Probiotics and Its Relationship with the Cardiovascular System

3.1. Obesity

Obesity, which causes a low-grade inflammation, is a risk factor for cardiovascular disease, diabetes, dyslipidemia, premature death, hepatobiliary disease, and several cancers. There is an estimate of 1.7 billion people in the world that are overweight. Obese individuals tend to have an altered composition of intestinal microbiota, which suggest that intestinal microbiocenosis can be considered the environmental factor that creates the development of obesity [5]. Some of the effects of altered bacteria composition in the gut is linked to obesity due to several changes such as downregulated activity of FIAF and AMK, impaired production of SCFAs, increased inflammation, altered LPS-endocannabinoid (eCB) system regulatory loops, and bile acid metabolism [5]. The cause of the alteration is believed to be linked through the host’s diet. An example of this is that there was a reduction in Lactobacillus and Bifidobacterium and was observed in mice when they consumed high-fat diets [5]. This change of environment is the basis of studies that have shown that gut microbiota plays a role in energy homeostasis and bodyweight, therefore affecting the pathophysiology of obesity [5, 18].

In obese individuals, the different microorganism environment is believed to affect adiposity and alter the regulation to fat storage [7]. Insulin-type fructan affects the gut ecology and stimulates immune cells leading to a decrease in the weight gain and fat mass in obese individuals [7]. In a meta-analysis, several studies found that there was an increased prevalence of Firmicutes shown with obesity phenotypes. These bacteria interfere in a negative relation with metabolism and insulin sensitivity [26]. Probiotics, while resulting in more subtle effects in humans versus mice studies, are now being studied as a way to modulate gut microbiota in relation to obesity [20]. This is because certain traits in probiotic cultures such as exopolysaccharides, CLA, and GABA production were found to have a positive effect on host lipid metabolism and gut microbial composition [8].

An increased number of Lachnospiraceae family in obese female microbiota were altered when probiotics containing L. rhamnosus CGMCC1.3724 (which reduces Lachnospiraceae family) were administered along with an energy-strict diet [38]. However, the probiotics that were related to fat mass in Ref. [38] also caused a decrease of leptin levels, which may lead to a need for the supplementation of leptin in order to maintain weight loss. Probiotics and weight loss have also been linked to a decrease in ghrelin, which could assist in maintaining the weight loss even with the loss of leptin [41]. When L. gasseri strain was given in fermented milk for 12 weeks, there was a decrease in abdominal visceral fat in adults with large visceral fat areas [18]. Supporting this, there have been other studies that when looked at the outcome of probiotic consumption, there was a decrease in both body mass index (BMI) and waist circumferences [13]. However, those were a limited number of studies, and additional studies are required, including those that will observe the effect of probiotics on energy balance-related hormones.

In multi-strain probiotic therapies, with 8 weeks of treatment, obese individuals showed a decreased weight, waist circumference, and serum cholesterol levels. This study also supported the idea that probiotics caused results not only by their own metabolism but through probiotic alteration of the gut microbe with an increase of L. plantarum population and other Gram-negative bacteria [20]. When prebiotics were added, there was control of overexpression of several host genes that have been known to be related to both adiposity and inflammation [27]. However, the altered level in gut microbe with one probiotic only had a subtle effect, and more studies are necessary to understand if and what probiotics provide a change to obese individual’s gut microbe.

Gut bacteria also play a role in obesity through the regulation of inflammation. The relation between low-grade systemic inflammation and obesity is weakened through peptides produced in the gut. These peptides’ synthesis is affected by the composition of gut microbiota [7]. An example of this is the serum amyloid A3 protein where the expression in adipose tissue is regulated by gut microbiota [7]. Any alteration to the gut microbiota could then also potentially play a role in body weight due to intestinal microbiota effects on adiposity and the regulation of fat storages.

3.2. Diabetes

Having diabetes or having the risk of diabetes is often associated with a higher risk for cardiovascular disease. This is because of a compensatory action resulting in hyperinsulinemia which leads to a variety of metabolic abnormalities. Individuals who have diabetes were found to have altered intestinal microbiota which can cause increased adiposity, B-cell dysfunction, metabolic endotoxemia, systemic inflammation, and oxidative stress related to their disease. SCFA is an important function in type 2 diabetes mellitus (T2DM); however, bacteria producing SCFA numbers are lower in diabetic individual [7]. Probiotics may offer a beneficial therapy for diabetic patients through increasing SCFA and other methods.

Oral supplements, which contained viable and freeze-dried stains, were found to reduce fasting plasma glucose when compared to a placebo group. Fermented food was also noted to not only aid in the prevention of diabetes but also cause favorable changes in those already diagnosed with diabetes [6]. This could be due to some probiotics delaying the glucose intolerance and hyperglycemia state in individuals. For those with diabetes, some probiotics in fermented food decrease insulin requirements and could increase insulin sensitivity for non-diabetics [6].

Diabetes has a connection to long-term inflammation. This is due to the consumption of high fats and high fructose which causes chronic inflammation leading to the induction of insulin resistance (IR) and disruption of gut flora. This is supported by studies, which have found that certain diets, for example, high-fat diets, tend to increase lipopolysaccharide (LPS) contained in gut microbiota which leads to a decrease of Bifidobacteria. This leads to an inflammation state which may be associated to insulin resistance and weight gain [1]. Different probiotics have differential immune pro- or anti-inflammatory action through the attenuation of nuclear factor kappa B (NF-kB) [4]. Lactobacillus is a lactic acid bacteria that contains immune stimulating properties [28]. Probiotics, L. reuteri, and L. plantarum have anti-inflammatory and antioxidant effects which can aid in the management of diabetes [9]. For example, C-reactive protein (CRP), an inflammation marker, is noted to decrease when these probiotic supplements are used [13].

In a meta-analysis, there was no statistically significant glucose-lowering effect of probiotics when combined with prebiotics [1]. However, prebiotics may affect the inflammation state due to prebiotics having immunomodulatory benefits. In a study, prebiotics were found to alleviate chronic inflammation, which could lower the risk of development of cardiovascular disease and diabetes [2]. Probiotics may even possibly assist in the prevention of diabetes through bacterial translocation to mesenteric adipose tissue. This is mediated through acetate production and an increase in gut epithelial integrity [26].

Hyperglycemia, which is a property of diabetes, is a term given when a person has continuous high-fasting blood glucose (>6.1) and is associated with different diseases, the main one being diabetes mellitus [1]. The first line of treatment is proper nutrition and physical activity [1]. Probiotic supplements along with prebiotics were found to improve the hyperglycemia state. When multi-strain probiotics along with symbiotic supplements were provided to individuals in a hyperglycemia state as their baseline, there was an improvement in their blood glucose level (BGL) [1]. Glucose tolerance and increased satiety with weight loss were found when individuals were administered OFS which lead to Bifidobacterium and endotoxin levels to be normalized. Butyrate, which has properties of propionate that can lower blood glucose, is produced by several bacteria [4]. Other studies found that with a symbiotic shake of L. acidophilus, Bifidobacterium and L. rhamnosus caused a 38% decrease in blood glucose levels for patients with T2DM. Though these studies demonstrate that supplementation with probiotics with symbiotic may help in the control of hyperglycemia and T2DM, larger studies are needed to confirm. The glucose-lowering effect is due to the metabolites of these bacteria which was shown to affect biological signaling pathways, modulated genes involved in ubiquitination and proteasome process, and altered autonomic nerve activity [1]. It is also vital to note that probiotics or synbiotic alone did not cause a significant reduction in fasting blood glucose levels.

3.3. Hypercholesterolemia

Cardiovascular disease, affecting both blood vessels and/or heart, usually is the result of hypercholesterolemia and dyslipidemia. There have not been direct studies that compare the effect of prebiotic intake on cardiovascular health; however, there has been an observation on the serum lipid profiles, which all have an effect on CV [2]. These experiments have observed the effect of probiotics and/or prebiotics both in vitro and in vivo on lowering cholesterol [7]. In order to use probiotics to help lower cholesterol, the probiotics adhesion property to the human intestinal epithelial cells is a critical characteristic that must be considered [14]. This characteristic is to ensure that there is extended probiotic transit time in the gastrointestinal trace which was found to cause cholesterol-lowering effects in vivo.

Studies have shown a lower low-density lipoprotein and total cholesterol, along with increases in high-density lipoprotein cholesterol, a reduction in systolic blood pressure (SBP), increases in antioxidant activity, and influences on leptin regulation as a result of probiotics [9]. This is done through an enzyme called bile salt hydrolase (BSH) which causes a decrease in the absorption of cholesterol in the blood stream and is an essential criterion for the selection of probacteria [9, 13]. This enzyme unconjugated bile acids, which eventually cause a decrease in circulating triglycerides and plasma LDL and VLDL levels [12, 20]. The most associated BSH active probiotics are Lactobacillus, Lactococcus, and Bifidobacterium [21]. These bacteria have been observed to lower cholesterol both in vitro and in vivo [28].

For example, see [14], which found that L. fermentum NCIMB 5221 and NCIMB 2797 were able to lower cholesterol in an in vitro analysis. They found that L. plantarum ATC 14917 had the best results [22]. Another study found that the BSH candidate L. reuteri NCIMB 30242 had the capabilities to lower cholesterol in otherwise healthy individuals [12]. This is because Lactobacillus species are able to colonize and survive in small intestines [21]. These studies have demonstrated why lactic acid bacteria with BSH are being classified as having hypocholesterol effect. More specifically, trials that used multiple strains versus single strains and fermented products versus capsule found that multi-strain and fermented methods both caused a decrease in total cholesterol and LDL [13].

Probiotic soy products in association with cardiovascular risk factors were observed. The fecal microbiota that was used was Lactobacillus spp., Bifidobacterium spp., Enterococcus spp., Enterobacteriaceae, and Clostridium spp. populations. Their results showed a negative correlation with Enterococcus spp., Lactobacillus spp., and Bifidobacterium spp. with cholesterol, non-HDL cholesterol, and autoantibody against LDL [29]. However, this study was performed with rabbits, and future studies with human subjects are necessary for a confirmed effect.

High-density cholesterol, HDL, is considered good cholesterol and is important for removing “bad” cholesterol from the blood stream. This study found that there was a positive correlation between Lactobacillus, Bifidobacterium, Enterococcus, and HDL-C levels [29]. However, in relation to T2DM patients, there were some studies, which found that probiotics failed to maintain a significant effect on lipid profiles [7]. Prebiotics, however, were found to maintain hypocholesterolemic effects in the T2DM individuals [7].

Other methods in which probiotics affect blood lipids include binding and incorporating cholesterol to their cell membrane, which decreases the amount of intestinal cholesterol available for absorption, and by producing SCFA which inhibit hydroxymethylglutaryl CoA reductase. Lactobacillus species have protease-sensitive receptors on their cell surface. These receptors bind to exogenous cholesterol or phosphatidylcholine vessels, which then incorporate cholesterol into their cell membrane. This is strain- and growth-dependent action [21].

Probiotics, performing the mechanism of a 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitor, was shown with dietary fibers (prebiotics) altering the functionality of gut microbiome including the stimulation of microbial metabolite production such as short-chain fatty acid which impacts cholesterol metabolism. The lowering of cholesterol with prebiotics is believed to occur through two mechanisms. The first one is it lowers cholesterol absorption by enhancing cholesterol excretion via feces and the second is through the production of SCFAs upon selective fermentation by intestinal bacterial microflora. Inulin and arabinoxylan, both prebiotics, can alter gut microbiome to stimulate SCFA production which has been already shown to effect cholesterol metabolism [12]. The mechanism behind this is that cholesterol is removed though the incorporation of cholesterol into cellular membranes in the intestine [13].

In terms of fermented food, Monascus purpureus rice was found have similar actions as statin and acted as a HMG-CoA reductase inhibitor, decreasing the makeup of cholesterol [6]. The studies that have conflicting findings could possibly be due to the delivery system. Studies varied whether the probiotics were given in capsule versus fermented foods. However, in a limited number of meta-analysis of studies, it was found that probiotics using fermented foods were more effective in reducing total cholesterol and LDL than in capsule [13]. In the majority of studies that were reviewed, there was no control for individual’s lifestyles in human subjects which could alter the findings.

3.4. Hypertension

Hypertension has several risk factors, such as sedentary lifestyle, lipid and hypercholesterolemia, chronic inflammation, inconsistent modulation of renin-angiotensin system (RAS), sodium sensitivity, personal habits, anxiety, and stress. While dietary strategies have been the focus of target for repairing the disturbed gut microbiota, probiotics have been found to decrease systolic/diastolic pressures (approximately 14–6.9 mm drop) in prehypertensive and hypertensive patients. This blood pressure (BP)-lowering effect through probiotics is due to a decrease in nitrogen oxide production in macrophages, reducing reactive oxygen species and enhancing dietary calcium absorption using different mechanism. These mechanisms have been found to be related to the production of SCFAs, CLA, GA A, and angiotensin-converting enzyme (ACE) inhibitor peptides [8]. Short-chain fatty acids (SCFAs), which have a role in both energy metabolism and adipose tissue expansion, also have two sensory receptors that have been linked to BP regulation. Some of the probiotic strains that were noted to cause a decrease in SBP were L. casei, Streptococcus thermophiles, L. plantarum, and L. helveticus [9]. Fermented milk products have been shown to have antihypertensive properties in both animal models and clinical trials [6]. Blood pressure release may also be due to a decrease in blood lipids, body weight, and IR.

On continuing, blood pressure is normally controlled with a variety of biochemical pathways, including the RAS system. The generation of antihypertensive bioactive peptides causes an ACE-inhibitory activity [8]. Different strains of probiotics have varying potencies as ACE inhibitory activity based on different bioactive peptides [18]. When prebiotics were used along with probiotics or the probiotic strains were enhanced via fermentation substrates, the proteolytic activity and ACE inhibition were increased [20]. Fermentation is able to produce bioactive ACE-inhibitory type peptides, casokinins and lactokinins. Probiotics are able to generate these peptides though fermentation having caseinolytic and lactose hydrolyzing enzyme systems [9]. Consuming probiotic soy milk led to a decrease in BP in a limited number of type II diabetic mellitus subject in a clinical trial lasting 8 weeks [15]. This study did not find any alterations of anthropometric measures which had been found in other studies. This could be that there are strain-specific properties [15]. However, subpopulation studies showed no significant difference and there are no definitive recommendations at this time.

3.5. CAD

Cardio-arterial diseases are often associated with hypercholesterolemia, diabetes, and other metabolic-related diseases. Alteration to the gut microbiota can cause a detrimental risk of obtaining a cardio-arterial disease/state such as atherosclerosis. The change in gut microbiota can cause an increase in the level of trimethylamine N-oxide (TMAO), which has been linked to an increased risk of major adverse cardiovascular events observed in large clinical cohorts. However, additional studies are needed to determine the mechanism of CVD through TMAO [7].

Apo A-V deficient mice were found to have increased precursors of small dense LDL, which is a predictor of coronary artery disease [16]. This deficiency has been observed with bile salt hydrolase expressing probiotics to have an important role in not only lipid metabolism but also atherosclerosis development. L. reuteri NCIMB 30242 when provided to non-diabetic subjects with hypertriglyceridemia caused a decrease in apolipoprotein B, which is associated with atherogenic VLDL and LDL products [16]. It was also shown to reduce CRP and fibrinogen which are two factors of atherogenesis [12]. However, this study only included small healthy hypercholesterolemia population, and the probiotic was given either in capsule or in yoghurt format. In mice, Lactobacillus species was found to lower arteriosclerosis [20]. When provided through powered supplement, L. curvatus and L. plantarum caused a significant increase in apo A-V [16]. With varying methods of providing the probiotics, more controlled studies are necessary to understand the relationship between probiotics and cardio-arterial disease.

Fermented products may provide a decrease in the development of atherosclerosis with the activation of G-protein-coupled bile acid receptor [25]. In a study that compared atherosclerotic lesions in the aortic vessel in animals treated with fermented soy product supplements versus a control group, the ones that were provided the supplement was found to have a lower percentage of aortic vessel covered with lesions [29]. Fermented whole grains are also able to lower coronary heart disease [6].

3.6. Heart failure

Heart failure causes a variety of systemic effects on multiple organs. While there are no heart failure changes observed to effect the gut microbial composition, there have been changes that could cause or increase the incidence of heart failures. New research is currently observing probiotics therapy providing direct cardio-protective effect to the heart. This protection would result in a reduced ischemic injury and improve cardiac function after an infarction [20]. TMAO, which is effected by gut microbiota, can be linked to both the development and progression of atherosclerosis and cardiovascular disease and is effected by gut microbiota [21]. However, a majority of studies have only observed the effects in mice. Continuing due to individuals not realizing that they are at risk for infarction, consuming probiotics as prophylaxis is unlikely and the prevalence of heart failure is stagnant.

3.7. Chronic kidney diseases

Patients with chronic kidney disease have an increased risk for cardiovascular disease through having hyperhomocysteinemia, increased lipoprotein, oxidative stress, and inflammation. Vascular dysfunction in both humans and experimental animals with CKD has been discovered to be due to an increased production and impaired renal excretion of p-cresyl sulfate and indoxyl sulfate which pairs CKD with vascular disease. These toxins along with others are normally cleared by the kidneys. When kidney patients were provided probiotics, there was a decrease in those toxins. However, due to the uremic environment of the gut that is often associated with CKD, probiotic may become ineffective or less ineffective [23].

3.8. Relationship to GI system

A population of microbes that assist the host’s biochemical metabolic and immunological balance necessary for health maintenance is termed normal microbiota [6]. Both composition and function characterize the biodiversity of microbiota [4]. The gastrointestinal microbiota includes bacteria, archaea, protozoa, fungi, and different viruses, with anaerobic bacteria and the predominant source [4]. The numbers range from 10 to 100 trillion microorganisms in the GI tract, which, based on an individual’s genetic age and diet, vary from individual to individual [9]. From the time an individual is born until his/her death, there will be more than 500 different species of microorganism that are contained in the human body [6, 7]. An individual’s microbial diversity changes throughout his/her life span and depends on a person’s health-related interaction between gut microbiota and host’s overall health [7]. There are even geographic variations that have been found in relation to the type of Lactobacillus, varying from the western and eastern hemispheres. The factors that can influence a person’s microbiota are genetics, age, diet, and antibiotic use [8].

The colon has the largest variety of microorganism and is the focus part of most studies [4]. Bifidobacterium, Lactobacillus, Propionibacterium, and Bacteroidetes are the dominant species of obligate microflora [5]. Lactic acid-producing Bifidobacterium and Lactobacillus are often the focal points of studies due to their beneficial effects that is caused by their expression of immunomodulatory and pathogen-antagonistic molecules [2]. These bacteria produce butyrate, which highlights some properties of propionate and is observed as the preferred metabolic fuel for colonocytes possessing antineoplastic properties. This contributes to energy production [4]. Propionate affects colonic muscular contraction, relaxation of resistance vessels, and stimulation of colonic electrolyte transport and insulin resistance [4].

There are several ways that a human’s microbiota aids overall health; examples of this include endogenous symbiont microorganisms, microbiota, changing not only gene expression but also have an effect on pH, redox balance, and the ratio between pro-inflammatory and anti-inflammatory cytokines. There are also studies which showed normal microbiota effect on brain metabolism, the immune system, and a couple of homeostatic routes [3]. There have been several studies that have noted a change of gut microbiota in several conditions/diseases such as obesity, fatty liver, insulin-resistant diabetes mellitus, and hypertension [11]. Some examples of these changes are an increase in Firmicutes and a decrease in Bacteroidetes [18]. With recent studies showing gut microbiota related to the pathogenesis of cardiovascular disease, probiotics, which are live microbial food supplements, could balance intestinal microbial resulting in the treatment or prevention of cardiovascular disease [9, 11].

The gut environment also plays a role in the type of bacteria found per location in the tract. The tract varies from an alkaline pH in the small bowel to an acidic pH in the stomach [31, 32]. Using the 16 s ribosomal RNA gene sequence-based metagenomics methods, it has been determined that 90% of bacteria of the gut belong mainly to the Bacteroidetes and Firmicutes phylum [27]. It has been discovered that both are lactic acid bacteria which are vital to the gastrointestinal track normal residents. These two are commonly used in fermented food for the prevention and treatment of different disorders ranging from constipation to high cholesterol levels [27].

When an individual is healthy, most of the microbiota act symbiotically with the host. The major metabolic function of microbiota is to assist with the harvest of nutrients and energy from different diets that human’s consume [4]. The interaction between the gut epithelial cells and the microbes and the metabolites produced is responsible for the maturation of intestinal epithelial cells, enteric nervous system, intestinal vascular system, and the mucosal immune system. However, an imbalance in gut bacteria has been shown in numerous studies to be linked to a variety of diseases. Intestinal disease state can affect the microflora, impair the gut barrier, and/or cause intestinal inflammation which can all lead to imbalance in gut bacteria population [31]. In order to reestablish a balance, probiotics, prebiotics, and synbiotics have been used and observed. Probiotics are able to affect the GI tract through their interaction with the intestinal epithelial cells, luminal flora, and mucosal immune cell components of the GI tract [28].

Antibiotics usage in early life has been determined to deplete some components of microbiota causing disrupted normal gut microbiota development [4]. Prebiotics such as fructo-oligosaccharides do not support the growth of antibiotic-related pathogens like C. difficile [31]. Several studies have observed the efficacy of different probiotic strains in the treatment of antibiotic/C. difficile-associated diarrhea. L. acidophilus, L. rhamnosus GG, L. delbrueckii, and L. fermentum are several bacteria that have been shown to decrease the occurrence of antibiotic-induced diarrhea [10]. C. difficile, a main concern with the usage of antibiotics pathogenesis, is the disruption of indigenous intestinal microbiome. Probiotics were shown in several studies to decrease C. difficile risks; those studies had several limitations such as the type of probiotic variation, the duration of use, and different dosages [35]. Therefore, C. difficile and probiotic relationship require more in-depth research.

There have been a variety of studies that observe and prove the health benefits and clinical effects of probiotics to GI abnormalities such as irritable bowel syndrome, gastric ulcer, and antibiotic-associated diarrhea and some cancers [8]. Lactobacillus and Bifidobacteria influence on resident microbiota can range from temporarily replacing missing parts or supplementing certain population, or by stimulating some of the resident microbiota. Lactobacillus species, which has been noted in several studies to provide beneficial effects when they are presented, is metabolically active and contains several properties that affect the whole intestinal microbiota biodiversity [4]. Prebiotics have been shown to suppress indigestion and diarrhea that were caused by pathogens [2].

Continuing, they can also aid in preventing the growth of harmful competitors, prevent the growth of exogenous microbes, and lower the substrate availability for pathogens [19]. L. fermentum ME-3 has been found able to suppress Gram-negative bacteria. Some probiotics have an antagonistic effect such as L. paracasei and L. plantarum with Salmonella (microaerobic), L. plantarum against C. difficile colitis (anaerobic), L. paracasei against Helicobacter pylori, and B. lactis/B. longum against Shigella sonnei and E. coli. Inflammatory bowel disease, which consists mainly of ulcerative colitis and Crohn’s disease, has been shown related to intestinal flora dysbiosis through clinical and research studies. In an analysis of several studies, probiotics were determined to have a better outcome than non-probiotics therapy for maintenance therapy. However, they did not give benefit in inducing the remission of ulcerative colitis. This could be due to various methods used, different sample sizes, and controlled variables [34].

Prebiotics can also influence the composition of bacteria in human gut [9]. Several studies showed that when given supplements of fructan and inulin, there was an increased number of Bifidobacteria [19]. Other types of prebiotics that have been found to positively affect the gut microbe are arabinoxylan and inulin. These two have a modifying ability through affecting the makeup of and function ability of gut microbe [12]. Bifidobacteria and Lactobacilli selected fermentation of prebiotics have supported symbiotic gut microbiota through improving numbers of these commensals and decreasing the number of neutral or pathogenic organisms. It is vital to know that these microbes’ preference to coproduce certain fermentation products depend on the prebiotic structures and the bacterial communities [2]. Example of acidic fermentation products are lactate and short-chain fatty acid, butyrate acetate, and propionate [2]. These products can have benefits in the gut, for example, butyrate supports intestinal epithelium, and along with other SCFAs, they have benefits that are distal to the gut system.