Application Potential of Probiotics in Acute Myocardial Infarction

Abstract

Myocardial infarction (MI) is associated with high rates of death and disability, and is the main cause of death due to cardiovascular disease and the most frequent cause of death in the developed world. Recent studies have shown that, in addition to traditional risk factors, such as hypertension, diabetes, hyperlipidemia, obesity, smoking and the environment, the gut microbiota plays an important role in MI development and progression. The discovery of an enteric-cardioid axis provides a new route to examine the complex mechanism of MI and has become a research hotspot in recent years. Experiments have suggested that probiotics decrease ischemia/reperfusion injury and inflammation, regulate lipid metabolism and decrease the myocardial infarction area. In this review, we discuss the relationship between probiotics and MI as well as potential underlying mechanisms, to provide new ideas for the prevention and treatment of MI.

Main article text

Introduction

Cardiovascular disease (CVD) is the leading cause of death worldwide, and myocardial infarction (MI) significantly contributes to CVD mortality [1, 2]. Risk factors such as hypertension, diabetes, hyperlipidemia, obesity, smoking, the environment and modern lifestyle changes are involved in the occurrence and development of acute myocardial infarction (AMI). Recent studies have found that gut microorganisms play important roles in the development and progression of CVDs [3, 4]. Millions of species of gut microorganisms are found in the human body, and they carry 100-fold more genes than the host genome [5, 6]. The composition of the gut microbiota is affected by host genetics, diet, hygiene and lifestyle. The destruction of the gut microbiota can trigger MI and lead to poor prognosis [7]; consequently, the gut microbiota is a potential therapeutic target for MI [8]. The possibility that certain microorganisms might be beneficial for the human body was first suggested in the early 1900s by Elie Metchnikoff, a Russian scientist who earned a Nobel Prize in 1908 for his work on immunity [9]. Since then, probiotics have been a major research topic. Studies have found that probiotics have anti-inflammatory, antioxidant, anti-apoptotic and anti-atherosclerotic effects; decrease ischemia/reperfusion (I/R) injury; and increase heart survival rates [10–13]. In this review, we discuss the relationship between probiotics and MI, as well as potential underlying mechanisms, to provide new ideas for the prevention and treatment of MI.

What are Probiotics?

Probiotics, which were first introduced in 1965 by Lilly and Stillwell, are live microorganisms that confer health benefit on hosts when administered in adequate amounts [9]. They can be formulated into many types of products, including foods, drugs and dietary supplements. Lactobacillus and Bifidobacterium are the most commonly used probiotics, but the yeast Enterococcus and Streptococcus are also used. After entering the intestinal tract, probiotics produce specific metabolites, such as short-chain fatty acids, hydrogen peroxide, diacetyl and bacteritin. Through their own growth and metabolism and interaction with the host flora, probiotics inhibit the growth of pathogenic bacteria [14, 15]. Probiotics are beneficial bacteria that can improve the gastrointestinal microenvironment, enhance immune function and improve the intestinal barrier [16–18]. Given the importance of probiotics to body health, probiotics have become a research hotspot.

Probiotics and Myocardial Infarction Risk Factors

Probiotics and Dyslipidemia

Dyslipidemia refers to the abnormal increase in lipid levels, represented by total cholesterol (TC), triglycerides and low-density lipoprotein cholesterol (LDL-C) in fat metabolism. Abnormal lipid metabolism is the most important risk factor for atherosclerosis, the main cause of the occurrence and development of CVDs. When serum TC level increases by 1 mmol/L above the upper limit of the reference range, the risk of coronary heart disease increases by 35%; in contrast the risk of cardiovascular and cerebrovascular diseases decreases by 2% to 3% when the serum TC level decreases by 1% [19]. In the 1970s, Mann [20] discovered that people who regularly eat fermented milk products have lower serum cholesterol than those who do not. Nakamura et al. [21] have treated an obese mouse model with Lactobacillus for 12 weeks. Treatment with Lactobacillus decreased the levels of LDL-C and triglyceride in plasma, significantly decreased the atherosclerosis index and increased the high-density lipoprotein cholesterol (HDL-C) level. Sheraji et al. [22] have shown that the levels of TC, LDL-C and malondialdehyde in rats fed a high-fat diet with probiotics for 8 weeks are lower than those in rats fed a high-fat diet alone. Kim et al. [23] have shown that a probiotic mixture effectively decreases TC, TG and LDL-C in hypercholesterolemic rats. The results of a randomized controlled trial of 38 children with dyslipidemia have indicated significantly lower total cholesterol and low density lipoprotein (LDL) after treatment with probiotics than placebo [24]. A clinical trial by Nakamura has demonstrated significantly lower triglyceride, TC and LDL-C in the Lactobacillus group than the placebo group, thus suggesting that the consumption of foods containing Lactobacillus amyloidum decreases body fat and prevents metabolic syndrome [25]. Rajkumar et al. [26] have evaluated the effects of probiotics on healthy people and have found that probiotic treatment, compared with placebo, results in significantly lower TC, LDL-C and triglycerides, but higher HDL-C. A meta-analysis of randomized controlled trials conducted to evaluate the effects of probiotics on lipid profiles has reported a mean net change of −8.40 mg/dL (95% CI −13.63, −3.61, P=0.02) for TC, −6.63 mg/dL (95% CI −10.63, −2.63, P=0.01) for LDL-C, 0.59 mg/dL (95% CI −0.92, 2.09, P=0.84) for HDL-C and −1.32 mg/dL (95% CI −6.49, 3.85, P=0.51) for triglycerides in 606 normal/hypercholesterolemic patients after probiotic supplementation. These results suggest that probiotics significantly lower serum TC and LDL-C levels, thus decreasing the risk factors for coronary heart disease [27].

Probiotics and Hypertension

Hypertension is a major risk factor for cardiovascular events. Approximately one-quarter of the world’s population has hypertension, and 41% of CVD-associated deaths are associated with hypertension [28]. Despite the wide variety of antihypertensive drugs, less than half of treated patients with hypertension reach the currently recommended blood pressure targets. Recently, the relationship between the intestinal microflora and the renal-cardiovascular system has enabled a unique approach for the treatment of hypertension. Probiotics such as Lactobacillus and Bifidobacterium regulate the renin-angiotensin system by producing angiotensin-converting enzyme inhibitory peptides, short-chain fatty acids, conjugated linoleic acid and γ-aminobutyric acid, which have antihypertensive effects [29, 30]. Yap et al. [31] have administered spontaneously hypertensive rats the Lactobacillus casei strain C1 via oral gavage for 8 weeks. The weekly systolic blood pressure, mean arterial pressure, diastolic blood pressure and aortic reactivity function markedly improved, the level of malondialdehyde decreased, and the levels of glutathione and nitric oxide increased, thus suggesting that the bacterium exerted vascular protection through antioxidative functions. Lactobacillus is a promising alternative for hypertension improvement. Kefir treatment for 60 days has been found to attenuate high blood pressure and tachycardia by approximately 15% in spontaneously hypertensive rats [32]. A meta-analysis [33] including nine parallel randomized controlled trials with 543 participants has found that probiotic consumption significantly decreased systolic blood pressure by −3.56 mmHg (−6.46 to −0.66) and diastolic blood pressure by −2.38 mmHg (−2.38 to −0.93) below control group levels. Treatments with multiple species, rather than single species of probiotics, were associated with greater decreases, particularly in diastolic blood pressure. The results suggest that consuming probiotics may modestly decrease blood pressure, and the effects may potentially be greater when baseline blood pressure is elevated, multiple species of probiotics are consumed, the duration of intervention is ≥8 weeks, or the daily consumption dose is ≥10¹¹ colony-forming units.

Probiotics and Obesity

Obesity is a highly prevalent human health problem. Hypertension, dyslipidemia and insulin resistance are all associated with obesity and increase the risk of CVD. Obesity, which results from an imbalance between energy intake and expenditure, is regulated by complex and coordinated mechanisms [34]. Recent studies have shown that the intestinal microflora may play an important role in regulating body weight and may be associated with obesity in some people [35–37]. Because the gut microbiota clearly differs between obese and lean individuals, selective modulation of the gut microbiota with probiotics has emerged as a potential therapy for the control of weight gain in people with obesity or susceptibility to obesity [38, 39]. An animal study has suggested that oral administration of probiotics may attenuate cardiomyocyte fibrosis and cardiac hypertrophy, and the autophagy-signaling pathway in obese rats [40]. Everard et al. have administered S. boulardii daily by oral gavage to leptin-resistant obese and type 2 diabetic mice for 4 weeks and observed a decrease in body weight, fat mass, hepatic steatosis, and inflammatory tone [41]. Obesity promotes the remodeling of adipose tissue and produces a systemic pro-inflammatory state, which is a major risk factor for CVD. The results of a randomized, double-blind trial involving overweight or obese women have shown that probiotic supplementation effectively decreases abdominal obesity and increases antioxidant enzyme activity [42]. A randomized controlled trial in 90 volunteers randomized to receive a placebo, low-dose Lactobacillus gasseri BNR or high-dose BNR for 12 weeks has reported significantly less visceral adipose tissue in the BNR-H group than the placebo group. Waist circumferences significantly decreased in both the BNR-L and BNL-H groups with respect to baseline values. These findings suggest that daily consumption of BNR17 may contribute to decreased visceral fat mass in obese adults [43].

Probiotics and Diabetes

Cardiovascular morbidity and mortality are significantly elevated in patients with diabetes, thus increasing the risk of coronary heart disease. In the state of hyperglycemia, LDL is glycosylated and remains in the blood for long durations because of its low affinity for LDL receptors. The glycosylated LDL is oxidized to form small dense LDL, which is engulfed by macrophages; the macrophages then become foam cells and ultimately lead to atherosclerosis. Diabetes increases atherosclerotic plaque formation and thrombosis, thereby contributing to myocardial infarction. In recent years, data have shown that gut microorganisms are closely associated with the occurrence and development of metabolic diseases such as diabetes [44–46]. Lactobacillus GG has been found to significantly decrease blood hemoglobin A(1C) levels and increases glucose tolerance in rats with neonatally streptozotocin-induced diabetes; serum insulin levels were significantly higher in the Lactobacillus GG group than the control group 30 min after glucose loading [47]. Hsieh et al. [48] have shown that Lr263 administration significantly suppresses the elevation of serum glucose, insulin, leptin, C-peptide, glycated hemoglobin and liver injury markers and the alterations in lipid profiles induced by a high-fructose diet. Lr263 may be a promising therapeutic agent in treating type 2 diabetes, owing to its effectiveness in decreasing insulin resistance and hepatic steatosis in high-fructose-fed rats; thus, Lr263 may be a promising therapeutic agent for treating type 2 diabetes. Although the results of human experiments on probiotics vary, meta-analyses have shown that probiotics decrease fasting blood glucose, glycosylated hemoglobin and insulin resistance, and moderately improve host blood glucose [49, 50]. A meta-analysis of 17 randomized controlled trials [50] has indicated that, compared with placebo, probiotic consumption significantly decreases fasting glucose (−0.31 mmol/L; 95% CI 0.56, 0.06), fasting plasma insulin (−1.29 μU/mL; 95% CI −2.17, −0.41) and homeostasis model assessment of insulin resistance (0.48; 95% CI −0.83, −0.13). Modification of the gut microbiota by probiotic supplementation may be a method for preventing and controlling hyperglycemia in clinical practice.

Probiotics and MI

Despite timely reperfusion treatment, the disability and fatality rates after AMI remain high. Determining how to further decrease the area of MI, prevent and delay the occurrence of heart failure, and maintain cardiac function will be very important to improve patient prognosis. The discovery of the gut-cardioid axis provides a new target for MI prevention and treatment.

Probiotics Decrease the Risk of MI

Diet plays a crucial role in the prevention and pathology of CVD [51]. Dietary improvements in the host intestinal microflora may be beneficial in the prevention and treatment of CVD [52]. Probiotics have been used safely in foods and dairy products for more than 100 years [53]. Recently, interest in probiotic use to prevent, mitigate or treat CVD has increased. Animal studies [54, 55] have shown that pretreatment with probiotics attenuates cardiac injury due to ischemia/reperfusion and improves cardiac function. Probiotic supplements may be a new option to decrease the risk of ischemic heart disease in the future. A meta-analysis of cohort studies in 385,122 participants has estimated the association of fermented dairy food intake with the risk of CVDs. Intake of fermented dairy foods is significantly associated with decreased MI risk (OR=0.82, 95% CI=0.76–0.89) [56].

Probiotics Decrease Myocardial Infarct Size

Metabolites derived from the intestinal microbiota are associated with the severity of MI [7]. Lam et al. [10] have fed probiotic Lactobacillus plantarum 299v for 14 days to rats with I/R injury and observed a decrease in circulating leptin levels by 41%, smaller myocardial infarcts (29% decrease) and greater recovery of postischemic mechanical function (23%).

Probiotics Delay the Progression of Heart Failure After Myocardial Infarction

Coronary artery occlusion can lead to different types of myocardial changes [57]. Myocardial necrosis and apoptosis caused by AMI can result in heart failure due to myocardial remodeling, myocardial thinning and ventricular aneurysm formation. Effective treatment of ventricular remodeling after AMI can prevent or delay the occurrence of heart failure and prolong life. Gan et al. [11] have randomly administered rats with coronary artery ligation either Lactobacillus rhamnosus GR-1 probiotics or placebo for 6 weeks. The left ventricular ejection fraction and fractional shortening were significantly preserved in the probiotic group. Probiotic treatment resulted in maintenance of taurine levels in the myocardium. Taurine inhibits ventricular myocyte hypertrophy induced by angiotensin II and improves left ventricular function in patients with heart failure, and is the most abundant amino acid in the heart [58]. A placebo-controlled randomized clinical study evaluating the effects of probiotics administration on attenuating cardiac remodeling in patients with MI [59] has indicated significant decreases in serum transforming growth factor beta (TGF-β) concentrations and trimethylamine N-oxide (TMAO) levels, which are biomarkers of cardiac remodeling, after Lactobacillus rhamnosus GG probiotic supplementation. The echocardiographic indices also showed greater improvements in the probiotic group than the control group. Probiotics may provide a potential treatment option for heart failure after MI.

Probiotics Ameliorate Depression-Like Symptoms After Myocardial Infarction

MI has a variety of health effects on surviving patients, and post-MI depressive symptoms are common, affecting approximately 15–30% of patients. The occurrence of AMI combined with depression not only affects patient quality of life but also further aggravates cardiomyocyte death, thus leading to a decline in cardiac function and possibly the occurrence of sudden cardiac death. Depression following myocardial infarction is a risk factor for recurrent non-fatal infarction and cardiac death [60–62]. Inflammation is associated with MI initiation, and the expression of inflammatory factors is highly correlated with the level of depression in patients with MI [63]. After MI, pro-inflammatory cytokines and angiotensin II-II in circulation promote the upregulation of angiotensin II-1 receptor signals and cytokines in the hypothalamic paraventricular nucleus, thus leading to neuroinflammatory responses. Even after peripheral inflammation subsides, neuroinflammation may persist [64]. Studies have shown that probiotics ameliorate depressive symptoms in patients with severe depressive disorder [65]. Trudeau et al. [66] have found that rats with Bifidobacterium longum treatment, compared with vehicle alone, spend more time socializing, learn more rapidly in passive avoidance tests and spend less time immobile in forced swim tests. Gilbert et al. [67] have observed depression-like behavior 2 weeks post-MI, which was attenuated with probiotic treatment. These results indicate that the administration of probiotics starting after the onset of reperfusion is beneficial by attenuating apoptosis in the limbic system and post-MI depression in rats. Combined treatment with Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 interferes with the development of post-MI depressive behavior and restores intestinal barrier integrity in MI rats [68]. A randomized and placebo-controlled clinical trial performed evaluating the effects of probiotic supplementation on symptoms of depression and quality of life in patients with AMI has reported a significantly lower total Beck Depression Inventory and higher mean quality of life score in the probiotic supplement group than the placebo group [69].

Mechanisms Associated with the Probiotic-Mediated Decrease in MI

The molecular mechanism through which probiotics decrease MI risk factors or events after MI is not completely clear, but may be associated with the regulation of lipid metabolism, anti-inflammatory, anti-oxidation, anti-apoptosis, and enhancement of host immunity and cellular immunity.

The anti-inflammatory effects of probiotics. A severe inflammatory reaction is induced after MI, which is involved in the repair of infarcted hearts, and is also associated with the enlargement of infarct foci and the aggravation of myocardial fibrosis, thus leading to poor ventricular remodeling. Studies have demonstrated that targeting leukocyte-mediated inflammation in reperfused MI markedly decreases infarct size, and thereby prevents the spread of ischemic cardiomyocyte injury [70–72]. Inflammation plays a key role in apoptosis and infarct size after reperfusion. A decrease in pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1) and interleukin-6 (IL-6), aids in decreasing MI size. Significant decreases in IL-1α, IL-1β, IL-6 and TNF-α have been observed in probiotic supplemented rats [73, 74]. Probiotics alter the balance between pro-inflammatory and anti-inflammatory cytokines, decrease the inflammatory response, and promote heart healing and remodeling after MI.

The antioxidant effect of probiotics. Oxidative stress refers to excessively high concentrations of reactive oxygen species (ROS) and reactive nitrogen free radicals generated in the body after exposure to adverse factors such as ischemia and hypoxia. The pathophysiological response of apoptosis and tissue damage caused by oxidative stress is considered a risk factor for MI [75]. Oxidative stress is the main consequence of I/R injury and the main cause of AMI. In MI, neutrophils or coronary vascular endothelial cells produce ROS, which induce the release of pro-inflammatory factors in I/R myocardium via NF-κB signaling [76]. Probiotics have antioxidant roles by scavenging ROS, increasing superoxide dismutase activity, and decreasing or preventing lipid peroxidation and ascorbic acid autooxidation [55, 77]. A clinical trial by Moludi et al. [69] has found greater increases in total antioxidant capacity and decreases in malondialdehyde in patients receiving probiotic supplementation rather than placebo.

The anti-atherosclerotic effect of probiotics. Atherosclerosis is a chronic metabolic disease that leads to atherosclerosis and secondary lesions due to abnormal accumulation of lipids and complex sugars in the inner arterial wall [78]. Atherosclerosis is the main pathological basis of MI. The role of the intestinal flora in the occurrence and development of atherosclerotic diseases has attracted increasing attention and has gradually been considered a potential target for the prevention and treatment of CVD [79]. Compared with vehicle treatment, Lactobacillus acidophilus ATCC 4356 treatment in ApoE(-/-) mice results in no changes in body weights and serum lipid profiles but smaller atherosclerotic lesion sizes in en face aorta [80]. Lactobacillus plantarum decreases serum TMAO levels and inhibits atherosclerosis caused by TMAO in mice [81]. Akkermansia muciniphila has been found to prevent and cure atherosclerotic lesion inflammation induced by a high sugar and high fat diet, decrease macrophage infiltration, decrease the expression of pro-inflammatory cytokines and chemokines, and significantly decrease endotoxemia, thus inhibiting the occurrence and development of atherosclerosis [82].

The anti-apoptosis effect of probiotics. Apoptosis is a spontaneous and programmed process of cell death under normal physiological or pathological conditions. Myocardial ischemia can cause cardiomyocyte death in the ischemic area and ischemic edge area, develop into MI, further aggravate cardiomyocyte death and eventually lead to heart failure. Cardiomyocyte apoptosis is a pathway of cardiomyocyte death in MI and is closely associated with ventricular remodeling after MI. Inhibition of cardiomyocyte apoptosis has beneficial effects in improving cardiac function. Girard et al. [13] have found that probiotics (Lactobacillus helveticus and Bifidobacterium longum in combination) decrease the Bax/Bcl-2 (pro-apoptotic/anti-apoptotic) ratio and caspase-3(pro-apoptotic) activity in the amygdala (lateral and medial) as well as the dentate gyrus, thus suggesting that probiotics, as a preventive therapy, decrease the predisposition to apoptosis in various cerebral regions after MI.

Conclusions

The discovery of the gut-heart axis has provided a new route to modulate MI risk factors and/or to decrease the extent of myocardial damage after a coronary event. Although many animal and clinical trials have demonstrated that many probiotics, such as Lactobacillus and Bifidobacterium, decrease inflammation and oxidation, and regulate lipid metabolism, understanding of the relationship between probiotics and MI remains incomplete. In addition, owing to individual differences, the types of probiotics, their intervention cycle and treatment doses, and their effects on intestinal flora and host metabolism also differ. To make probiotics more safe, stable, accurate and effective, and provide a more scientific and reliable basis for the clinical application of MI, more in-depth and systematic research and trials are needed in the future. Compared with traditional drugs for CVD, probiotics have milder effects. With the expanded marketing of probiotics in functional foods and health products, the combined application of probiotics with traditional cardiovascular drugs has great potential and broad prospects.

Acknowledgments

The authors thank all staff and participants in this study for their important contributions.

Funding

This research received no grant from any funding agency in the public, commercial or not-for-profit sectors

Conflicts of Interest

The authors declare no conflicts of interest.

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