Gut microbiota: a key regulator of ageing-associated atrial fibrillation?

This editorial refers to ‘Gut microbiota dysbiosis promotes age-related atrial fibrillation by lipopolysaccharide and glucose-induced activation of NLRP3-inflammasome’ by Zhang Y. et al., pp. 785–797.

Atrial fibrillation (AF) is one of the most common diseases in elderly patients, and its prevalence increases with age. Approximately 10% of people over 80 years of age suffer from AF. The high prevalence of AF in the elderly has been attributed to degenerative changes in the ageing heart and the rise in comorbid conditions such as coronary artery disease, chronic kidney disease, heart failure, and hypertension.¹ Inflammation has been suggested as a pathophysiological mechanism underlying AF development.² In addition, emerging evidence suggests that alterations in the gut microbial composition might contribute to AF development.

1. Microbiota changes in atrial fibrillation

Collectively, the bacteria, fungi, protists, and viruses living on or in us are referred to as the microbiota. Bacteria comprise the major component of the microbiota, and most of these bacteria reside in the gut. The gut microbiota not only aids in digestion but is now recognized for playing critical roles in modulating host physiology. The gut microbiota has been shown to influence host metabolism, blood pressure, and immune system maturation. Conversely, disruption of the gut microbiota community structure, termed gut dysbiosis, has been shown to play a causal role in the development of atherosclerosis, hypertension, and contribute to poorer outcomes following stroke. Intriguingly, ageing is a risk factor for many of the disease states associated with gut dysbiosis, and significant changes to the gut and its resident microbiota have been described with ageing. Specifically, there is a breakdown of the gut epithelial barrier and excess pro-inflammatory cytokine production in the gut wall with ageing. Ageing is also associated with a decrease in the richness and diversity of the gut microbial community, which is characterized by a loss of species with anti-inflammatory properties. It is likely that these alterations to the gut microbiota contribute to the low-level chronic inflammation associated with ageing. In support of this idea, germ-free mice transplanted with microbiota from aged mice exhibited significant increases in pro-inflammatory gene expression in the gut, increased T-helper type 1 (TH1) and TH2 cells in the spleen, and elevated bacterial products in circulation, as compared to germ-free mice transplanted with microbiota from young mice.³ Manipulation of the gut microbiota has been proposed as a prevention or treatment strategy for ageing-associated diseases. Recent studies have begun to examine a potential link between gut dysbiosis and AF. Observational studies have described significant differences in the makeup of the gut microbiota and microbial metabolites of AF patients. Patients with AF were shown to have an increased abundance of Ruminococcus, Streptococcus, and Enterococcus, as well as reduction of Faecalibacterium, Alistipes, Oscillibacter, and Bilophila.⁴

Zhang et al.⁵ demonstrate that ageing-associated gut dysbiosis plays a causal role in the pathogenesis of AF. Using a faecal microbiota transplantation (FMT) model, they showed that transplanting the microbiota of aged rats to young hosts promotes atrial fibrosis and increases AF susceptibility, whereas, recolonizing aged rats with the microbiota of youthful rats suppressed ageing-related AF development. The findings revealed that aged microbiota alters the intestinal structure and induce gut barrier dysfunction, resulting in increased circulating lipopolysaccharide (LPS) and glucose. Elevated serum LPS and glucose levels subsequently activate the ‘NOD-, LRR-, and pyrin domain-containing protein 3’ (NLRP3) inflammasome pathway in atria and enhance atrial arrhythmogenesis as previously reported⁶ (Figure 1). In addition, the NLRP3 inflammasome was more activated in atrial tissue samples from elderly patients with a history of AF, relative to elderly patients without AF or young patients. This work not only provides new evidence for the importance of the gut-heart axis but also mechanistically connects a key risk factor of AF (i.e. ageing) with the recently established NLRP3 inflammasome pathway. Mechanistically, alterations in gut metabolites and endotoxins may play a key role in causing ageing-related AF. Despite these interesting findings, several questions remain. One technical limitation of the Zhang et al.⁵ study was the lack of validation that the recolonized microbiota resembled that of the donor groups. In addition, gene targeting approaches could be employed to determine the role of toll-like receptor 4 (TLR4, the presumed LPS target in atria) or NLRP3 specifically within cardiac fibroblasts.

Figure 1.

Mechanisms underlying the gut dysbiosis-mediated pathogenesis of atrial fibrillation. APD, action potential duration; BA, bile acid; DAD, delayed after-depolarization; IL-1β, interleukin-1β; IL1R, IL-1 receptor; LPS, lipopolysaccharides; Kv1.5, voltage-gated ultra-rapid K⁺ channel; M2R, M2 muscarinic receptor; NCX, Na⁺/Ca²⁺ exchanger; RyR2, ryanodine receptor type-2; TMAO, trimethylamine-N-oxide; TLR, toll-like receptor. This figure was created using BioRender.com.

2. Linking gut microbial metabolites to key atrial fibrillation mechanisms

Preclinical studies have implicated several microbial metabolites that may contribute to the pathogenesis of AF. For example, the gut microbiota converts dietary carnitine and choline to trimethylamine, which is oxidized in the liver to form trimethylamine-N-oxide (TMAO). TMAO has been shown to exacerbate cardiac fibrosis via activation of the NLRP3 inflammasome. Additionally, injection of atrial ganglionated plexi with TMAO resulted in p65 NF-kB activation and promoted arrhythmia (Figure 1). The AF-RISK study found that higher levels of TMAO associated with more progressed forms of AF.⁷ Whether the age-related gut dysbiosis alters TMAO levels, thereby enhancing NLRP3 inflammasome activation and atrial arrhythmogenesis, was not addressed in the current study. Bile acids (BAs) have also been shown to affect proarrhythmic mechanisms. Primary BAs, generated in the liver, are deconjugated and converted to secondary BAs by the gut microbiota. While most BAs are recycled via the enterohepatic circulation, a small portion of BAs enter the systemic circulation. Thus, gut dysbiosis can alter the BA profile experienced by peripheral tissues. Conjugated BAs have been shown to influence cardiomyocyte membrane potential via stimulation of the M2 muscarinic receptor and the Na⁺/Ca²⁺-exchanger (Figure 1). Additionally, the primary BA chenodeoxycholic acid (CDCA) has been shown to bind the nuclear receptor FXR and induce cardiomyocyte apoptosis and fibrosis. BAs have also been shown to modulate the activation of the NLRP3 inflammasome. Bile acids signalling through FXR has been shown to inhibit NLRP3 activation, while BA-induced Ca²⁺ influx can activate the NLRP3 inflammasome.⁸ Increased NLRP3 inflammasome activity leads to IL-1β release,⁹ which upon binding to the IL-1 receptor can trigger NF-κB transcription and myofibroblast differentiation leading to atrial fibrosis.¹⁰ Collectively, these findings suggest multiple mechanisms through which microbial metabolites may induce atrial arrhythmogenesis. Further experimental examination of the effect of gut dysbiosis on NLRP3 inflammasome, Ca²⁺ dysregulation, gap junction remodelling, and electrical remodelling are warranted. Because the gut microbiota composition is influenced by many factors including physical activity, diet, and sleeping habits, the practicality of restoring balance to dysbiotic microbiota in the ageing population could be challenging. However, several therapeutic options including FMT, administration of pre- or pro-biotics, and altering the disease-causative metabolites offer promise but require detailed pre-clinical and clinical investigations.

Funding

This work was supported by National Institutes of Health grants (R01HL136389 and R01HL147108 to N.L., R01HL134838 to D.D., and R01HL147108, R01HL153358, and R01HL089598 to X.H.T.W.).

Conflict of interest: none declared.

 

The opinions expressed in this article are not necessarily those of the Editors of Cardiovascular Research or of the European Society of Cardiology.