Butyrate attenuates sympathetic activation in rats with chronic heart failure by inhibiting microglial inflammation in the paraventricular nucleus

Abstract

Sympathetic activation is a hallmark of heart failure and the underlying mechanism remains elusive. Butyrate is generated by gut microbiota and influences numerous physiological and pathological processes in the host. The present study aims to investigate whether the intestinal metabolite butyrate reduces sympathetic activation in rats with heart failure (HF) and the underlying mechanisms involved. Sprague-Dawley rats (220‒250 g) are anaesthetized with isoflurane, and the left anterior descending artery is ligated to model HF. Then, the rats are treated with or without butyrate sodium (NaB, a donor of butyrate, 10 g/L in water) for 8 weeks. Blood pressure and renal sympathetic nerve activity (RSNA) are recorded to assess sympathetic outflow. Cardiac function is improved (mean ejection fraction, 22.6%±4.8% vs 38.3%±5.3%; P<0.05), and sympathetic activation is decreased (RSNA, 36.3%±7.9% vs 23.9%±7.6%; P<0.05) in HF rats treated with NaB compared with untreated HF rats. The plasma and cerebrospinal fluid levels of norepinephrine are decreased in HF rats treated with NaB. The infusion of N-methyl-D-aspartic acid (NMDA) into the paraventricular nucleus (PVN) of the hypothalamus of HF model rats increases sympathetic nervous activity by upregulating the NMDA receptor. Microglia polarized to the M2 phenotype and inflammation are markedly attenuated in the PVN of HF model rats after NaB administration. In addition, HF model rats treated with NaB exhibit enhanced intestinal barrier function and increased levels of GPR109A, zona occludens-1 and occludin, but decreased levels of lipopolysaccharide-binding protein and zonulin. In conclusion, butyrate attenuates sympathetic activation and improves cardiac function in rats with HF. The improvements in intestinal barrier function, reductions in microglia-mediated inflammation and decreases in NMDA receptor 1 expression in the PVN are all due to the protective effects of NaB.

1. Introduction

Chronic heart failure (CHF), the health and economic burden of which has recently been increasing worldwide, remains a leading cause of morbidity and mortality globally [1]. CHF represents an end stage of many cardiovascular diseases (CVDs), including ischaemic heart disease [2], myocardial infarction (MI) [3], hypertension [4], and valvular and vascular heart disease [5]. Despite the availability of classical drugs for CHF treatment, such as angiotensin-converting enzyme inhibitors, beta-adrenergic blockers and angiotensin II receptor blockers, the morbidity and mortality of CHF patients have not greatly improved.

Continual activation of the sympathetic nervous system is strongly related to CHF and has adverse effects on the initiation and development of CHF, especially myocardial remodeling [6–9]. Thus, inhibiting sympathetic activation is a crucial therapeutic strategy for this complex syndrome. However, the mechanisms underlying sympathetic activation in CHF are not completely understood.

Elevated peripheral sympathetic output in CHF patients is induced by increased activity of specific central neuronal circuits and the release of excitatory neuron transmitters. The paraventricular nucleus (PVN) is located on either side of the superior aspect of the hypothalamus in the third ventricle and plays an important role in autonomic and neuroendocrine functions. Indeed, several studies have shown increased glutamatergic signaling in the PVN in rats with myocardial infarction [10]. In addition, inflammatory mediators can cause central sympathetic excitation [11]. Elevated inflammation in the PVN, which contains presympathetic neurons that project to the rostral ventrolateral medulla, plays an important role in sympathetic excitation in CHF [12–14]. However, the mechanisms underlying the increase in inflammation in the PVN of rodents with CHF are not fully clear.

The gut microbiota, considered an endocrine organ, consists of trillions of bacteria in the gastrointestinal tract and produces hundreds of different metabolites. It is involved in the pathogenesis of a wide range of diseases [15]. The gut microbiota may exert its effects on the brain via various metabolites [16]. Gut microbe fermentation by indigestible dietary fiber results in the production of short-chain fatty acids (SCFAs), including acetate, propionate, and butyrate [17]. The relative abundance of microbes that produce butyrate was found to be reduced in atherosclerosis and