The correlation between gut microbiome and atrial fibrillation: pathophysiology and therapeutic perspectives

Abstract

Regulation of gut microbiota and its impact on human health is the theme of intensive research. The incidence and prevalence of atrial fibrillation (AF) are continuously escalating as the global population ages and chronic disease survival rates increase; however, the mechanisms are not entirely clarified. It is gaining awareness that alterations in the assembly, structure, and dynamics of gut microbiota are intimately engaged in the AF progression. Owing to advancements in next-generation sequencing technologies and computational strategies, researchers can explore novel linkages with the genomes, transcriptomes, proteomes, and metabolomes through parallel meta-omics approaches, rendering a panoramic view of the culture-independent microbial investigation. In this review, we summarized the evidence for a bidirectional correlation between AF and the gut microbiome. Furthermore, we proposed the concept of "gut-immune-heart" axis and addressed the direct and indirect causal roots between the gut microbiome and AF. The intricate relationship was unveiled to generate innovative microbiota-based preventive and therapeutic interventions, which shed light on a definite direction for future experiments.

Keywords: Atrial fibrillation (AF); Gut microbiome; Immunity; Meta-omics; Metabolites.

Fig. 1

Meta-omics for host-microbiome interactions. Consolidation of data from meta-omics approaches provides expanded insights into microbiome capabilities, including metagenomics, metatranscriptomics, metaproteomics, and metabolomics. Currently, the most extensively practiced of the four omics are metagenomics and metabolomics. A cluster of pipelines for the proper execution of meta-omics research is presented, which inspects diverse aspects of the gut ecosystem at multiple levels with their advantages. GC gas chromatography, LC liquid chromatography, MS mass spectrometry, NMR nuclear magnetic resonance, WGS whole genome sequencing, gDNA genomic DNA, cDNA complementary DNA

Fig. 2

Molecular pathways of gut microbiome and the metabolites involved in atrial fibrillation (AF) progression. The pathogenesis of AF is ordinarily based on the substrate, including re-entry-promoting structures, connexin (Cx), and electrical remodeling, as well as Ca²⁺-handling remodeling facilitated by triggered activity. The TLR4/MyD88/NF-κB pathway primes and triggers the atrial NACHT, LRR, and PYD domains-containing protein-3 (NLRP3) inflammasome in response to lipopolysaccharides (LPS) stimulation, resulting in elevated secretion of downstream cytokines such as IL-1. Intestinal flora shape trimethylamine oxide (TMAO) synthesis, facilitate M1 macrophage polarization and pyroptosis and accentuate atrial structural remodeling. TMAO decreases Cx40 expression and Cx43 phosphorylation, possibly as a result of its contribution to increased infiltration of inflammatory cytokines such as IL-1β, IL-6, and tumor necrosis factor-α (TNF-α) in atrial tissue. Short-chain fatty acids (SCFAs) from intestinal symbionts attenuated NLRP3 signaling-mediated atrial fibrosis via GPR43 and downregulated the expression levels of phosphorylated calmodulin kinase II (CaMKII) and CaMKII-related ryanodine receptor 2 (RyR2) phosphorylation in the atria, thereby preventing Ca²⁺-handling disruption. Phenylacetylglutamine (PAGln) exacerbates oxidative stress and apoptosis and enhances activation of CaMKII and RyR2 in atrial myocytes by stimulating α2A, α2B and β2-adrenergic receptors (β2aRs). Bile acids (BAs) signaling via farnesoid X receptor (FXR) quench NLRP3 activation, whereas BA-induced Ca²⁺ influx can activate NLRP3 inflammasome. Moreover, discrepancies in levels of upstream factors, including the autonomic nervous system (ANS), systemic inflammation, and reactive oxygen species (ROS), can also interfere with both ectopic firing and re-entry-promoting substrate, thus directly contributing to the onset and evolution of AF. APD action potential duration, CASP1 caspase-1, DAD delayed afterdepolarizations, DAMPs damage-associated molecular patterns, IL interleukin, M2R M2 receptor, NCX Na⁺/Ca²⁺ exchanger, NF-κB nuclear factor-κB, NGF nerve growth factor, SR sarcoendoplasmic reticulum, TLR Toll-like receptor, TMA trimethylamine, FMO flavin-containing monooxygenase, MyD88 myeloid differentiation primary response protein 88, GPR43 G-protein-coupled receptor 43, Kv voltage-gated potassium

Fig. 3

Gut-immune-heart axis. The gut microbiome can manipulate the immune system to control risk factors and indirectly induce the pathology of atrial fibrillation (AF) through the gut-immune-heart axis. a In the lesioned heart, monocytes and macrophages undergo phenotypic alterations and are massively recruited to the injury site, impacting the cardiomyocyte action potential by regulating repolarization, conduction velocity, and heterogeneity. b Macrophages can trigger the transformation of cardiac fibroblasts to myofibroblasts by releasing cytokines, leading to collagen deposition and facilitating structural remodeling. c Cytokines emitted by leukocytes can also influence ion channel expression (e.g., sarcoplasmic/endoplasmic reticulum Ca²⁺ ATPase 2a), which leads to abnormal Ca²⁺-handling in cardiomyocytes. d Cytokines released from leukocytes can impede intercellular conduction between cardiomyocytes and non-cardiomyocytes (e.g., leukocytes) by decreasing the expression of connexin (Cx) protein. e Microbiome is an emergent mediator of macrophage function and can influence the generation of pro-inflammatory cytokines by macrophages through metabolites (of which TMAO and LPS are promoters, while SCFAs and indole derivatives are inhibitors). LPS lipopolysaccharides, RyR2 ryanodine receptor 2, SCFAs short-chain fatty acids, SR sarcoplasmic reticulum, TMAO trimethylamine oxide, SERCA2a sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase 2a, Cx40 connexin 40, Cx43 connexin 43, IL interleukin, TGF-β transforming growth factor-β

Fig. 4

Candidates to formulate individualized measures for atrial fibrillation (AF) patients targeting microbes. The dysbiosis and symbiotic state of gut microbiota interact with the progression of diseases. The mechanistic link between the gut microbiome and AF poses these interactions as promising therapeutic targets. There are diverse interventions that can be implemented to prevent the deleterious biological effects of ecological dysbiosis, mainly including dietary interventions, probiotic/prebiotic supplementation, drugs, and fecal microbiota transplantation (FMT). Mediterranean diet and high-fiber diet can reduce circulating lipopolysaccharides (LPS) and trimethylamine oxide (TMAO) levels, alleviating oxidative stress and thus slowing AF development. The utilization of well-defined microbial components (probiotics) and non-microbial substances (prebiotics) that may modify the structure of the microbial community has revealed promising results in AF treatment. Moreover, nonabsorbable inhibitors, antibiotics, statins, and oral anticoagulants may exert effects on arrhythmic substrates through gut microbiota. 3,3-dimethyl-1-butanol (DMB), a prototype of lyase inhibitor, can alleviate AF progression by diminishing trimethylamine (TMA)/TMAO synthesis. FMT from healthy donors can alter the patients’ gut flora to treat the disease, but the therapeutic effect of FMT on AF remains to be further explored