Impact of gut microbiome on atrial fibrillation: Mechanistic insights and future directions in individualized medicine

Abstract

Atrial fibrillation (AF) is a growing global health burden, with a prevalence of over 52.55 million cases. Rising disability-adjusted life-years, increasing age, and disparities in care have contributed to the worsening severity and mortality of AF. Modifiable risk factors, such as hypertension, obesity, and diabetes mellitus, are associated with alterations in gut microbiota, making the gut-heart axis a potential therapeutic target. Gut dysbiosis influences AF pathogenesis through inflammation, metabolic disruption, and autonomic dysfunction. Key mechanisms include gut barrier dysfunction, short-chain fatty acid (SCFA) depletion, lipopolysaccharides (LPS)-induced inflammation, and ferroptosis-mediated atrial remodeling. Trimethylamine N-oxide, bile acids, and tryptophan metabolites contribute to arrhythmogenic remodeling. Emerging evidence suggests that dietary interventions, including prebiotics and probiotics, as well as gut surveillance, may help mitigate AF progression. Clinical implications of gut modulation in AF include personalized dietary strategies, microbiome assessment through metagenomic sequencing, and targeted interventions such as SCFA-based therapies and ferroptosis inhibition. Metabolite surveillance, including LPS and indoxyl sulfate monitoring, may influence the effectiveness of anticoagulant and antiarrhythmic therapy. Despite growing mechanistic evidence linking gut dysbiosis to AF, clinical applications remain unexplored. This review summarizes the current understanding of the gut microbiome's role in AF.

Key Words: Atrial fibrillation; Gut microbiome; Dysbiosis; Inflammation; Short-chain-fatty-acid; Trimethylamine N-oxide; Ferroptosis; Lipopolysaccharides; Microbiome-based therapy; Individualized care

Core Tip: Gut microbiome alteration contributes to the generation of harmful metabolites, loss of gut integrity, and cardiac remodeling. Gut dysbiosis interacts with modifiable risk factors to promote cardiac tissue remodeling. Animal models and clinical studies indicate that microbial composition is associated with arrhythmogenesis, atrial fibrillation (AF) recurrence, and modulates medication response. Integrating microbiome surveillance and gut microbiome modulation therapy into AF management may slow disease progression and reduce the arrhythmia burden. However, clinical trials are needed to establish causality and support the incorporation of gut modulation into clinical care.

INTRODUCTION

Atrial fibrillation (AF) affects an estimated 52.55 million people worldwide[1]. The rising number of disability-adjusted life-years (DALY), an indicator of disability, highlights the widening care gap in AF management and disease burden[1]. DALY rose from 3.3 million cases in 1990 to 8.3 million in 2021[1]. Over the past 30 years, increasing age, higher rates of modifiable risk factors, greater public awareness, and disparities in care have contributed to the growing severity and mortality of AF[1].

Gut dysbiosis is characterized by a high Firmicutes/Bacteroidetes (F/B) ratio and contributes to atrial tissue remodeling. Microbial imbalance (dysbiosis) interacts with modifiable AF risk factors, such as hypertension, obesity, and diabetes mellitus, which are linked to dietary factors (Figure 1)[2]. Chen et al[3] emphasizes that intestinal microbiome imbalance plays a significant role in the emergence and progression of AF[3]. The gut microbiota, a complex community of bacteria residing in the intestines, is directly influenced by dietary intake and can, when imbalanced, impact cardiovascular health[4]. Gut microbiome-targeted therapies are key areas for intervention.

Figure 1 Gut dysbiosis and its role in atrial fibrillation. F/B: Firmicutes/Bacteroidetes.

This review examines the clinical significance of gut microbiota in AF, with a focus on current evidence and future implications. It reviews the mechanisms through which intestinal flora and their metabolites contribute to the onset of AF. We will also examine the bidirectional relationship between gut health and cardiac function. By correlating gut dysbiosis to established risk factors, this review underscores the potential for targeted interventions, the need for clinical evidence, and randomized controlled trials to characterize this association further.

Despite growing evidence linking gut dysbiosis to AF, a gap remains in clinical studies connecting gut microbiome-modulating therapies with improved AF outcomes[5]. This review discusses individualized therapeutic interventions to optimize AF management, including dietary modification, microbiome surveillance, and pharmacological strategies. Finally, we will highlight future research directions in this evolving field.

PATHOGENESIS

The gut microbiota is a complex community of bacteria, viruses, and fungi in our intestines[6]. It is primarily composed of Bacteroidetes, Firmicutes, Actinobacteria, and Proteobacteria. The F/B ratio is a relative estimate of intestinal microbial health (lower F/B ratio) or disease state (higher F/B ratio)(Figure 1)[7]. This ecosystem develops from birth and changes in response to diet, medication use, and overall health[8]. It produces substances crucial for the host's immune system development and regulation. Imbalances in the gut microbiota have been linked to various disorders, including cardiovascular diseases[9,10].

The gut microbiome is involved in cardiometabolic disease pathogenesis[11]. Diabetes, obesity, and hypertension increase AF risk and demonstrate gut dysbiosis[12–14]. However, the role of gut microbiota in AF within specific patient populations needs to be explored, and its potential as a therapeutic target warrants further investigation. Gut dysbiosis has been observed in individuals with AF through observational and small cohort studies. Zuo et al[15] found that patients with paroxysmal and persistent AF have distinct gut microbiota and metabolite profiles compared to non-AF individuals[15].

Additionally, the composition of gut bacteria varies with AF duration and treatment modality. Persistent AF is linked with a decreased abundance of Butyricicoccus and Paraprevotella and an increased abundance of Blautia, Dorea, and Coprococcus. However, the exact nature of the causal relationship between AF and gut microbiota requires further exploration.

Gut dysbiosis contributes to AF through multiple interconnected pathways. Dysbiosis leads to a reduction in beneficial short-chain fatty acid (SCFA), loss of gut integrity, and leakage of harmful metabolites[10]. These disruptions trigger systemic inflammation, ferroptosis, and atrial remodeling, ultimately promoting AF (Figure 2). In the section below, we will discuss the various components involved in these pathways and their clinical relevance.

Figure 2 Pathological link between gut dysbiosis and atrial fibrillation. AF: Atrial Fibrillation; FGF: Fibroblast growth factor; GPCR: G-protein coupled receptor; GPR: G-protein-coupled receptor; IL: Interleukin; LPS: Lipopolysaccharides; NF-κB: Nuclear factor kappa B; NLRP3: Nod-like receptor protein 3; PAGln Phenylacetylglutamine; SCFA: Short-chain fatty acids; TNF: Tumor necrosis factor; TLR: Toll-like receptor; TMAO: Trimethylamine N-oxide.

Gut lining

Gut dysbiosis damages the gut lining by triggering an inflammatory response and reducing the production of SCFAs. Low SCFA butyrate levels weaken the gut barrier, as butyrate increases tight junction proteins in the gut lining[10]. Harmful metabolites enter the circulation through dysfunctional mucosa. Reduced mucin production promotes AF through immunomodulation[16].

The endocannabinoid system dose-dependently improves gut integrity in mouse models[17]. It acts similarly on human coronary endothelial cell models. Enhanced integrity due to the endocannabinoid system prevents endothelial damage in response to hyperglycemia[18]. Dietary fibers and probiotics enhance gut integrity.

Ferroptosis cell death

Ferroptosis is a cell death mediated by iron-dependent lipid peroxidation and is involved in AF pathogenesis[19]. It is regulated by glutathione peroxidase 4 (GPX4), an enzyme that inhibits lipid peroxidation[20]. Decreased GPX4 promotes iron accumulation, leading to phospholipid membrane dysfunction[21]. Membrane lipid peroxidation releases reactive oxygen species (ROS) and harmful metabolites, damaging organelles[20]. Iron buildup in the body upregulates cardiac ferroptosis by increasing the availability of availability of activated iron. Additionally, damage-associated molecular patterns cause immunomodulation.

Gut bacteria upregulate ferroptosis in response to cell damage or inflammation[22]. They regulate ferroptosis locally by modulating iron absorption and storage[23]. Additionally, gut microbiota influences hepcidin[24].

Ferroptosis causes mitochondrial dysfunction, oxidative stress, electrical remodeling, ion channel dysregulation, and impaired autophagy, contributing to AF[19]. Loss of mitochondria depletes the energy available for contraction. Iron-dependent Fenton reactions generate ROS that remodel atria[25,26]. Cytoplasmic calcium leakage, rectifier potassium channel upregulation, and alterations in connexin propagate electrical remodeling. Cellular changes reduce conduction velocity and shorten the atrial refractory period[27]. Additionally, it triggers the interleukin (IL)-6/signal transducer and activator of transcription 3 pathway and plays a role in hypercoagulability[28].

Clinical implication: Probiotics can regulate iron absorption. Probiotics containing Lactobacillus alimentarus NKU556 have improved iron absorption[29]. Bifidobacteria and Lactobacillus may enhance iron bioavailability by decreasing pondus hydrogenii. Conversely, Escherichia coli (E. coli) downregulates the Fenton reaction to reduce inflammation[30]. Lactobacillus rhamnosis reduces ROS generation by influencing NADPH oxidase 1 (NOX1), and Butyrate-producing bacteria reduce ROS by inhibiting NOX2.

GUT METABOLITES

Gut bacteria contribute to the AF substrate through their influence on metabolite production. These metabolites cross the intestinal lining, modulate immune responses, and function as signaling molecules within the host[11]. Nod-like receptor protein 3 (NLRP3) inflammasome activation generates a substrate for AF both directly and indirectly[31,32]. Inflammasome activation leads to the release of inflammatory cytokines and the development of AF[33]. Gut dysbiosis activates signaling pathways nuclear factor kappa B (NF-κB), toll-like receptor (TLR)-4, and NLRP3[34]. These pathways interact with CD40L, leukemia inhibitory factor receptor, IL-2 receptor subunit Beta, and Fms-related tyrosine kinase-3 ligand, resulting in the release of IL-6, IL-7, sulfotransferase 1A1, tumor necrosis factor (TNF), and fibroblast growth factor 5. These molecules potentiate AF risk through complex interactions. Additionally, the autonomic nervous system sustains AF and is a target for research focusing on pulmonary vein and atrial tissue changes[35,36].

Trimethylamine N-oxide

The gut microbiota plays a crucial role in the production of trimethylamine N-oxide (TMAO). It converts dietary choline or L-carnitine into trimethylamine. This gaseous product enters the circulation and is oxidized into TMAO by hepatic flavin-containing monooxygenases[37]. MAO triggers inflammatory pathways, increasing autonomic activity and inducing AF. Yu et al[38] injected TMAO into specific nerve clusters in canine hearts, which resulted in rapid electrical changes compared to controls. Increased pro-inflammatory molecules, such as IL-1β, IL-6, and TNF-α, accompanied this. Similarly, elevated TMAO levels increased cardiac dysfunction, heart weight gain, and cardiac fibrosis in mice[39]. Cardiac changes were attributed to collagen accumulation, higher profibrotic markers, elevated inflammatory factors, and activation of the NLRP3 inflammasome.

While TMAO is linked to cardiovascular disease, its specific role in AF remains contested due to inconsistent findings across studies[40]. Svingen et al[41] noted that plasma TMAO levels and AF have a consistent association after adjusting for traditional AF risk factors and dietary choline intake. Conversely, Büttner et al[42] and Florea et al[43] observed no significant difference in plasma TMAO levels between individuals with and without AF when patients with coronary artery disease were removed from the analysis. The selection of the patients, the number of comorbidities, and the adjustment of confounders could explain the differences between the findings mentioned above.

Clinical implications: Due to the common risk factors shared by AF and many cardiac diseases, it is currently challenging to determine whether TMAO is a direct cause of AF or an incidental factor. Further clinical evidence is needed to validate its potential as a therapeutic target in the future.

SCFAs

Colonic microbiota ferment glucose and dietary fiber, producing SCFAs. SCFA is an energy source utilized by the gut, resulting in secondary byproducts. The byproducts differentially modulate the host's immune system. Acetate, butyrate, and propionate are the most active and important, accounting for 95% of the SCFA[44]. Sodium butyrate exhibits anti-inflammatory properties against lipopolysaccharides (LPS), an endotoxin found in Gram-negative bacteria[45]. Butyrate lowers blood pressure by increasing the levels of nitric oxide synthase.

SCFA enhances T-cell differentiation into effector T cells, such as T helper (Th) 1 and Th17 cells, while also promoting the coexistence of anti-inflammatory IL-10+ regulatory T cells. SCFAs bind to G-protein-coupled receptor 43 (GPR43), significantly modulating inflammatory responses[46,47]. G-protein coupled receptor activation reduces the expression of genes implicated in cardiac hypertrophy, cardiorenal fibrosis, and inflammation[48–50]. Animal studies have demonstrated that stimulation of GPR43 by SCFAs is essential for reducing inflammation. Conversely, GPR43-deficient immune cells, particularly leukocytes, exhibit increased production of inflammatory mediators and enhanced immune cell recruitment[51].

AF, aging, and gut dysbiosis reduce SCFA production. AF lowers SCFA-producing bacterial species (prevotella), Kyoto Encyclopedia of Genes and Genomes orthologues, and enzymes involved in SCFA synthesis. Leukocyte GPR43/NLRP3 interactions may be utilized for microbiome evaluation, as they mediate the effect of SCFAs on AF[52,53]. Fang et al[54] demonstrated that reduced acetic acid disrupted GPR43 and NLRP3 expression in peripheral blood leukocytes and contributed to left atrial enlargement. GPR43 mRNA levels correlate positively with acetic acid levels in the fecal samples and negatively with NLRP3 mRNA expression. Crucially, GPR43 levels are inversely correlated with the diameter of the left atrium.

Clinical implication: Direct evidence linking SCFAs to AF is limited. Indirectly, low SCFA levels are associated with traditional AF risk factors such as hypertension, obesity, heart failure (HF), and atherosclerosis[55]. Gut surveillance through a constructed GPR43–NLRP3 score demonstrates the potential for predicting AF.

LPS

LPS are an endotoxin found in the outer layer of gram-negative bacteria. LPS-producing microbes are more prevalent in the gut of AF patients. They are implicated in AF development due to their role in immunomodulation, inflammation, and loss of gut integrity. Kong et al[56] noted that a high-fat diet alters gut microbiota and increases LPS production.

LPS decreases the expression of L-type calcium channel subunits (α1C and β2) and increases the expression of connexin 43. TLR-4 activation upregulates NF-κB activation, which increases pro-inflammatory cytokines in the atria[10]. These changes shorten the effective refractory period and induce AF[57,58]. Aging exerts a similar effect on the atrial tissue as a rise in LPS concentration[34].

Incorporating LPS measurements into risk models significantly enhances their ability to predict new-onset AF (NOAF) in specific sub-groups. Ren et al[57] observed that elevated LPS levels in patients with ST-elevation myocardial infarction (MI) predicted the development of NOAF. Similarly, Xu et al[59] correlated the risk of NOAF after lung cancer surgery with LPS elevation.

Clinical implication: Incorporating LPS measurement into standard risk assessment models may improve NOAF prediction. Following a Mediterranean diet rich in fruits and legumes reduces circulating LPS levels and warrants further clinical inquiry[60].

Primary and secondary bile acids

Bile acids (BAs) are systemic signaling molecules involved in fat and vitamin absorption[61]: Taurine and glycine conjugation in the liver results in primary BAs (cholic and chenodeoxycholic acid). Gut microbiota deconjugation produces secondary BAs, including deoxycholic and lithocholic acid, which are then reabsorbed[62]. Farnesoid X receptor (FXR), a nuclear transcription factor, regulates BAs. It prevents BA overload, reducing bile acid-mediated adverse effects on atrial cardiomyocytes[63].

Gut dysbiosis decreases secondary BAs and increases primary BAs. AF patients have elevated chenodeoxycholic acid levels, which are associated with atrial enlargement and electrical abnormalities. BA ratio alteration promotes atrial cardiomyocyte apoptosis[64–66]. Additionally, primary BA induces structural remodeling, cardiac fibrosis, and NLRP3 inflammasome activation[66]. In contrast, secondary BAs, such as ursodeoxycholic acid, exert antiarrhythmic effects through stabilization of the cell membrane potential[67,68]. However, specific secondary BAs (glycolithocholate sulfate and glycocholenate sulfate) are linked with AF risk in African-American cohorts, suggesting a complex interaction[69].

Clinical implication: Steroidal and Nonsteroidal FXR agonists are currently the subject of pre-clinical and clinical trials and may have a potential therapeutic role[63].

Tryptophan metabolite and indole derivatives

Tryptophan is an amino acid involved in obesity-mediated inflammation[70]. The gut microbiome differentially metabolizes tryptophan into either beneficial or harmful metabolites, depending on the available substrate[71]. Clostridium sporogenes metabolized tryptophan into beneficial indoleacetic acid and indole propionic acid (IPA). Conversely, E. coli metabolizes tryptophan into the harmful indole through the tnaA-encodedtryptophanasee enzyme. The microbial composition determines whether tryptophan metabolism is detrimental or beneficial by regulating the metabolites formed. IPA maintains the gut lining by regulating the TLR pathway[72]. Downstream IPA inhibits atherosclerosis and exhibits an anti-inflammatory effect[73,74].

Indole sulfate is a harmful metabolite formed from indole in the liver and excreted by the kidneys[75]. It is implicated in arrhythmogenesis. In rabbit models, indoxyl sulfate (IS) promoted arrhythmogenesis in the arrhythmogenesis in the pulmonary veins and left atrium[76]. Arrhythmias are attributed to disruptions in cardiomyocyte calcium handling, profibrotic signaling, and oxidative stress[76,77]. However, discrepantly high IS plasma concentrations identified in animal models require contextual consideration, as humans have significantly lower circulating levels. Finally, kidney function regulates IS clearance; its accumulation in chronic kidney disease patients may create a proarrhythmic environment, as observed in animal models[75].

Clinical implication: The gut microbiome differentially metabolizes tryptophan into beneficial or harmful metabolites based on substrate availability.

Phenylacetylglutamine

Post-MI mouse models with gut dysfunction demonstrated Phenylacetylglutamine (PAGln) elevation and correlated it with the risk of NOAF in the cohort. PAGln-producing bacteria impair claudin-1 and occludin gut barrier proteins, resulting in PAGln translocation across the gut. PAGln activates the NLRP3 inflammasome in cardiac tissue, increasing atrial ectopy through the release of IL-1β, IL-6, and TNF-α[78]. Ferroptosis and PAGln-mediated collagen deposition impair electrical conduction through fibrosis and loss of ion channels[78].

Clinical implication: Improvement in gut integrity can reduce the risk of AF in post-MI patients.

CLINICAL IMPLICATIONS OF GUT MODULATION IN AF

Therapy targeting gut dysbiosis can decrease atrial tissue degeneration[55]. Compared to other cardiovascular diseases, gut microbiome surveillance, dietary alteration, and physical activity are underutilized in AF care. The lack of robust clinical evidence limits their use in clinical practice. Gut modulation therapy includes prebiotics, probiotics, dietary modification, supplementation, weight loss, and fecal microbiota transplantation. However, recent advances based on animal, clinical, and trial data highlight the potential of gut health in the care of AF (Table 1)[53,54,57,59,71,78,79].

Table 1 Recently published evidence supporting the role of gut microbiome targeted therapy in atrial fibrillation management.

Ref.	Study year	Category	Index	Key findings
Ren et al[57]	2024	Observational study	57	LPS levels associated with NOAF in ST-elevation MI patients
Xu et al[59]	2024	Observational study	59	Serum LPS linked to NOAF in cancer patients
Sinha et al[71]	2024	In vivo and in vitro	71	Gut microbiome alters tryptophan metabolism
Fang et al[54]	2024	Humans	54	SCFA-dependent G-protein-coupled receptor 43/Nod-like receptor protein 3 score is associated with AF risk
Liu et al[53]	2024	Animal model	53	Relationship between gut dysbiosis, aging, and AF risk. Use of SCFA and fecal microbiota transplant to mitigate damage
Shi et al[79]	2025	Animal model	126	Lactobacillus gasseri prevents ibrutinib-associated AF
Wang et al[78]	2025	Animal model	78	Phenylacetylglutamine is associated with increased AF risk in post-MI mice

AF: Atrial fibrillation; LPS: Lipopolysaccharides; MI: Myocardial infarction; NOAF: New-onset atrial fibrillation; SCFA: Short-chain fatty acids.

Microbiome assessment techniques

Microbiome evaluation can be done through fecal sampling. Organism culture, 16S ribosomal sequencing, and mouse models have traditionally been used for assessment but are limited by their precision. Shotgun metagenomic sequencing has revolutionized microbiome assessment[80]. It leverages computing algorithms for data analysis and can identify species that cannot be cultured in the laboratory. Additionally, metaproteomics and metabolomics help us identify proteins involved and byproducts formed in the gut[81,82].

Metabolite surveillance is central to effective gut modulation. Human studies have noted a decrease in IS after successful catheter ablation. Higher IS levels increase the risk of AF recurrence after ablation[83]. Notably, kidney function influences IS levels. Future research warrants further investigation in groups stratified by kidney function[84]. The complex interactions of metabolites with the human body contribute to inaccuracies and limit their use.

GPX4, a regulator of ferroptosis, can predict AF recurrence. Adding GPX4 levels and TGF-β levels to the Left atrial diameter measurements enhances the predictive ability to detect AF recurrence, based on a study of 249 patients[85]. Recent advances can help design wearable sensors that continuously monitor the gut microbiome. Ingestible capsules are implantable chemical sensors being investigated to monitor gut health[86,87]. These sensors are independent circuits with bioreceptors that can analyze body fluids and provide continuous feedback remotely. A similar wearable biosensor was recently used to monitor C-reactive protein continuously through sweat[88]. However, no agreement exists on assessing the microbiota composition or dietary patterns. In the future, prediction models may leverage existing clinical evidence, epidemiologic data, and metabolite evaluation to provide recommendations.

Integration of gut microbiome in personalized AF management

Personalized AF management identifies patients who benefit from gut modulation based on genetic information and comorbidity clustering (Figure 3). Therefore, identifying high-risk or high-benefit groups through microbiome evaluation enables physicians to provide individualized care. Additionally, patients may be divided into subgroups such as older patients, HF patients, post-MI patients, alcohol users, post-ablation patients, or those on certain drugs.

Figure 3 Gut modulation-based individualized care in atrial fibrillation. AF: Atrial fibrillation; GPC: G-protein coupled; HF: Heart failure; MI: Myocardial infarction; SCFA: Short-chain fatty acids.

Age-mediated gut dysbiosis increases the risk of AF in older patients[34]. Aging contributes to elevated LPS levels, loss of gut integrity, and increased serum levels of harmful metabolites. These patients may benefit from glucose management, tryptophan supplementation, a high-fiber diet, and monitoring of indole-sulfate levels.

In two recent nested case-control studies, tryptophan supplementation increased the (1) Kynurenine: Tryptophan ratio; and (2) Reduced AF risk[89,90]. In mouse models, tryptophan has been shown to protect against age-mediated dysbiosis[91]. Enhanced gut integrity, improved microbiome diversity, and decreased pro-inflammatory cytokines may explain its beneficial effects[92].

Indole sulfate monitoring can guide tryptophan requirements. The oral tryptophan challenge test (OTCT) categorizes patients into low IS or high IS producers by measuring IS levels 48 hours after tryptophan administration[93]. High IS producers are at an increased AF risk and could benefit from low-tryptophan diets. A high-fiber diet in high IS producers shifts tryptophan metabolism to reduce levels of IS. Further research is needed to explore the clinical applications of OTCT in precision nutrition.

HF-driven intestinal congestion damages the gut mucosa and alters the gut microbiome[94,95]. This congestion gives rise to cardiac cachexia and is associated with poor outcomes[96]. Gut modulation can reduce gut inflammation and improve integrity. Patients with concomitant AF and HF may benefit from gut microbiome-altering therapy.

Alcohol displays a strong link with increased AF risk[97,98]. In these patients, autonomic nervous system dysfunction, ion channel damage, and fibrosis contribute to atrial remodeling[99]. SIRT3 signaling and ferroptosis have been identified as potential therapeutic targets for the treatment of various diseases. Ferroptosis inhibition is a novel therapy to reduce the risk of AF in populations with high alcohol consumption[100].

Dietary strategies to modulate gut microbiome as part of AF management

To effectively implement dietary recommendations, healthcare providers must be grounded in clearly defined biochemical pathways that are tailored to specific patient subgroups and supported by evidence[101]. Clinical evidence suggests that weight loss, physical activity, increased fiber intake, and supplementation can improve gut health[102-104]. Clustering patients based on comorbidities and microbiome phenotypes enables targeted modulation of the gut microbiome for therapeutic benefit.

Weight loss in obese patients restores a healthier F/B ratio and increases beneficial Rikenellaceae levels[102]. The increase in Rikenellaceae is crucial, as it mediates IL-6, linking the gut microbiome alteration to obesity-related inflammation. Animal models of Metabolic dysfunction-associated steatotic liver disease consistently demonstrate that a high-fat diet correlates with reduced Rikenellaceae levels, whereas low body mass index correlates with increased Rikenellaceae levels[103,104].

Moreover, improved glucose control suppresses LPS-driven NLRP3-inflammasome activation, a mechanism central to gut dysbiosis[34]. Aging-related gut barrier dysfunction permits increased LPS translocation, underscoring the importance of tight glycemic control in mitigating gut dysbiosis, particularly in older adults.

Fibre slows colon transit time, improves carbohydrate availability, and promotes the microbiome to produce beneficial SCFA-producing metabolites. In contrast, rapid transition limits carbohydrate availability and shifts the substrate to protein, which generates harmful metabolites[105]. Qi et al[106] followed 9290 patients for 5.7 years and reported that a high-fiber diet shifted tryptophan metabolism toward the beneficial IPA.

A high-fiber diet offers distinct benefits for AF and HF and positively influences tryptophan metabolism[71]. At a microbial level, HF is associated with low SCFA producers, such as Bifidobacterium and Lachnospiraceae[107]. Dietary Fibre indirectly boosts SCFA-producing species. Higher SCFA consequently counters atherogenesis, dyslipidemia, and neurohormonal activation[108]. Omega-3 fatty acid (FA), found in fish oil, reduces the harmful metabolites and increases levels of SCFA, such as butyrate[109,110]. A pooled analysis of 54799 patients showed a reduced incidence of AF with omega-3 FA supplementation[111]. Omega-3 FA increased beneficial Akkermansia, restored a healthier F/B ratio, and reduced TMAO, collectively improving endothelial function in a randomized controlled trial[112]. Additionally, mouse models have shown that Akkermansia reduces AF by lowering TMAO[113].

EFA includes FAs such as omega-3 and omega-6 precursors, alpha-linolenic acid (ALA), and linoleic acid (LA). An omega-6/omega-3 ratio of 10/1 to 3/1 is optimal[114,115]. However, Western diets commonly exceed this ratio, with a 15:1 ratio. This results in an omega-3 deficiency because omega-3 and omega-6 compete for the same enzyme, delta-6 desaturase.

ALA supplementation of up to 2.5 g/day reduced AF risk in a cohort of 54260 over a 16-year follow-up[116]. Despite the substrate’s preference for ALA, ALA and LA compete for delta-6-saturation reactions. Low ALA, compared to LA, increases anti-inflammatory Arachidonic acid production. Conversely, high ALA forms cell membranes and exhibits anti-inflammatory effects[117]. These findings highlight the gut microbiome's role in balancing the omega-3/omega-6 ratio and the benefits of ALA supplementation.

Pharmacomicrobiomics of AF

Harm from drugs with narrow therapeutic indexes and arrhythmogenic side effects of medications can be mitigated through gut modulation.

Warfarin

Vitamin K production by gut bacteria potentiates the effect of warfarin. Warfarin has a narrow therapeutic index requiring close monitoring. Enterococcus is associated with an increased response to warfarin[118]. Conversely, Bacteroides, Shigella, and Klebsiella are associated with a reduced response. Further exploration of warfarin's relationship with bacteria prevalent in patients with AF can improve individualized treatment regimens and enhance patient safety.

Colchicine

Omega-3 FAs are being investigated for their potential to improve gastrointestinal (GI) tolerability by influencing the gut microbiome[119]. Colchicine prevents AF recurrence after cardiac ablation; however, GI intolerance has limited its use[120,121]. GI side effects can be mitigated by using probiotics.

Digoxin

Actinobacterium Egerthella lenta metabolizes digoxin into inactive metabolite dihydro-digoxin through its action at the cardiac glycoside reductase (CGR) operon[122]. Digoxin has a narrow therapeutic index, with high concentrations correlated with mortality in AF patients[123,124]. The CGR protein to Eggerthella lenta ratio can predict the amount of digoxin lowered. Enhanced prediction of digoxin levels is critical to patients with HF and AF and requires continued inquiry[122].

Amiodarone

Based on mouse models, the Probiotic E. coli-induced cytochrome p450 2C activation alters amiodarone metabolism[125]. Conversely, amiodarone exhibits antibacterial activity against E. coli, highlighting a bidirectional relationship[126]. Amiodarone is frequently prescribed in AF, and gut modulation may influence its effectiveness in the future.

Ibrutinib

SCFA-producer Lactobacillus gasseri reduces the risk of Ibrutinib-induced AF[79]. Ibrutinib is an anti-cancer drug that increases AF risk via the C-terminal Src kinase-Src pathway[127]. It also damages gut integrity. As a result, the gut microbiome mediates Irutinib's effect on atrial tissue and electrophysiology.

CURRENT CHALLENGES

Gut modulation therapy is not yet well defined or integrated into standard care. Animal and clinical studies suggest that dysbiosis contributes to AF progression. However, several important issues must be addressed before gut microbiota can be considered a viable target for AF management.

Specifically, despite the correlation between gut dysbiosis and AF, the safety and efficacy of gut-modulating therapy are yet to be tested robustly in randomized controlled trials.

Most current studies on gut microbiota and AF have focused on bacteria, overlooking the potential involvement of other microorganisms such as fungi, viruses, archaea, and protists. The contribution of non-bacterial microorganisms, individually or as part of microbial communities, to AF development warrants further exploration. Additionally, extracting, sequencing, and identifying microorganisms with smaller genomes, such as bacteriophages, is challenging[128]. Instead of focusing on individual microbes, it is essential to explore the combined effects of microbial communities on gut microbiota.

Dietary habits significantly contribute to long-term changes in gut microbiota, but our understanding of this relationship remains limited. However, research indicates that nutritional patterns modulate the stability of gut microbiota over a six-month period[129]. More research is needed to determine the duration of dietary interventions required to produce lasting effects on gut microbiota.

Future studies should also consider whether certain probiotics and postbiotics can influence AF in humans and whether their use could be incorporated into risk factor modification programs for both primary and secondary prevention of AF[128,130].

Studies of association should be investigated through well-designed, randomized clinical trials that incorporate standardized, prospective microbiota analyses to establish causation. Future research should elucidate and characterize both the direct and indirect benefits of gut-modulating therapy in patients with AF.

FUTURE PERSPECTIVES AND EMERGING THERAPIES

Endocannabinoid system

Human research exploring the role of dysbiosis management in AF care is minimal[131]. The endocannabinoid system enhances gut integrity in mouse models in a dose-dependent manner[17]. It acts on tight junctions[132]. Human coronary endothelial cell models exhibit similar effects on membrane permeability at high glucose levels[18]. Decreased permeability mitigates endothelial damage in response to hyperglycemia. However, this needs human research.

Photobiomodulation

Photobiomodulation altered the gut microbiome in obese mouse models[133]. The infrared and red light projected on mice’s abdomens over 2 weeks increased Allobaculum levels. Allobaculum improves gut integrity. Interestingly, exercise also increased Allobaculum levels in obese mice. However, this study was limited in number and requires further inquiry.

CONCLUSION

Gut dysbiosis plays a pivotal role in AF pathogenesis through inflammatory, metabolic, and autonomic pathways. Despite growing evidence linking gut microbiome alterations to the risk and progression of AF, clinical applications remain underexplored. Targeted interventions—such as dietary modifications, microbiome surveillance, and pharmacological strategies—offer promise for the prevention and management of AF.

Technological advancements in microbiome assessment, including metagenomics and wearable biosensors, offer new opportunities for personalized AF care. However, robust clinical trials are essential for validating gut-modulating therapies and establishing their role in routine AF management. Future research should focus on integrating microbiome-based precision medicine into AF care to bridge the evidence gap and improve patient outcomes.