of the National Academy of Sciences of the United States of America. 2011;108 (Suppl. 1):4592-4598.
Amar J, Serino M, Lange C, Chabo C, Iacovoni J, Mondot S, et al. Involvement of tissue bacteria in the onset of diabetes in humans: evidence for a concept. Diabetologia. 2011;54(12):3055-3061.
Karlsson FH, Fak F, Nookaew I, Tremaroli V, Fagerberg B, Petranovic D, et al. Symptomatic atherosclerosis is associated with an altered gut metagenome. Nature Communications. 2012;3:1245.
Liu S, Bennett DC, Tun HM, Kim JE, Cheng KM, Zhang H, et al. The effect of diet and host genotype on ceca microbiota of Japanese quail fed a cholesterol enriched diet. Frontiers in Microbiology. 2015;6:1092.
Turnbaugh PJ, Backhed F, Fulton L, Gordon JI. Diet-induced obesity is linked to marked but reversible alterations in the mouse distal gut microbiome. Cell Host & Microbe. 2008;3(4):213-223.
Pryde SE, Duncan SH, Hold GL, Stewart CS, Flint HJ. The microbiology of butyrate formation in the human colon. FEMS Microbiology Letters. 2002;217(2):133-139.
Greer RL, Morgun A, Shulzhenko N. Bridging immunity and lipid metabolism by gut microbiota. The Journal of Allergy and Clinical Immunology. 2013;132(2):253-262; quiz 63.
Biddle A, Stewart L, Blanchard J, Leschine S. Untangling the genetic basis of fibrolytic specialization by Lachnospiraceae and Ruminococcaceae in diverse gut communities. Diversity. 2013;5(3):627-640.
Macdonald IA, Bokkenheuser VD, Winter J, McLernon AM, Mosbach EH. Degradation of steroids in the human gut. Journal of Lipid Research. 1983;24(6):675-700.
Stepankova R, Tonar Z, Bartova J, Nedorost L, Rossman P, Poledne R, et al. Absence of microbiota (germ-free conditions) accelerates the atherosclerosis in ApoE-deficient mice fed standard low cholesterol diet. Journal of Atherosclerosis and Thrombosis. 2010;17(8):796-804.
Sekimoto H, Goto Y, Goto Y, Naito C, Yasugi T, Okido M, et al. Changes of serum total cholesterol and triglyceride levels in normal subjects in Japan in the past twenty years. Research committee on familial hyperlipidemia in Japan. Japanese Circulation Journal. 1983;47(12):1351-1358.
Li L, Baumann CA, Meling DD, Sell JL, Beitz DC. Effect of orally administered Eubacterium coprostanoligenesATCC 51222 on plasma cholesterol concentration in laying hens. Poultry Science. 1996;75(6):743-745.
Liu S, Tun HM, Bennett DC, Leung FC, Zhang H, Cheng KM. Interaction of genotype and diet on atherosclerosis development and bacterial dysbiosis in the small intestine of Japanese quail fed a cholesterol enriched diet. Frontiers in Microbiology. 2016 (Manuscript in prep).
Jones ML, Martoni CJ, Prakash S. Cholesterol lowering and inhibition of sterol absorption by Lactobacillus reuteriNCIMB 30242: a randomized controlled trial. European Journal of Clinical Nutrition. 2012;66(11):1234-1241.
Hofker MH, van Vlijmen BJ, Havekes LM. Transgenic mouse models to study the role of APOE in hyperlipidemia and atherosclerosis. Atherosclerosis. 1998;137(1):1-11.
Molacek J, Treska V, Kobr J, Certik B, Skalicky T, Kuntscher V, et al. Optimization of the model of abdominal aortic aneurysm--experiment in an animal model. Journal of Vascular Research. 2009;46(1):1-5.
Gerrity RG, Natarajan R, Nadler JL, Kimsey T. Diabetes-induced accelerated atherosclerosis in swine. Diabetes. 2001;50(7):1654-1665.
Granada JF, Kaluza GL, Wilensky RL, Biedermann BC, Schwartz RS, Falk E. Porcine models of coronary atherosclerosis and vulnerable plaque for imaging and interventional research. EuroIntervention: Journal of EuroPCR in Collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology. 2009;5(1):140-148.
Hamada N, Miyata M, Eto H, Shirasawa T, Akasaki Y, Nagaki A, et al. Tacrolimus-eluting stent inhibits neointimal hyperplasia via calcineurin/NFAT signaling in porcine coronary artery model. Atherosclerosis. 2010;208(1):97-103.
Lavine SJ. Effect of changes in contractility on the index of myocardial performance in the dysfunctional left ventricle. Cardiovascular Ultrasound. 2006;4:45.
Shiomi M, Yamada S, Matsukawa A, Itabe H, Ito T. Invasion of atheromatous plaques into tunica media causes coronary outward remodeling in WHHLMI rabbits. Atherosclerosis. 2008;198(2):287-293.
Fernandez ML, Volek JS. Guinea pigs: a suitable animal model to study lipoprotein metabolism, atherosclerosis and inflammation. Nutrition & Metabolism. 2006;3:17.
Anderson JL, Ashwell CM, Smith SC, Shine R, Smith EC, Taylor RL, Jr. Atherosclerosis-susceptible and atherosclerosis-resistant pigeon aortic cells express different genes in vivo. Poultry Science. 2013;92(10):2668-2680.
Chapman KP, Stafford WW, Day CE. Produced by selective breeding of Japanese quail animal model for experimental atherosclerosis. Advances in Experimental Medicine and Biology. 1976;67(00):347-356.
Shih JC, Pullman EP, Kao KJ. Genetic selection, general characterization, and histology of atherosclerosis-susceptible and -resistant Japanese quail. Atherosclerosis. 1983;49(1):41-53.
Haust MD. The natural history of human atherosclerotic lesions. In: Moore S, editor. Vascular Injury and Atherosclerosis. New York: Marcell Dekker; 1981. p. 1-23.
Walsh CJ, Guinane CM, O'Toole PW, Cotter PD. Beneficial modulation of the gut microbiota. FEBS Letters. 2014;588(22):4120-4130.
Rajpal DK, Brown JR. Modulating the human gut microbiome as an emerging therapeutic paradigm. Science Progress. 2013;96(Pt 3):224-236.
Cammarota G, Ianiro G, Gasbarrini A. Fecal microbiota transplantation for the treatment of Clostridium difficileinfection: a systematic review. Journal of Clinical Gastroenterology. 2014;48(8):693-702.
David LA, Maurice CF, Carmody RN, Gootenberg DB, Button JE, Wolfe BE, et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature. 2014;505(7484):559-563.
Cannon CP, Braunwald E, McCabe CH, Grayston JT, Muhlestein B, Giugliano RP, et al. Antibiotic treatment of Chlamydia pneumoniaeafter acute coronary syndrome. The New England Journal of Medicine. 2005;352(16):1646-1654.
Conraads VM, Jorens PG, De Clerck LS, Van Saene HK, Ieven MM, Bosmans JM, et al. Selective intestinal decontamination in advanced chronic heart failure: a pilot trial. European Journal of Heart Failure. 2004;6(4):483-491.
de Vrese M, Schrezenmeir J. Probiotics, prebiotics, and synbiotics. Advances in Biochemical Engineering/Biotechnology. 2008;111:1-66.
Martin FP, Wang Y, Sprenger N, Yap IK, Lundstedt T, Lek P, et al. Probiotic modulation of symbiotic gut microbial-host metabolic interactions in a humanized microbiome mouse model. Molecular Systems Biology. 2008;4:157.
Costanza AC, Moscavitch SD, Faria Neto HC, Mesquita ET. Probiotic therapy with Saccharomyces boulardiifor heart failure patients: a randomized, double-blind, placebo-controlled pilot trial. International Journal of Cardiology. 2015;179:348-350.
Kumar M, Nagpal R, Kumar R, Hemalatha R, Verma V, Kumar A, et al. Cholesterol-lowering probiotics as potential biotherapeutics for metabolic diseases. Experimental Diabetes Research. 2012;2012:902917.
Kumar H, Salminen S, Verhagen H, Rowland I, Heimbach J, Banares S, et al. Novel probiotics and prebiotics: road to the market. Current Opinion in Biotechnology. 2015;32:99-103.
Mosinska P, Storr M, Fichna J. The role of AST-120 and protein-bound uremic toxins in irritable bowel syndrome: a therapeutic perspective. Therapeutic Advances in Gastroenterology. 2015;8(5):278-284.
Lekawanvijit S, Kompa AR, Manabe M, Wang BH, Langham RG, Nishijima F, et al. Chronic kidney disease-induced cardiac fibrosis is ameliorated by reducing circulating levels of a non-dialysable uremic toxin, indoxyl sulfate. PLoS One. 2012;7(7):e41281.
Fujii H, Nishijima F, Goto S, Sugano M, Yamato H, Kitazawa R, et al. Oral charcoal adsorbent (AST-120) prevents progression of cardiac damage in chronic kidney disease through suppression of oxidative stress. Nephrology, Dialysis, Transplantation: official publication of the European Dialysis and Transplant Association—European Renal Association. 2009;24(7):2089-2095.