An Aged Gut Microbiome Increases Susceptibility of Arrhythmia in a Mouse Model
The balance of microbial populations making up the gut microbiome changes with age, in ways that negatively affect health. Pro-inflammatory microbes increase in number while populations producing beneficial metabolites decrease in size. Researchers here discuss the evidence for an aged gut microbiome to contribute to various aspects of cardiovascular disease, and show that in mice an aged gut microbiome increases risk of arrhythmia. The researchers suggest that the mechanism of interest is increased oxidative stress resulting from the activities of microbial populations, which is then disruptive to the normal metabolism of the heart. There may be other mechanisms.
The prevalence of arrhythmias and incidence of sudden cardiac death (SCD) increases markedly with age, leading to higher morbidity and mortality in the elderly. The frequency of arrhythmias, particularly atrial fibrillation (AF) and ventricular tachyarrhythmias (VT), is expected to increase with aging. Gut microbiota has been recognized as an important factor in the development of cardiovascular diseases, such as AF, heart failure (HF), ischemia, and reperfusion. It is also considered to be an endocrine organ that plays a role in the manipulation of host immunity and metabolic homeostasis. It has been shown to play both beneficial and adverse roles in AF rats and patients, which could be related to the heterogeneity of the microbiota.
Research indicates that in patients with AF, the relative abundance of Ruminococcus, Streptococcus, and Enterococcus increase, while that of Faecalibacterium, Oscillospira, and Bilophila decreases. From the perspective of intestinal content metabolism, the bacteria producing trimethylamine oxide (TMAO) in gut microbiota of AF patients increase. Moreover, local injection of TMAO in canine can activate atrial autonomic nerve plexus, shorten effective refractory period (ERP) value, and then promote arrhythmia, which because of the activation of p65/NF-κB signaling and inflammatory cytokines.
Here, we demonstrated that arrhythmia susceptibility in aged mice could be transmitted to young mice using fecal microbiota transplantation (FMT). Mechanistically, increased intestinal reactive oxygen species (ROS) in aged mice reduced ion channel protein expression and promoted arrhythmias. Gut microbiota depletion by an antibiotic cocktail reduced ROS and arrhythmia in aged mice. Interestingly, oxidative stress in heart induced by hydrogen peroxide (H2O2) increased arrhythmia. Moreover, aged gut microbiota could induce oxidative stress in young mice colon by gut microbiota metabolites transplantation. Vitexin could reduce aging and arrhythmia through OLA1-Nrf2 signaling pathway.
Overall, our study demonstrated that the gut microbiota of aged mice reduced cardiac ion channel protein expression through systemic oxidative stress, thereby increased the risk of arrhythmias.