As the prevalence of heart disease continues to rise, researchers are hard at work trying to discover the mechanisms at play. One factor to emerge in recent years is the gut and its associated microbes. Read on to learn how gut ecology can influence heart health and heart disease.
I’ve now written quite a few blog posts on the gut microbiome, including its connections to skin, allergies, food cravings, bone health, ocular health, thyroid, autoimmune disease, brain health, detoxification, and even its involvement in human evolution. Though I’ve already touched on the gut–heart connection on my podcast, I wanted to offer my clinician audience a more in-depth analysis of this topic. In this article, I’ll discuss the role of the gut and gut microbiota in heart health and disease.
Microbes affect cardiovascular risk factors
Many risk factors have been identified for cardiovascular disease. Some, like family history, age, gender, ethnicity, and socioeconomic status, are non-modifiable risk factors. Others, such as those listed below, are modifiable and influenced by the gut microbiota.
Studies of germ-free (GF) and wild-type mice have revealed an intricate relationship between obesity and the gut microbiota. GF mice raised in sterile incubators without any exposure to microbes are leaner than their wild-type, conventionally raised counterparts, despite consuming more food (1). Additionally, fecal transplant of gut microbes from obese mice to GF mice results in greater adiposity in the GF recipients than fecal transplants from lean donors (2).
Gut microbes play a complex and not completely understood role in lipid metabolism (3). Certain bacteria in the colon transform bile acids into secondary bile acids. This alters the bile acid pool, which, through FXR signaling, can modulate hepatic or systemic lipid and glucose metabolism (4). Several microbial taxa have been closely associated with lipid profiles, including Eggerthella, Pasteurellaceae, and Butyricimonas (5).
Did you know the health of your gut can affect the health of your heart?
Heavy metals and environmental pollutants have both been suggested to contribute to cardiovascular disease development and progression (6, 7). As I discussed in the last article of this series, microbes can influence the absorption, metabolism, and excretion of these toxins and others. They can directly alter chemical structure and activity, produce metabolites that compete for detoxification pathways, and affect the expression of detoxification enzymes.
Leptin and insulin resistance
The hormones leptin and insulin also influence risk for cardiovascular disease. Butyrate, a short-chain fatty acid produced from the microbial fermentation of dietary fiber, has been shown to increase leptin expression in adipocytes (8) and improve insulin sensitivity (9, 10).
The gut microbiota plays a key role in the development, maturation, and function of the immune system. As such, gut microbes are key mediators of inflammatory signaling. A recent study pinpointed the microbiome as a key player in age-associated inflammation (11). This age-associated dysbiosis and the accompanying inflammation may in part explain the age-associated increase in the incidence of cardiovascular disease (12).
Gut microbes can influence the availability of nutrients. Gut microbes have been shown to synthesize many B vitamins, as well as vitamin C and vitamin K (13), some of which can be absorbed and used by the host. On the other hand, greedy microbes that consume large amounts of a nutrient may occlude the host from absorbing it (14).
I have discussed the TMAO–heart disease relationship previously on my podcast and written extensively about it in several different articles. Trimethylamine-N-oxide, or TMAO, is produced via the microbial metabolism of choline to trimethylamine (TMA) and subsequent oxidation in the liver. In a large cohort study, TMAO levels were able to predict major adverse cardiac events independently of traditional CVD risk factors (15). However, serum TMAO will only be formed in significant quantities if the bacteria that convert exogenous substances to TMA are present, and emerging evidence suggests that it is microbial dysbiosis, and not dietary choline, that is the problem (16, 17).
Gut–liver–heart crosstalk during nutrient deprivation
A study from the labs of prominent microbiome researchers Jeff Gordon and Rob Knight published in 2009 found that the gut and heart may be connected through another organ: the liver. Because the heart must maintain a constant energy supply to support its function, it has evolved the capacity to use different substrates, depending on their availability. In most mammals, fasting conditions will cause an increase in the production of ketone bodies in the liver, which is accompanied by an increase in ketone utilization by the heart, skeletal muscle, brain, and other tissues.
Interestingly, ketogenesis is reduced in fasted germ-free mice, and the mass of the heart is significantly reduced in both germ-free fasted and fed mice. The authors hypothesized that this may be due to reduced acetate production in the gut of germ-free mice, as acetate provides an increased pool of hepatic acetyl CoA, the starting molecule for ketone production. Instead, fasted GF hearts rely on glucose metabolism and, as a result, have greater glucose utilization.
Further experimentation found that during fasting, a microbiota-dependent increase in hepatic ketogenesis occurs, regulated by PPAR-ɑ signaling. Myocardial metabolism is then directed toward ketone body utilization. In other words, the gut microbiota is able to regulate which energy substrates the heart is able to use. While most people suffering from cardiovascular disease are far from calorically deprived, this research certainly opens questions as to how microbial dysbiosis might influence energy flux through the heart (18).
Gut pathologies and cardiovascular disease
By now, we’ve seen that the gut influences cardiovascular risk factors and has indirect effects on heart metabolism via the liver. In this section, I’ll discuss how gut pathologies are linked with heart health.
As I touched on earlier in the section on TMAO, gut dysbiosis may precede the development of cardiovascular disease. One study found that animals with hypertension had an increased Firmicutes-to-Bacteroidetes ratio, along with reduced gut bacterial diversity and richness. They also had reduced levels of the microbial metabolites acetate and butyrate, which correlated with higher amounts of systemic inflammation (19). Human chronic heart failure patients have also been shown to have reduced gut bacterial diversity and lower abundance of key bacterial genera (20).
Vitamin K2 is an essential micronutrient that acts as a cofactor for the γ-carboxylation of glutamic residues in a number of proteins, including matrix Gla protein (MGP), which, when activated, prevents the calcification of blood vessels (21). One study found that patients with small intestinal bacterial overgrowth (SIBO) were more likely to have elevated arterial stiffness and reduced Gla-protein activation, two markers of subclinical atherosclerosis (22). This may be due to reduced vitamin K absorption from the diet in SIBO patients, as vitamin K is primarily absorbed in the small intestine, and/or reduced vitamin K production by colonic bacteria. SIBO also causes systemic inflammation, which, as we know, is a major risk factor for cardiovascular disease.
Observational and epidemiological evidence has shown higher rates of atherosclerosis in people with Chlamydia pneumoniae and Helicobacter pylori infections (23, 24). One study found that compared to normal individuals, patients with chronic heart failure had massive quantities of pathogenic bacteria, including Campylobacter spp., Shigella spp., Salmonella spp., Yersinia enterocolitica, and Candida spp. (25). Bacterial DNA can be identified in more than 50 percent of all plaques (26).
Some studies have found that eradication of H. pylori decreases risk factors associated with atherosclerosis, such as oxidative stress, C-reactive protein, body fat, and blood pressure (27), while others found that H. pylori eradication increased the incidence of hyperlipidemia and obesity (28). It is likely that the effects of eradication are dependent on the individual and the antibiotics used.
One of the primary routes by which bacteria might enter the bloodstream and become associated with plaque formation is through an impaired intestinal barrier. A leaky gut can allow bacteria and their products to enter the bloodstream and become associated with the epicardium. TLR4, a receptor of the adaptive immune system, binds to lipopolysaccharide (LPS), a component of the cell walls of gram-negative bacteria, and initiates inflammatory signaling. Ablation of TLR4 in mice has been shown to reduce atherosclerotic plaque formation (29).
Leaky gut may also contribute to heart disease by inducing inflammation and weakening the stability of plaque. The stability of plaque is a major factor in the risk of heart attack, as rupture of a plaque and its subsequent occlusion of the artery may be the initiating event of a heart attack. Indeed, patients with chronic heart failure have increased intestinal permeability compared to healthy controls (30, 31).
Heart-healthy pro- and prebiotics
Cardiovascular disease is certainly multifactorial in nature, and while we can’t alter patients’ genetics, family history, or socioeconomic status, we can certainly educate them about the importance of a diet and lifestyle that supports a healthy gut and heart. Both probiotics (healthy bacteria) and prebiotics (substrates that selectively feed specific groups of bacteria) can be used as means to modulate cardiovascular risk.
A systematic review and meta-analysis found that probiotics are able to reduce both systolic and diastolic blood pressure (32). The greatest effect was found in studies where baseline BP was elevated, multiple probiotic species were consumed, the duration of the intervention was eight weeks or longer, or when daily consumption was greater than 100 billion colony-forming units (CFU).
In both animal models and humans, Lactobacilli have been shown to reduce blood cholesterol levels. This may be due to the fact that some bacteria express the enzyme bile salt hydrolase, which can affect intestinal cholesterol reabsorption (33, 34). Several other studies have reported that probiotic-containing yogurts significantly reduce total serum cholesterol and LDL cholesterol and improve the LDL:HDL cholesterol ratio (35, 36, 37).
In a mouse model of atherosclerosis, inulin consumption for 16 weeks reduced serum cholesterol, serum triglycerides, and atherosclerotic lesion size by 35 percent (38). Inulin and oligofructose have both been shown to modulate lipid metabolism, an effect that may be mediated by their ability to stimulate butyrate production (39). In humans, several epidemiological studies have found an inverse association between fiber intake and cardiovascular disease (40).
Now I’d like to hear from you. Did you know about the role of the microbiota in cardiovascular disease? How will you use this information? Start the discussion in the comments below!