Unraveling the Complex Relationship Between Gut Microbiome and Cardiovascular Diseases

Our gut microbiome, which includes the combined genetic and metabolic capacities of both the microorganisms and the intestines they inhabit, impacts numerous physiological processes via alterations in our metabolism, immunity, hemostasis and inflammation. Some studies suggest that a diverse microbiome is associated with better cardiovascular outcomes, while others propose that maintaining a balanced microbial community is what matters. While attractive in concept and even utilized by some clinicians, gut (fecal) microbial diversity as a measure is like the number of pages in a book – having more pages does not necessarily translate into a better book – and quantifying gut microbial diversity of composition has yet to translate into broader clinical applications and medical interventions.

Meanwhile, the contributions of structurally specific gut microbiota-generated metabolites to cardiovascular and metabolic health have emerged as a multifaceted area of research with potential for advancement to therapeutic interventions. For example, circulating levels of short-chain fatty acids (SCFA, Figure) are produced by gut bacteria through the fermentation of dietary fibers, are associated with both cardiovascular and inflammatory processes, and animal model studies have shown links between provision of SCFA and increase expression of anti-inflammatory factors, improve intestinal barrier integrity, inhibition in pro-inflammatory cytokines, while promoting beneficial changes in lipid metabolism, blood pressure, myocardial repair, and vascular reactivity. In a recent double-blind, placebo-controlled randomized controlled trial in patients with hypercholesterolemia, 8 weeks of oral propionate supplementation, a plasma SCFA generated by gut microbiota, significantly lowered low-density lipoprotein and total cholesterol levels, likely via modulating the gut immune system and intestinal cholesterol absorption (Figure).(1) Few studies in the microbiome field have translated into human diagnostic or clinical impact, but multiple promising avenues are under investigation.

Figure. Scheme illustrating gut microbial pathways and metabolites with clinical and mechanistic links to cardiometabolic diseases.

Shown are the nutrient precursors, gut microbial metabolites, host receptors (where known), known pathophysiological functions mediated by the microbial and metaorganismal pathways, and diseases linked to the indicated gut microbiome related metabolites and pathways.

Perhaps one of the most well studied pathway with links to cardiovascular disease pathogenesis involves gut microbial conversion of dietary phosphatidylcholine by specific choline trimethylamine (TMA) lyases, producing the intermediate TMA, which upon absorption into the portal circulation in the host is converted rapidly into the biologically active metabolite trimethylamine N-oxide (TMAO) (Figure). Numerous clinical and animal studies have demonstrated mechanistic links between gut microbial TMAO generation and host susceptibility to multiple cardiometabolic and vascular diseases. Moreover, selective targeting of the gut microbial TMAO pathway, especially via small molecule pharmacological targeting of microbial TMA generation,(2) has demonstrated striking improvements in host disease outcomes, including protection from atherosclerosis, thrombosis, renal functional decline and fibrosis, myocardial fibrosis and heart failure, and even delaying aortic aneurysm development and progression.(3) Since the enzyme activity targeted is unique to procaryotes and is non-lethal (i.e. does not kill the microbes like antibiotics), selective targeting of a gut microbial process has emerged as a potential therapeutic approach to elicit beneficial outcomes for the host with reduced potential for development of microbial drug resistance. Further, by designing therapeutic agents with limited systemic absorption in the host, pharmacological targeting of the gut microbiome has the potential for enhanced safety profile and limited potential for off-target adverse effects(2). However, gut microbial metabolites can be generated from multiple distinct bacterial biochemical pathways, making their pharmacological inhibition more complicated. In the case of phenylacetylglutamine, a phenylalanine-derived gut microbial metabolite recently clinically and mechanistically linked to cardiovascular disease risks in diabetics (Figure), recent studies revealed the contribution of two distinct gut microbial catalytic strategies as being important in PAGln generation and cardiovascular disease development.(4) Studies in animal models colonized by engineered microbial mutants (e.g. specific gain of function or loss of function mutants) have already enabled significant advances in mechanistic understandings of microbial contributions to host diseases. Analogous to the development of technologies like transgenic and knock out mice, utilization of germ free mice colonized with complex synthetic microbial communities that either lack or are newly endowed with a specific metabolic function is an area of future development and growth that is much needed in the field.

Gut microbial community structure and architecture is highly responsive to dietary patterns, though the extent and reproducibility to which dietary interventions can modulate cardiovascular risk through the microbiome remains speculative. Genetic and environmental factors no doubt influence how the gut microbiome interacts with diet, making personalized dietary recommendations a challenging task. In the case of TMAO, chronic exposure to a diet high in red meat has been shown to substantially increase TMAO levels in some individuals, whereas an isocaloric diet devoid of red meat but still containing the same level of protein (25%) can substantially reduce TMAO levels through multiple mechanisms. In yet other studies, links between gut microbiome and cardiometabolic diseases have been observed with the gut microbial metabolite imidazole propionate (Figure). A microbial product of dietary histidine (5), imidazole propionate has been shown to impair glucose metabolism, and both activate p38γ/δ-mTOR and reduced AMPK activity. Beyond its contributions to diabetes, recent studies suggest this may be involved in the significant clinical associations observed between imidazole propionate and heart failure development and disease progression (5) (Figure).

Another potential therapeutic approach for a gut microbiome-linked process involves probiotics. Well ahead of the scientific evidence, the market for probiotics and prebiotics has experienced a boom as individuals seek to leverage these supplements for improved gut health and, by extension, cardiovascular well-being. Probiotics (which by definition are beneficial live microbial components used for perceived health benefit) and prebiotics (which nourish these microbes) have shown some promise in improving gut microbial balance and reducing inflammation in animal models. However, controversies surrounding their efficacy persist, and proof of benefit in randomized human studies for cardiometabolic benefit remains to be established.

Looking forward as we continue to make advances regarding the role of the gut microbiome in cardiometabolic health and disease, the potential for advancing these insights into changes in clinical care is remarkably bright. The field is little over a decade old, and the complexity of microbial interactions, the individualized nature of responses, and methodological challenges in targeting gut microbiota-specific processes are all obstacles that need to be overcome. Focus on human clinical studies for discovery of gut microbiota pathways and products that are associated with the future development of disease in hosts, and mechanistic studies testing for underlying causal links have served as a proven path for discovery of relevant gut microbiota pathways with links to disease susceptibility. Pharmacological targeting of gut microbial pathways with mechanistic links to disease causation represents a new and untapped frontier in cardiovascular and metabolic disease therapeutics – one that holds promise to significantly reduce residual cardiovascular and metabolic disease risks.