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The Microbiome and Cardiac Transplantation: What We Know and What We Need to Know

Matthew R. Carazo, MD

Howard Eisen, MD
Drexel University College of Medicine
Philadelphia, PA, USA

The microbiome is everywhere? Literally, it is: on your skin, in your enteric system, in your blood, and throughout the literature. Our first encounter with the microbiome is in utero and during birth. My first cognizant encounter was as a fourth year medical student doing a GI rotation at HUP. My GI attending physician would one day be my Department Chair when I was on faculty at Temple. My GI fellow is presently my Department Chair at Drexel. These wise men presciently identified the potential importance of the microbiome that we encountered every morning in the endoscopy suite. They pointed out that there were vast numbers of bacteria, which produce important compounds (hello, Vitamin K), and when perturbed could be catastrophic (C. difficile colitis which back then in the early 80's was an uncommon disease.) The role of microbes living symbiotically within the human body has become a focus of attention within the medical community. As more and more studies have shown, an appreciation of the diversity of microbes within the gastrointestinal tract, skin, lungs, and genitourinary tract has grown, and research has concentrated on the role of these organisms and their functions within various organ systems. Because of the complicated role food plays as one of the largest sources of environmental exposures to the body, more researchers have begun to examine the complex interplay between the intestinal microbiome and cardiovascular health.

The intestinal tract is host to over 100 trillion microbial cells, far exceeding the total number of human host cells [1]. These microbes are then influenced by diet, lifestyle, exposure to antibiotics, and genetic background and are responsible for fermenting non-digestible carbohydrates into short-chain fatty acids, which are then coupled to receptors that modulate energy use. Additionally, the microbiota stimulates innate immune molecules, which then trigger inflammatory pathways. Studies have shown in both animal and human models that gut microbiota are linked in the pathogenesis of obesity and type II diabetes, and increasingly, a relationship between atherosclerosis and microbes is being established [2]. Chronic inflammation and obesity are associated with hypercoaguability and a reduction in fibrinolysis, and enhanced bacterial translocation across the intestinal membrane barriers has been shown to activate inflammatory and coagulation cascades [2, 3]. Repeated exposure to bacterial endotoxins in mice has resulted in dyslipidemia, hyperglycemia, hepatic insulin resistance, obesity, hyperinsulinemia, and macrophage infiltration of adipose tissue [4]. Recent studies have also shown that atherosclerotic plaques host their own microbiota, presumably from bacterial gut translocation [5].

Prebiotics, which are non-digestible food substrates that selectively stimulate growth from one or more limited genera/species, have been demonstrated to lower total cholesterol, triglyceride, and total cholesterol:HDL levels in human subjects as compared to controls [5, 6]. The prebiotics are thought to form gel-like emulsion complexes with dietary fats, which prevent pancreatic lipase from hydrolyzing them [7]. Supplementation with oligofructose, a prebiotic, is presumed to render bile acids and cholesterol insoluble [8]. Furthermore, probiotics, which are live organisms that are known to confer a health benefit to the host and include such genera as Lactobacillus and Bifidobacterium, promote additional breakdown of bile acids into amino acid conjugates, and when these conjugates are excreted, cholesterol is then broken down to replace the bile acids, eventually leading to lower serum cholesterol levels [9-11].

Probiotics may also have a cardioprotective role too as demonstrated by Lam et al, who showed that administering a solution with Lactobacillus plantarum 299v to rats 24 hours before subjection to ischemia and reperfusion ultimately demonstrated a reduction in infarct size and improvement in post-infarct left ventricular function [12]. Addition of Lactobacillus rhamnosus GR-1 to drinking water for rats subjected to coronary artery occlusion resulted in attenuation of left ventricular hypertrophy and improvement in systolic and diastolic function on echocardiography [13].

Dietary factors, including carnitine and phosphotidylcholine (PC), both of which are found in red meat, are converted to trimethylamine (TMA) by intestinal microbes, and TMA is then transported to the liver, where it is converted into trimethylamine-N-oxide (TMAO), which has been shown to escalate formation of atherosclerosis in mice. Other PC metabolites, including choline and betaine as well as TMAO, have been associated with decreased reverse cholesterol transport, increased forward cholesterol transport, and increased risk of cardiac events, such as myocardial infarction, stroke, and death [14]. TMAO levels have also been found to be elevated in patients with chronic heart failure, and higher levels have been linked with severity of symptoms and survival [15, 16]. In chronic heart failure, reductions in cardiac output and systemic venous congestion within the mesenteric vascular system may result in repeated episodes of microischemia to the intestinal villi, creating an environment in which bacteria may translocate into the bloodstream [17].

Although the association between intestinal microbes and cardiovascular disease is increasing, there is a paucity of data in patients who have undergone cardiac transplantation. However, in the liver transplant patient, immunosuppressive therapy, in conjunction with ischemia-reperfusion injury and altered nutritional status, has been associated with damaged intestinal barriers, changes in the innate immune response, alteration of gut microbiota with proliferation of pathogenic organisms, and intestinal bacterial translocation, all of which affect graft failure, early infection, and mortality [18]. A decrease in the overall diversity of intestinal microbes has been linked to poorer clinical outcome post-transplant in patients receiving liver, kidney, and hematopoietic stem cell transplantation [19]. Increased gut colonization by pathogenic species has been shown in rats with acute cellular rejection after liver transplantation [20]. Tacrolimus and mammalian target of rapamycin inhibitor use after liver transplantation is associated with increased intestinal permeability, bacterial endotoxin levels, inflammation, and mortality [21-23].

Given the direct exposure to the external environment as well as the teeming upper respiratory tract, the transplanted lung is particularly susceptible to alterations in its microbiome. Bronchoalveolar lavage (BAL) samples taken from lung transplant subjects showed a 44-fold increase in DNA from potentially pathogenic bacteria when compared to samples from control subjects. Additionally, BAL from healthy volunteers showed little fungal DNA, mainly comprised of environmental organisms, while BAL from transplant subjects contained predominantly pathogens, including Candida and Aspergillus [24]. The overall diversity of microbes is decreased in lung transplant recipients when compared to non-transplant controls [25]. The role of diminished microbial diversity, especially with predominance of potential pathogenic organisms, may influence adaptive and innate immune responses to the lung microbiome.

Thus, further investigation into the microbiota of cardiac transplantation patients is necessary. The role of intestinal flora and innate immunity, especially with regard to donor-specific molecules, needs to be elucidated. Given that microbial environments vary between geographic regions, the microbiome of donors may impact the cellular response of the recipient in the settings of acute and chronic rejection. Co-morbidities, such as liver or renal failure, may also alter hormonal and immunological responses from the microbiome. Immunosuppressive agents and their pharmacokinetics may become modified as a result of microbial influences. The viral component of the microbiome has been shown to be influenced by the regimens of antiviral medications and immunusuppressants following transplant. The virome is a sensitive marker related to drug dosage as a similar composition of viral DNA is found in blood samples taken from healthy, non-transplanted subjects and transplant subjects with minimal drug exposure. In contrast, those compositions are markedly distinct from samples taken from transplant subjects with heavy drug exposure. Additionally, the total viral load increases after onset of immunosuppressive therapy, especially with respect to anelloviridae, a ubiquitous family of viruses that cause chronic human infections but have yet to be associated with specific pathology [26]. The link between oral, intestinal, pulmonary, genitourinary, and cutaneous organisms and cardiovascular health is not well understood. The role of the microbiome in cardiac pathology is fertile for new and exciting clinical research. ■

Disclosure Statement: The authors have no conflicts of interest to disclose.


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