Gut microbiota and myocardial fibrosis

https://doi.org/10.1016/j.ejphar.2022.175355Get rights and content

Highlights

  • The effect of the “gut-heart axis” on myocardial fibrosis.

  • Proposing methods to treat myocardial fibrosis by altering the gut microbiota.

  • Future directions in the treatment of myocardial fibrosis with gut microbiota.

Abstract

Myocardial fibrosis (MF) is a pathophysiological condition that accompanies various myocardial diseases and comprises a damaged myocardial matrix repair process. Although fibrosis plays a vital role in repair, it ultimately alters cardiac systolic and diastolic functions. The gut microbiota is a complex and dynamic ecosystem with billions of microorganisms that produce bioactive compounds that influence host health and disease progression. Intestinal microbiota has been shown to correlate with cardiovascular disease, and dysbiosis of the intestinal microbiota is involved in the development of MF. In this review, we discuss the role of intestinal microbiota in the process of MF, including alterations in microbiota composition and the effects of metabolites. We also discuss how diet and medicines can affect cardiac fibrosis by influencing the gut microbiota, and potential future therapies targeting the gut-heart axis. A healthy gut microbiota can prevent disease, but dysbiosis can lead to various symptoms, including the induction of heart disease. In this review, we discuss the relevance of the gut-heart axis and the multiple pathways by which gut microbiota may affect cardiac fibrosis, including inflammatory factors, immune cells, and gut microbiota metabolites, such as trimethylamine-N-oxide (TMAO) and short-chain fatty acids (SCFAs). Finally, we discuss the involvement of gut microbiota in the treatment of cardiac fibrosis, including drugs, fecal microbiota transplantation, and oral probiotics or prebiotics. With future studies on the relationship between the heart and gut microbiota, we hope to find better ways to improve MF through the gut-heart axis.

Introduction

Myocardial fibrosis (MF) results from chronic heart disease (CHD). Fibrosis is considered an excessive deposition of extracellular matrix (ECM) proteins in parenchymal tissue. In MF, all organs (kidneys, gastrointestinal tract, lungs, and liver) change and become dysfunctional (Kong et al., 2014). This dysfunction results in adverse outcomes, and the adult mammalian heart has negligible regenerative capacity to heal through scar formation. Myocardial infarction (MI), a common cause of fibrosis, with sudden coronary artery blockage and stimulation of inflammation, leading to scar formation. Obesity, aging, and hereditary cardiomyopathy can also promote myocardial interstitial fibrosis and reduce ventricular compliance, potentially contributing to the pathogenesis of heart failure with preserved ejection fraction (HFpEF) (Frangogiannis, 2021).

Like the activation of other critical organs, gut microbiota, also considered an essential organ in the human body, renews itself every three days (Mazidi et al., 2016). It also participates in metabolism, immune system, mental health, modulation of gastrointestinal hormone release, and minimization of risk factors for numerous diseases (Kim et al., 2020; Ma et al., 2020; Tang et al., 2019a; Zhang et al., 2022a). Gut dysbiosis is a disturbance in the population, diversity, space, or quantity of the gut microbiota. It can be caused by various factors including age, nutrition, medicines, and toxins (Lynch and Pedersen, 2016). Dysbiosis is associated with the development of atherosclerosis, arrhythmia, cardiovascular disease (CVD), and cardiac fibrosis (Hansson et al., 2006; Tilg, 2016; Zhang et al., 2022a).

Many metabolites, such as short-chain fatty acids (SCFAs), bile acids, and trimethylamine-N-oxide (TMAO), are affected by interactions between the gut microbiota and the host, affecting gut health and function, as well as different host metabolic pathways (Ahmad et al., 2019). Animal models have demonstrated the effects of microbiota on MI (Ahmad et al., 2019), hypertension (Marques et al., 2017), and diabetes (Chen et al., 2015), resulting in cardiac fibrosis. In clinical research, probiotic supplementation has been shown to have a beneficial effect on cardiac remodeling in patients with MI (Moludi et al., 2021).

Cardiac fibrosis is often secondary to underlying myocardial diseases, such as MI, atrial fibrillation, myocardial ischemia-reperfusion injury, and hypertension. Specific circulating metabolites could contribute to the risk of cardiovascular events and subsequent pathological responses owing to alterations in the microbiota. Various studies have demonstrated the existence of a gut-heart axis (Bartolomaeus et al., 2020; Jaaouani et al., 2021; Khan et al., 2022; Zhang et al., 2021; Zou et al., 2021). Thus, the relationship between intestinal microbiota and underlying cardiac diseases has been well studied (Chen et al., 2020; Li et al., 2021; Tang et al., 2019b). However, the relationship between intestinal microbiota and the cardiac pathological state and cardiac fibrosis has not been well described. To address this, we reviewed the available literature to discuss the role of gut microbiota in the development and progression of cardiac fibrosis. Based on our review of the current literature, altering the microbiome appears to be a potential therapeutic approach for preventing the progression of cardiac fibrosis.

Section snippets

Normal cardiac interstitium and myofibroblasts

In the adult mammalian heart, ventricular myocytes are arranged in layers 3–5 cell-thick (Leonard et al., 2012), with neighboring myocytes being tightly coupled, both electrically and mechanically. Cardiomyocyte layers are surrounded by cardiac ECM, which is mainly composed of fibrillar collagens (Souders et al., 2009). The ECM not only contains collagen types I and III (Robinson et al., 1988) but also comprises a complex array of biomolecules (Borg and Baudino, 2011; Graham et al., 2008;

Brief overview of gut microbiota

The intestinal microbiota is an endophytic ecosystem of bacteria, archaea, eukaryotes, and viruses, of which four bacterial phyla (Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria) account for 98% of the total microbial population (Patrignani et al., 2014). It has co-evolved with the host as a symbiotic superorganism that regulates normal intestinal functions. Previous studies of human fecal microbiota sequencing have shown that the composition of gastrointestinal microbes is

Gut microbiota compositional changes and association with fibrosis

The “gut-heart axis” has been proposed and studied in recent years of research in CVDs and gut microbiota. Alterations in the gut microbiota community are usually accompanied by several disease states, such as atrial fibrillation, MI, and hypertension (Jie et al., 2017; Li et al., 2021; Zhang et al., 2022b). A study that included 30 post-MI patients demonstrated that alterations in gut microbiota were accompanied by decreased left heart diastolic function, implying that intestinal bacteria may

Treatments

Treatments impacting the gut microbiota include diet, exercise, antibiotics, probiotics, fecal microbiota transplant (FMT), anti-TMAO treatment, and traditional medicine. Nevertheless, these treatments still require further clarification before considering the gut microbiota as a contributory factor to cardiac fibrosis that can be targeted, as summarized in Table 1.

Conclusion

Microbiota dysbiosis is associated with various diseases and has emerged as an influential factor in cardiac fibrosis. It is associated with the systemic inflammatory state of the host and plays a role in the oxidative state by acting through the gut-heart axis. It is now increasingly clear that the intestinal microbiota acts between organs through humoral, neurological, and immune systems. A healthy gut can help an organism prevent and alleviate certain diseases. However, the exact mechanisms

Funding

This study did not receive any specific grants from funding agencies in the public, commercial, or not-for-profit sectors.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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