Microbiome-Associated Drug Response Variability in Heart Failure Treatment

1. Introduction to the Gut Microbiome and Cardiovascular Health

Despite tremendous advances in cardiology, heart diseases remain the leading cause of death worldwide [1]. While established risk factors contribute to the development of cardiovascular disease (CVD), new research suggests that changes in the gut microbiome community may play an additional unfavorable role in the occurrence and progression of cardiovascular pathologies, particularly heart failure [2,3]. Many drugs, used in cardiology, such as antihypertensives, cholesterol lowering substances, and antithrombotic medication have been shown to modulate gut microbial composition and diversity [4]. Some findings suggest that statins may have implication in reducing systemic inflammation by promoting the growth of various beneficial bacterial phyla, thereby improving overall cardiovascular outcomes [5]. Agents targeting the renin-angiotensin-aldosterone system may also alter the microbiome composition, potentially attenuating the risk of hypertension related complications [6,7]. On the other hand, changes in the gut microbial profile may alter drug metabolism, affecting the efficacy and safety of antithrombotic therapies [8]. This review explores the complex bidirectional interactions between cardiovascular pharmacotherapy and the gut microbiome, with a focus on implications for heart failure management and personalized medicine.

2. The Gut-Heart Axis, Dysbiosis and Systemic Inflammation

The human gut hosts an average of 1000 to 1150 microbial strain [9]. Trillions of commensal microorganisms residing in the intestinal lumen - in varying proportions – constitute a complex organ, that plays a crucial role in maintaining gut barrier integrity, metabolic homeostasis, and the inflammatory response [10]. Large-scale populational studies, including the European Metagenomics of the Human Intestinal Tract (MetaHIT) and the US-led Human Microbiome Project, managed to provide a characterization of different microbial compositions in health and disease [11,12].

Although challenges had been arisen in identifying a “healthy” gut microbiome composition due to the high inter-individual variability, it has been shown that in healthy states the gut microbial ecosystem remains relatively stable. Approximately 90% is dominated by the Firmicutes and Bacteroides species, while Proteobacteria, Actinobacteria, Cyanobacteria, Fusobacteria, and Verrucomicrobia comprise the majority of the remaining fraction [11,13]. These species are responsible for maintaining intestinal mucosal barrier, enhance digestion, supply nutrients, prevent infections, and support normal coagulation [14].

Nevertheless, in pathological conditions, an imbalance of the gut microbial milieu may arise, leading to dysbiosis [15]. This disruption, in turn leads to intestinal mucosal damage and increases the permeability of the intestinal barrier. The resulting “leaky gut” facilitates endotoxin translocation, metabolite and cytokine influx into systemic circulation. This can trigger dysbiosis-related systemic inflammation, which has been implicated in cardiovascular pathogenesis [16,17]. A self-promoting cycle can emerge in which inflammatory pathways - including the expansion of cardiac myosin specific Th17 cells, toll-like receptor signaling, and increased production of proinflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) – further compromise gut barrier function [17,18].

3. Role of the Key Gut-Derived Metabolites

Different microbiota species produce a variety of bioactive compounds, depending on the host’s individual microbiome composition and dietary habits. Emerging evidence suggests that key metabolites implicated in cardiovascular pathogenesis include trimethylamine-N-oxide (TMAO), short-chain fatty acids (SCFAs), and secondary bile acids (SBAs). These metabolites modulate vascular inflammation, lipid and glucose homeostasis, blood pressure regulation and thrombosis risk, underlining the significance of the gut-heart axis in cardiovascular disease [19].

3.1. Trimethylamine-N-oxide (TMAO)

The association between TMAO - a gut microbiome-dependent byproduct of dietary choline, phosphatidylcholine, and carnitine (found in eggs, fish and red meat) - and CVD risk was first described by Wang et al. in 2011 and has been extensively studied since [20]. Recent meta-analysis revealed a 67% risk of CVD development linked to high TMAO levels [21]. Accordingly, the relation between increased TMAO levels and the risk of major adverse cardiac events (MACE) has been demonstrated by numerous animal and human experiments [21,22,23]. By altering cholesterol metabolism - either promoting lipid deposition in the arterial walls or inhibiting reverse cholesterol transport – TMAO contributes to the development of atherosclerosis [24]. Furthermore, it aggravates vascular inflammation, induces endothelial dysfunction, enhances foam cell formation, and subsequently facilitates atherosclerotic plaque development and progression [21]. Longitudinal studies have shown that elevated plasma TMAO levels have prognostic value for arterial thrombosis, stroke and myocardial infarction [25,26]. In addition, heart failure patients exhibit higher TMAO plasma concentration than healthy individuals, and they positively correlate with B-type natriuretic peptide (BNP) levels [15]. One large-scale clinical cohort study demonstrated an impressive 2.5-fold increase in the risk of MACE for patients in the highest quartile of plasma TMAO levels compared to those in the lowest quartile [4].

3.2. Short Chain Fatty Acids (SCFAs)

SCFAs - including acetate, propionate, and butyrate – are synthesized during the fermentation of indigestible dietary fibers - are among the most well-defined, beneficial microbiome-derived metabolites [27,28]. The main gut bacteria responsible for converting complex carbohydrates into monosaccharides include Bacteroides, Bifidobacterium and Faecalibacterium spp. SCFAs have been established to contribute significantly in sustaining eubiosis, enhancing lipid and glucose metabolism, modulating immune responses, preserving intestinal mucosal integrity, and preventing bacterial translocation into systemic circulation [29,30]. Butyric acid exhibits anti-inflammatory properties and increases nitric oxide concentrations, thereby reducing atherosclerotic burden. Propionic acid supports metabolic homeostasis, while acetic acid helps regulate blood pressure and modulates lipid profiles [31,32].

3.3. Secondary Bile Acids (SBAs)

It is widely recognized that BAs are essential for cholesterol excretion. The deconjugation of primary BAs into secondary BAs - such as deoxycholic and lithocholic acids - occurs in the distal ileum through microbial enzymatic activity [33]. SBAs participate in multiple metabolic pathways. Besides aiding in the absorption of dietary fats and lipid-soluble vitamins, they modulate glucose and cholesterol metabolism via the activation of Farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5), and exhibit anti-inflammatory properties by inhibiting pro-inflammatory cytokines, like TNF-α [34]. Current evidence on the role of SBAs primarily stems from preclinical studies. It has been confirmed that FXR activation preserves intestinal lining integrity and permeability, alongside with controlling inflammation and fibrosis. In vitro studies have shown that higher FXR expression may reduce myocardial ischemia-reperfusion injury, whereas FXR suppression is associated with increase myocyte apoptosis and infarct size [35]. Additionally, a link has been identified between FXR activation and the upregulation of angiotensin II type 2 receptor, which was shown to prevent salt-sensitive hypertension in rat models - suggesting potential therapeutic application [36]. (Figure 1)

4. Impact of CVD Drugs on the Gut Microbiome - Pharmacomicrobiomics

Advances in genome sequencing technologies and bioinformatics have enabled detailed description of the gut microbiome’s composition, genetic diversity, and its interaction with pharmaceutical agents [37]. Large-scale human cohort studies – including the Dutch LifeLines-DEEP cohort, the Belgium Flemish Gut Flors Project, and the TwinsUK cohort - have identified associations between various medications and changes in gut microbiome composition and function [38]. Many cardiovascular drugs rank among the top microbiome-associated pharmaceuticals, including statins, angiotensin-converting enzyme inhibitors, beta-blockers, and antithrombotic agents [38,39] (Figure 2)

4.1. Statins

Statins have proven to be the most beneficial treatment for patients with hypercholesterolemia, both in primary and secondary prevention, significantly reducing cardiovascular morbidity and mortality [40]. Recent studies have shown an interplay between statin therapy and the gut microbial landscape [41]. Sun et al found that patients with extensive bacterial heterogeneity – particularly Lactobacillus, Bifidobacterium, Faecalibacterium and Eubacterium species, known for their cholesterol lowering properties - showed better response to statin treatment, successfully lowering serum low density lipoprotein (LDLc) levels below 100 mg/dL within three months [42,43]. Likewise, Liu et al identified “good responders” – patients with a significant 58.9% reduction in LDLc - among those presenting high proportions of Firmicutes phylum [44]. Species from the Oscillibacter and Akkermansia genera have also been associated with cholesterol-lowering effects [45,46,47].

Another study conducted by Khan et al, though based on a relatively small sample size, suggested that atorvastatin may selectively restore anti-inflammatory bacteria, such as Akkermansia muciniphilia and Faecalibacterium prausnitzii, which in turn promote the growth of Oscillospira species. Although the atorvastatin treated group demonstrated lower bacterial diversity compared to healthy participants, a significant reduction of pro-inflammatory taxa and enrichment of anti-inflammatory phyla were observed [48]. In contrast, Kummen et al in a randomized controlled trial found only a modest effect of rosuvastatin use on gut microbiome composition on short term follow up of two to four weeks. While the sample size limited the ability to detect subtle microbial changes, a notable increase in pro-atherogenic microbiome derived metabolites was seen among patients with poor HDL/LDL ratio improvement, suggesting a link between statin response and microbiome activity [49]. Furthermore, Kaddurah-Daouk et al. demonstrated positive correlation between plasma simvastatin concentration and increased levels of secondary BAs, which predicted the cholesterol-lowering efficacy in good responders [50,51].

4.2. Angiotensin-Converting Enzyme Inhibitors/ Angiotensin Receptor Blockers

Renin-angiotensin-aldosterone system (RAAS) blockade remains the cornerstone in heart failure management and is active throughout the gastrointestinal tract. Both angiotensin receptors - type I (AT1R) and type II (AT2R) - are expressed in epithelial villi, submucosal layers, muscular layers, the myenteric plexus and local vasculature [52]. Accordingly, angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs) reduce intestinal wall rigidity, enhance villi length, decrease pro-inflammatory cytokine concentration, preserve gut barrier integrity, and improve microbial diversity – as pointed out in animal experiments [53]. Recent clinical research by Dong et al. assessed the effects of ACEI/ARB treatment on gut microbiome and metabolites. Although the study used a cross-sectional design and had a small sample size, it suggested that RAAS inhibition reduces pathogenic bacteria such as Enterobacter and Klebsiella, while promoting beneficial ones like Odoribacter. Additionally, significant metabolomic shifts were observed, with higher levels of inositol in the well-controlled group [54].

Furthermore, microbiome may play a significant role in the hydrolysis of quinapril and ramipril, reducing the concentration of active drug, while others, like lisinopril is less susceptible to microbial degradation [55]. These findings were revealed by Yang et al in a research on spontaneously hypertensive rats, demonstrating that, Coprococcus comes exhibits esterase activity, capable of directly breaking down esterified ACEIs (quinapril and ramipril), a phenomenon absent with non-ester ACEIs, such as lisinopril [56].

4.3. Cardiac Glycosides

Digoxin, the most commonly used cardiac glycoside, is largely prescribed for the treatment of heart failure and atrial fibrillation. It has been widely known for its marked interindividual variability in terms of bioavailability [57]. Emerging evidence shows that digoxin can be metabolized by the gut microbiome into an inactive form, dihydrodigoxin, in around 10% of patients [57,58]. The bacteria responsible for this inactivation was identified in the early 1980s as Eubacterium lentum, a member of the Actinobacteria phyla, later renamed as Eggerthella lenta [59]. In a 2014 study, Haiser et al. used RNA-sequencing to identify a two-gene operon encoding a cytochrome in E. lenta, referring as the cardiac glycoside reductase, which was significantly upregulated in the presence of digoxin. These genes were claimed to be a predictive microbial biomarker for digoxin inactivation [60]. Moreover, they showed that the growth of E. lenta is dependent on arginine levels, which both supports its proliferation and inhibits digoxin inactivation [61]. Consequently, increasing arginine levels – whether through dietary intake or from microbial source – may offer a reasonable strategy to prevent this undesired bacterial activity [62].

4.4. Antiplatelets

Aspirin, is a widely used antiplatelet agent in the prevention and treatment of CVD, acts by inhibiting cyclooxygenase-1 enzymes and prostaglandin synthesis. According to latest findings, aspirin causes gastrointestinal damage and toxicity in up to 90% of patients. Long-term aspirin treatment leads to alterations in gut microbiome composition, impacting bacterial genera like Prevotella, Bacteroides, Barnesiella as well as Ruminococcaceae family. In contrast, studies have suggested, that dysbiosis may also influence aspirin metabolism [63,64]. For instance, Parabacteroides goldsteinii was identified by Li and Ding et al. to have beneficial effect on restoring aspirin related intestinal layer damage by suppressing bile acid receptor FXR signaling. They further established that the growth of Parabacteroides goldsteinii is inhibited by aspirin [59,65]. Clopidogrel, another platelet agent, has also been associated with distinct microbial fingerprint and enhanced diversity, as shown in metagenomic analyses from large populational studies, including the Twins UK cohort [59].

4.5. Beta Blockers

Known as the fundamental treatment in heart failure, beta-blockers exert their effect through modulating the sympathetic nervous system, reducing morbidity and mortality in patients with heart failure [66,67]. Until recently, little was known about their interaction with the gut microbiome. Experimental models focusing on metabolism indicate that beta-blockers are not only able to reduce intestinal microbial diversity, but their pharmacokinetics can be notably influenced by specific microbial strains. Long-term users may reveal higher abundance of harmful microbial species, such as Streptococcus and Lactobacillus genera. [25]. In 2024 a research published by Shearer et al. involving 134 participants diagnosed with cardiometabolic disease, found that beta-blocker therapy contributed to the depletion of Akkermansia muciniphila and compromised the activity of Egerthella lenta, both of which are important for energy metabolism and immune regulation [68]. However, other findings from animal models suggest that when beta-blockers used in combination with other heart failure medication, such as diuretics, ACEIs or aspirin they may enhance the abundance of butyrate-producing bacteria like Roseburia genus, contributing to additive blood pressure-lowering effects [69].

4.6. Other Classes of Heart Failure Drugs

Additional cardiovascular drugs may also modulate gut function. For example, a randomized, open-label clinical trial by Deng et al. found that patients with type 2 diabetes and several CVD risk factors treated with empagliflozin, express higher microbiome diversity. They reported a significant shift in favor of SCFAs producing bacteria, including Roseburia, Eubacterium, and Faecalibacterium [70].

Similarly, spironolactone as well facilitates the restoration of SCFAs producing bacterial species, supports Firmicutes/Bacteroidetes ratio, and reduces systemic inflammation, thus helping maintain eubiosis [36,52]. The first evidence of spironolactone’s dysbiosis reducing effect was provided by González-Correa et al. in a study on spontaneously hypertensive rats followed by a five-week treatment. As a result, administration of spironolactone lead to the restoration of acetate-producing Bacteroides and Prevotella genus on one hand and decreased the concentration of butyrate-producing bacteria on the other hand, especially Eubacteriacea family and Clostridiales order [71].

Finally, a few attempts have been made to investigate novel heart failure drugs, such as the sacubitril/valsartan combination and microbiome interactions, though these findings remain preliminary. Animal models have shown that sacubitril/valsartan treated diabetic mice exhibit reduced harmful bacterial genus like Escherichia and Shigella, and express increased proliferation of others with beneficial traits, such as Lactobacillus, Bacteroides, and Parabacteroides, potentially supporting gut barrier integrity and promoting SCFA production [72]. (Table 1)

5. Limitations and Future Directions

Due to significant development in metagenomics and next-generation sequencing, there has been an escalation in gut microbiome research over the past two decades [73]. Numerous preclinical and clinical studies have reported interrelation between changes in intestinal microbiome composition and its metabolic function. However, the underlying molecular mechanisms responsible for host-microbiome interactions remain only partially understood [74]. Although there is an undoubtful association between cardiovascular pathology and microbiome activity - highlighting the significance of the gut-heart axis - the complex, bidirectional dynamics and pathophysiological mechanisms involved in drug-microbiota interactions are far from straightforward [75]. Researches utilizing metagenomic sequencing techniques have uncovered correlations between medication consumption and gut microbial alterations. Nevertheless, the multifactorial nature of pharmacogenomic and microbiome-mediated interactions remains insufficiently elucidated [76].

Current data emphasize the detrimental impact of gut barrier dysfunction in the development and progression of CVD, particularly in relation to atherosclerosis, coronary artery disease, heart failure and hypertension. Still, these results are essentially associative, rather than casual, limiting the strength of clinical conclusions [18]. It appears that in patients with heart failure, atherosclerotic CVD, or hypertension, the altered gut microbial ecosystem influences oral drug bioavailability – a phenomenon mostly established in preclinical settings [77,78]. Hence, large randomized controlled trials and multi-omics profiling are needed, in order to shift the focus on potential causation [79,80]. Clinical translation of current findings is further impeded by the lack of precise methodological design, small sample size, short follow-up and disregard of various confounding factors - such as polypharmacy, drug-drug interactions, medication dosage and formulation, and individual variability in drug response [81,82].

Overall, cardiovascular disease management is shifting towards a more personalized care, potentially integrating genetic, epigenetic, and microbiome-based approaches. Pharmacomicrobiomics represents a promising frontier in the new era of individualized medicine [62,83]. The integration of microbiome analysis into clinical settings may enable the prediction of drug responses, minimization of adverse effects and optimization of cardiovascular therapy – ultimately supporting patient outcomes. (Table 2)

6. Conclusions

Long-term treatment of heart failure patients requires a complex and dynamic therapeutical strategy based on pharmacological interventions. Yet, in the light of recent researches, there is a need to take into consideration implications of gut microbial changes in pharmacological mechanisms, while applying the targeted, scientifically well-founded CV medication. The future outlook is the identification of specific bacterial genes and phyla in order to anticipate drug metabolism, or the development of new biomarkers aimed to lead treatment decisions. Exploring the unique microbial profile of an individual may expand medical treatments with strategies able to modify the patient’s microbiome. Including specific probiotics and prebiotics or even selected antibiotics might be beneficial to enhance drug efficacy and safety. However, due to the extensive inter-individual variability of the microbiome makeup, influenced by lifestyle, diet, environment, medical conditions and polypharmacy, major challenges arise when studying the microbiome. There is an undoubted need for well-designed studies with systematic patient selection and standardized sample collection to reduce the overload of these variables in order to optimize cardiovascular therapeutical efficacy alongside microbiome health.