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Love your bugs ... new links between the microbiome and heart health

This post is just in time for Valentine's Day!

With the increasing ease at which the complexities of the microbiome can be investigated, more and more diseases are becoming linked to changes in its composition. Next on the list of diseases is heart health, and it’s a biggy! Cardiovascular disease is the leading cause of death in the US, and has been for over a century. It accounts for over 30% of all deaths and costs nearly $1 trillion annually! It is well established that cardiovascular disease is primarily associated with lifestyle factors, once dubbed the "rich person’s" disease, associated with obesity, sedentary lifestyle patterns, certain dietary factor and aging. So how could this possibly relate to our gut microbes?

Well, it comes down to causation and correlation, and this particular link is riddled with correlation. These correlations primarily reside between those modifiable risk factors associated with cardiovascular disease, and shifts in the composition of the microbiome; thus it is intriguing to speculate that the development of gut dysbiosis (a shift towards an unhealthy microbiome) may present as a downstream mechanism by which these risk factors facilitate cardiovascular disease.

New research suggests the gut microbiome may be central to heart health and preventing cardiovascular disease.

Causation versus Correlation… getting to the heart of the problem

So lets start with the biggest risk factor associated with cardiovascular disease… aging. Nearly 50% of people with cardiovascular disease are older than 60, and unsurprisingly, the microbiome changes substantially throughout life. Although, these changes are not typically considered “bad”, it is well documented that the microbiome becomes less abundant as we age and more variable between people. But what about the actual composition of the microbiome? Do we get more bad guys as we age? Apparently yes! Several studies have shown increases in the types of bacteria that are typically associated with inflammation in older people. However, given the myriad of complexities and uncontrolled variables in these cohorts, authors were unable to definitively say whether these changes were the result of aging, or due to the cumulative effect of lifestyle factors that older people have been exposed to. For example, diet and exercise presumably decrease with age, prescription medication use increases, rates of hospitalisation increase and the impact of long-term residential care must also be considered. So as it currently stands, aging and the microbiome remains correlative at best.

Diet and exercise are the next two risk factors critical to the development of cardiovascular disease. Unfortunately, the relationship between exercise and the microbiome remains largely studies in animal models and thus our ability to translate that to humans must be done with caution. However, it has been reported that elite athletes have a more diverse microbiome compared to sedentary controls, and higher levels of “protective” bacterial families. Importantly, however, microbial diversity in the athletes was correlated with dietary protein intake, which raises a similar question to that posed with aging: what is the extent to which exercise per se alters the microbiome independent of other lifestyle factors that often accompany exercise? So the jury remains hung.

However, the case for diet-induced changes in the microbiome appears to be substantially stronger, and may represent the single most important factor shaping its composition. There is a vast amount of information out there on the effect different macronutrients have on the composition of the microbiome, and of course, they are all different. The general consensus remains that plant based diets are associated with decreases in Bacteroides and increases in Bifidobacterium and Lactobacillus; all of which have been linked to positive health outcomes. Conversely, animal-based protein intake appears to have the opposite effects on these specific bacterial species, and has been linked to increased circulating levels of trimethylamine N-oxide (TMAO), thought to be involved in cardiovascular disease.

A step closer to causality

In a field that is dominated by correlation, research must now focus on methods that enable causality to be investigated. Germ-free mice remain the gold-standard method of determining the true role of the microbiome in disease development. These germ-free mice are completely free of every microbe, and thus enable researchers to firstly establish and characterise disease models in the absence of the microbiome. This answers whether the microbiome is truly important in the development of the disease. Specific bacteria of interest can then be added, enabling precise manipulation of the environment and the study of specific bacterial species on disease development. However, germ-free mice are expensive, require specialized facilities and the mice do display inherent differences in their immune function. Alternative methods of manipulating the microbiome are also of use in this setting, such as antibiotics (which wipe out the microbiome), prebiotics (which feed the microbiome) and probiotics (which enhance the microbiome).

However, the most attractive approach from a translational standpoint remains faecal microbiome transplantation (FMT). FMT involves the transfer of faecal material from a donor (with a microbiome composition deemed beneficial) to an individual with a particular disease or deficit. It does not require specialised facilitates and can be used to regenerate human microbial profiles in experimental models. Unfortunately, few studies have investigated the effect of FMT on cardiovascular disease. Of those that have, results from one study show that an FMT from lean/healthy donors was ante tp improve insulin sensitivity in men with metabolic syndrome, although this was only transient with sensitivity returning to baseline at 4 months later. The question now remains how we maintain the beneficial effects of FMT, and if there is a more palatable method of improving the gut microbiome.

So… should we love our bugs more?

Well, from a simplistic stand point, yes, because there is really no harm in maintaining a good diet, exercising and leading a generally healthy diet. BUT, I think we are far from recommending probiotics or FMT for the prevention and reversal of cardiovascular disease. Researchers must now work harder to identify the specific forms of bacteria that are involved in disease development, symptom severity and relative risk reduction to better guide the design and formulation of microbial-targeted agents. Importantly, the far reaching and expanding effects of the microbiome on human physiology provide extraordinary opportunity for collaborations among investigators across numerous disciplines that can accelerate our understanding of the microbiome and facilitate the development of microbiome-targeted therapeutic strategies. So why not #loveyourbugs!

Did you like this content? If so, please see recent review by Battson et al, (Journal of Nutritional Biochemistry) for a more comprehensive overview.

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