“You are what you eat” The gut microbiota and cardiometabolic disease

The human gut is inhabited by a rich community of trillions of microorganisms known as the gut microbiota. The presence of these bacteria, yeasts, viruses and protozoa inside the human body is a consequence of millions of years of co-evolution, during which microorganisms have adapted to take advantage of the sheltering environment that is our gut. The gut microbiota as a “super-organism/ organ” has developed strategies so as to be immune-tolerated by our body. The host (our body) enjoys the fruits of these commensal microorganisms since they offer a protection against pathogenic gastrointestinal infections, improve digestion and provide key macro and micronutrients essential for health. However, the gut microbiota must be tightly controlled by our body since changes within this microbial community may initiate health disorders.

Recent research has identified a strong link between the gut microbiota and cardiovascular health, shedding light on a novel and promising field of potential intervention for CVD patients. Indeed, the gut microbiota not only plays a critical role in regulating physiological processes such as digestion, metabolism and immune response but can be considered as a hidden but essential metabolic organ. For instance, alteration in the gut microbiota, a phenomenon known as “dysbiosis”, has been associated with health disorders such as gastrointestinal disease, metabolic syndrome and systemic inflammation – all of which can contribute to progression of CVD. Therefore, manipulating the gut microbiota could constitute a reliable strategy for fighting cardiometabolic disorders.

The gut microbiota lies at the interface between our diet and our intestine which is the largest human immune interface (6 metres long) with the external environment. It is directly exposed to our daily dietary habits and can change its composition within days of exposure to a poor diet. Moreover the proximity of the gut microbiota to the gut lining means signaling between this organ and the human body is continuous with potential for good and bad outcomes. Certain diets promote a healthy microbiota that in turn benefits our gut health and by extension the general health of the host. For instance, the “Mediterranean” diet – rich in plant-based ingredients, nuts and fibre – is associated with a thriving microbiota rich in beneficial bacterial species. This type of diet has also been shown to promote weight loss and reduces the cardiovascular effects of obesity and metabolic syndrome. On the other hand, a “Westernised” diet rich in fats, sugars and processed ingredients leads to dysbiosis with a microbiota depleted of beneficial bacterial species and is typically associated with obesity and cardiometabolic related disorders.

Beyond diet, certain food components appear to be particularly efficient in shaping the gut microbiota and promoting health. Dietary fibre and certain prebiotics are not digested by the body but instead are fermented by the gut microbiota, promoting the growth of beneficial bacterial species. Initiating their beneficial effect on the microbiota prebiotics also improve host health and may be a modifier of CVD risk. Indeed, clinical studies have found that prebiotics can promote weight loss, improve lipid profiles, reduce low grade inflammation, and improve insulin sensitivity, all of which are risk factors for CVD. Moreover, reports from preclinical studies suggest that prebiotics may tackle some of the root mechanisms of CVD by preventing cellular and metabolic events that precede full blown CVD.

It is also possible to intervene on the microbiota directly using bacteria or yeast preparations, enriched for chosen beneficial species, to colonise our guts. Probiotics are described as live microorganisms that can provide health benefits when consumed in adequate amounts. Probiotics can also be combined with prebiotics in an attempt to obtain a greater effect than individual components; this is called a synbiotic treatment. Probiotics and synbiotics exhibit numerous health benefits and have been shown to reduce some CVD risk factors in clinical studies. Finally, it is also possible to colonise patient’s microbiota with the microorganisms of a healthy donor. This technique is called faecal microbiota transplantation (FMT) and its success could reside in the transfer of beneficial microbiota properties from donor to patient. FMT has been most successful in treating gastrointestinal disease driven by clostridium difficle. While this technique is still experimental in other diseases, early studies have shown promising results in reducing inflammation and improving metabolic health, paving the way to clinical trials in the near future.

Although microbiota-targeted strategies show promising results in preventing CVD and other disorders, there is still a vast chasm in our knowledge deficit within this emerging field of research. The gut microbiota is an incredibly diverse environment composed of trillions of organisms with vast numbers of different species interacting at a protein, carbohydrate, complex sugar, amino acid, fatty acid and hormonal level. This complexity makes mechanistic interpretation of microbe-host interactions very difficult to decipher short of reductionist methods on one hand or machine learning tools on the other. Moreover, each human being has a unique microbial signature that evolves constantly throughout our life having been hardwired as early as neonatal life with respect to training of the host’s immune system. Therefore, the major challenge of this field does not reside in the capacity of gut microbes to prevent CVD but rather in our ability to harness their power reliably at the scale of human populations.

In response to this challenge, current biomedical research strives to decipher the core mechanisms that rule the interactions between host and gut bacteria. As discussed above gut bacteria are involved in several biological processes participating in the maintenance of cardiovascular health. Here are some major concepts involved in understanding the interaction between the gut microbiota and cardiovascular organs

Intestinal permeability: The outer cellular layer of our body that is in direct contact with our intestinal content is called the intestinal epithelium. The major role of epithelium is to absorb nutrients while constituting an impermeable barrier to gut microbes. It has been repeatedly observed that patients suffering from cardiometabolic disorders suffer from a derangement of this intestinal barrier, a phenomenon called intestinal permeability. This process is explained by the weakening of the tight connections between epithelial cells as well as reduction in the protective mucous layer that lines the gut epithelium. As a result, gut bacteria or surface constituents of bacterial membranes/capsules enter into contact with the deeper cellular layers of the intestine, triggering immune defences and contributing to local tissue inflammation. It is still not clear how this phenomenon is initiated but studies suggest that an altered gut microbiota could more easily escape these defences and breach the gut permeability barrier.

Systemic inflammation: Obesity and cardiometabolic syndrome are associated with elevated levels of pro-inflammatory molecules in the blood, a phenomenon called systemic low grade inflammation (LGI). This effect is likely a direct result of spill over from local activation of inflammation within the gut mucosa. LGI can lead to activation of immune responses in distal organs including the liver, heart and vascular system. Systemic inflammation appears to be central in this interaction between dysbiosis and end organ disease in the case of CVD.

Microbial lipopolysaccharides (LPS): LPS are highly inflammatory bacterial toxins found on the cell walls of gram-negative bacteria. The presence of LPS in the systemic circulation is called endotoxemia, and has been detected in obese subjects especially in the presence of metabolic syndrome, suggesting that bacterial components may cross the human intestinal barrier to reach the circulation. Moreover, “Westernised” diet that promotes gut dysbiosis is also associated with an increased proportion of LPS producers within the gut microbiome. The immune response to LPS has been shown to contribute to systemic inflammation and activate CVDrelated biological mechanisms in heart tissue and blood vessels.

Microbial products: gut bacteria ferment food components into secondary products. Short-chain fatty acids (SCFAs) for instance are produced from dietary fibre fermentation. SCFAs support intestinal barrier function by promoting epithelial cell growth. The beneficial effects of these molecules also reaches into the cardiovascular system due to their anti-inflammatory and metabolic properties. CVD is associated with reduction in these beneficial SCFAs at an intestinal and systemic level.

The above concepts connect dietary habits to cardiovascular health through their respective ties to the gut microbiota and the immune system. Maintaining a good microbiota through dietary intervention therefore promotes intestinal barrier function protecting against systemic inflammation and in turn, against CVD.

The clinical potential of microbiotatargeted interventions is only emerging and remains to be fully proven in preclinical gain and loss of function studies to nail down specific biological mechanism(s). The precise factors and interactions between microbiota and gut must be identified in order to develop reliable therapeutic tools. So far, several promising cardiovascular targets have been found that may be modulated as targets for gut microbiota intervention.

NLRP3 (NOD-like receptor family, pyrin domain containing 3): The NLRP3 pathway belongs to the innate immune system response. Upon activation, NLRP3 releases pro-inflammatory cytokines that have been shown to promote CVD processes such as cellular hypertrophy and death. NLRP3 activation has been linked to cardiac remodelling in heart failure and atrial fibrillation. NLRP3 activation has been found to be increased following gut microbiota alteration and endotoxemia. Interestingly, the activation of NLRP3 in atrial fibrillation has been attributed to increased circulating LPS originating from age-related microbiota dysbiosis.

TLR4 (Toll-like receptor 4):

TLR4 is a key receptor of the innate immune system for recognizing microbial products such as LPS. Increased TLR4 activation has been shown to contribute to CVD progression such as atherosclerosis, that can be attributed to increased endotoxemia.

TNFR1 (Tumour necrosis factor receptor 1): TNFR1 is a receptor for a major pro-inflammatory cytokine TNF-α. Increased TNFR1 activation has been associated with cardiovascular disorders such as atherosclerosis, heart failure and atrial fibrillation. TNFR1 activation has been shown to increase with systemic inflammation originating from the gut.

Several inflammatory targets appear to be involved in CVD progression following gut microbiota alteration, and all of these factors and their cognate receptors appear to have amplified activity within the end organs implicated in CVD. Therefore, future gut microbiota-targeted intervention should aim at reducing the source of inflammatory signals from the gut that trigger the activation of inflammatory receptors in the cardiovascular system. These future studies will include preclinical models where reductionist approaches can identify necessary and sufficient pathways for microbiota-CVD interaction, machine learning approaches that interpret the complex interplay between diverse microbial constituents in the gut and therapeutic approaches that go beyond current crude live bacterial therapy to druggable products that result from mechanistic mining of the microbe-host interaction in the gut. Finally, insights from latest clinical and pre-clinical research in the field of the gut microbiota point toward a more holistic approach to CVD in general. Cardiovascular disorders in the past half century appear to be manifestations of a more general societal disease state that can be traced back in part to gut microbiota alteration and industrial food production and dietary habits. Therefore, modern clinical engagement with CVD should not only include conventional risk factor modification and therapies but new approaches to diet that incorporate a more sophisticated understanding of the interaction between food, gut microbiota, host intestinal permeability, low grade inflammation and cardiovascular disease progression

As a closing remark, we can note that the concept “We are what we eat” becomes literal when considering this microbial community as a part of us and of our cardiovascular wellbeing.

Written by Gaston L. Cluzel1, Noel M. Caplice2 1PhD Student , APC Microbiome Ireland 2Professor Cardiovascular Sciences, Cardiologist, PI APC Microbiome IrelandUniversity College Cork, Cork University Hospital