Salt and Gut Microbiota in Heart Failure

Abstract

Purpose of Review

The role and underlying mechanisms mediated by dietary salt in modulating the gut microbiota and contributing to heart failure (HF) are not clear. This review summarizes the mechanisms of dietary salt and the gut-heart axis in HF.

Recent Findings

The gut microbiota has been implicated in several cardiovascular diseases (CVDs) including HF. Dietary factors including high consumption of salt play a role in influencing the gut microbiota, resulting in dysbiosis. An imbalance of microbial species due to a reduction in microbial diversity with accompanying immune cell activation has been implicated in the pathogenesis of HF via several mechanisms.

Summary

The gut microbiota and gut-associated metabolites contribute to HF by reducing gut microbiota biodiversity and activating several signaling pathways. High dietary salt modulates the gut microbiota composition and exacerbate or induce HF by increasing the expression of the epithelial sodium/hydrogen exchanger isoform 3 in the gut, cardiac expression of beta myosin heavy chain, activation of the myocyte enhancer factor/nuclear factor of activated T cell, and salt-inducible kinase 1. These mechanisms explain the resulting structural and functional derangements in patients with HF.

Introduction

Heart failure (HF) is a complex clinical syndrome resulting from various pathological processes impacting heart structure or function of ventricular filling or ejection of blood [1]. HF is manifested mainly by dyspnea and fatigue and additional symptoms in some patients that include exercise intolerance and fluid retention that is characterized by edema [1]. Within the first 5 years of diagnosis around 50% of HF patients die [2, 3]. The most common risk factors associated with HF are hypertension, atherosclerotic disease, metabolic syndrome, and diabetes mellitus [1]. Although sodium (from dietary salt) is an essential mineral and nutrient critical in maintaining blood volume and blood pressure, excess intake is associated with increased risk for development of hypertension, chronic kidney disease, stroke, and cardiovascular diseases (CVDs) such as HF [4]. Further, dietary salt contributes to dysbiosis, an “imbalance” in the gut microbial community that results in several processes that contribute to the development of CVDs [5••]. The gut microbiota also contributes to HF pathogenesis independent of dietary salt, and HF has a reciprocal deleterious effect on gut microbial homeostasis by disturbing intestinal barrier function [6] as will be explained in detail later.

The gut microbiota contains several phyla of healthy bacteria with gram negative Bacteroidetes such as Bacteroides or Prevotella and gram positive Firmicutes such as Clostridium and Lactobacillus constituting more than 90% of all microbiota [7]. The gut microbiota can metabolize various indigestible carbohydrates and proteins to yield short-chain fatty acids (SCFAs) (acetic, propionic, and butyric acid) that provide energy for intestinal epithelial cells and aid in the synthesis of vitamins and amino acids [7]. Conditions favoring growth of one phyla from another has been implicated in disease and health [8]. In the recent years, the gut microbiota composition has been postulated as one of the drivers in the development or worsening of both the risk factors for HF and HF itself [8, 9•]. In this review, we first highlight the mechanisms underlying gut microbiota-associated HF and further highlight current and emerging evidence of how salt modulates the gut microbial community composition and contributes to HF. We then discuss gaps and potential therapeutic targets to alleviate HF.

Mechanisms of Gut Microbiota-Associated Heart Failure

Leaky Gut Dysfunction in HF

A healthy gut microbiota plays a role in maintaining intact tight junctions between epithelial cells and protects against localization of pathogenic bacteria by complex mechanisms, including competitive metabolic interactions, niche exclusion, nutrient competition, and induction of host immune response [10]. Conditions that interrupt barrier function result in translocation of gut microbiota into systemic circulation, resulting in systemic inflammation that contributes to chronic HF [11]. Chronic HF is linked to structural and functional changes of intestinal mucosa or epithelial cells resulting in increased intestinal permeability, wall thickness and bowel ischemia (Fig. 1) [11].

Fig. 1.

Leaky gut theory in heart failure. Fluid retention in heart failure leads to edema and disruption of intestinal epithelial tight junctions leading to increased permeability. Dysbiosis induces inflammation and oxidative stress and also contributes to increased permeability resulting in bacteria translocation and systemic inflammation that contributes to HF pathogenesis. LPS, lipopolysaccharide; TNF-α, tumor necrosis factor alpha; ROS, reactive oxygen species

Ischemia results from poor gut perfusion in HF that affects intestinal villus, causing increased tension, acidosis, and atrophy [12]. Increased bowel wall thickness in HF is mediated by congestion in multiple organs, including the gut from edema [11]. Increased intestinal permeability allows endotoxins such as Lipopolysaccharides (LPS) to sip into systemic circulation and induce inflammatory reactions through interaction via Toll-like receptor 4 (TLR4) expressed by many cell types including macrophages, dendritic cells, cardiomyocytes, and cardiac fibroblasts [13]. Activation of macrophages and dendritic cells causes them to secrete inflammatory cytokines such as tumor necrosis factor alpha (TNF-α), IL-1β, and IL-6 which induce intestinal permeability, systemic inflammation [14–16] and worsen HF [17, 18] (Fig. 1).

As summarized in Fig. 2, increased intestinal epithelial tight junction permeability by TNF-α is induced through activation of myosin light-chain kinase (MLCK) protein and nuclear factor kappa B (NF-κB) signaling pathways [16].

Fig. 2.

Mechanisms that disrupt intestinal gap junctions. TNF-α, tumor necrosis factor alpha; MLC, myosin light-chain; MLCK, myosin light-chain kinase; ERK1/2, extracellular signal-regulated kinase ½; TNFR, tumor necrosis factor receptors; NFkB, nuclear factor kappa-light-chain-enhancer of activated B cells; MAPK, mitogen-activated protein kinases; AP-1, activator protein-1; JNK, c-Jun NH2-terminal kinase; mRNA, messenger RNA

Activation of the MLCK protein leads to the phosphorylation of myosin light-chain (MLC) that activates Mg²⁺⁻myosin ATPase, providing the metabolic energy required for the mechanical contraction of perijunctional actin and myosin filaments resulting in opening of the tight junction barrier [16]. Activation of the MLCK pathway by TNF-α is associated with an increase in NF-κB activation and induction of apoptosis [19]. The study by Ma et al. suggests that NF-κB activation results in translocation of NF-κB from the cytoplasm into the nucleus, where NF-κB binds to the MLCK promoter region. This activates the MLCK promoter activity, leading to increased MLCK mRNA transcription and expression that results in the contraction of perijunctional actin-myosin filaments and opening of the intestinal epithelial tight junction barrier [16]. The TNF-α–induced increase in tight junction permeability through the MLCK pathway is also mediated by activation of the mitogen-activated protein (MAP) kinase pathway via the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway that leads to phosphorylation and activation of the ETS domain-containing transcription factor Elk-1 [15]. Elk-1 then moves into the nucleus to bind to the MLCK promoter region in the same manner as NF-κB [15]. IL-6 induces increased intestinal epithelial permeability via the c-Jun N-terminal kinase (JNK) pathway. Activation of the activator protein-1 (AP-1), which then binds to its binding sequence on the claudin-2 promoter region, results in increased claudin-2 gene transcription, protein synthesis and increased intestinal epithelial tight junction permeability [14].

Dysbiosis and Heart Failure

Several studies have demonstrated increases in pathogenic bacteria species such as Campylobacter, Shigella, Salmonella, Yersinia enterolytica, and Candida in stool samples of patients with stable congestive HF that correlate with increased gut permeability as measured by cellobiose sugar test [20]. Patients with HF tend to have decreases in Coriobacteriaceae, Erysipelotrichaceae, Bifidobactericeae, and Ruminococcaceae on the family level and decreases in Blautia, Collinsella, unclassifified (uncl.) Erysipelotrichaceae, uncl. Ruminococcaceae, Clostridium, and Dorea on the genus level and increases in the genuses Prevotella, Hungatella, and Succinclasticum [21, 22]. In general, HF patients have decreased diversity of microbiota composition and hence, diminished healthy and protective species that render them susceptible to adverse complications due to increased inflammation [23]. Gut associated inflammation is one of the strong drivers of worsening HF [23].

Gut Microbiota-Generated Metabolites and Heart Failure

TMA/TMAO

Trimethylamine N-oxide (TMAO) is a colorless amine oxide produced from trimethylamine (TMA) in the liver by the enzymatic action of flavin-containing monooxygenase 3 (FMO3). TMA is produced by various gut microbial taxa from dietary quaternary amines phosphatidylcholine, choline, and L-carnitine found in high-fat foods [6] (Fig. 3).

Fig. 3.

TMAO generation and effects on the heart. FMO3, flavin-containing monooxygenase 3; NFkB, nuclear factor kappa-light-chain-enhancer of activated B cells; NLRP3, NLR family pyrin domain containing 3; ASC, apoptosis-associated speck-like protein containing a CARD

The dietary precursors of TMAO have been implicated in CVD development, atherosclerosis, and hypertension by enhancing macrophage foam cell formation that correlates with increased expression of macrophage scavenger receptor CD36 and scavenger receptor A1 (SRA1) protein [24, 25]. TMAO also contributes to HF by inducing myocardial hypertrophy, cardiac mitochondrial dysfunction, decreased left ventricular pump function and fibrosis [26–29] by activating inflammatory and oxidative stress pathways that induce myocardial remodelling and the development of HF phenotypes. For example, TMAO can activate the nucleotide binding oligomerization domain–like receptor family pyrin domain-containing-3 (NLRP3) inflammasome, a multiprotein complex that modulates the activity of innate immune cells and inflammatory signalling by activating caspase-1, which in turn induces the release of the pro-inflammatory cytokines IL-1β, TNF-α, and IL-18 [30] (Fig. 3). NLRP3 also induces vascular inflammation via the sirtuin-3-superoxide dismutase 2-mitochondrial reactive oxygen species (SIRT3-SOD2-mtROS) pathway [31] and the NF-kB pathway [32]. Measuring plasma TMAO levels can be used to predict long-term mortality risk in patients with HF [33]. However, the underlying mechanisms of TMAO’s contribution to HF are still unclear.

Short-Chain Fatty Acids

SCFAs such as butyrate, acetate, and propionate are the main metabolites produced from indigestible polysaccharides by the microbiota in the large intestine [34]. SCFA have anti-inflammatory effects on the cells of the immune system via signaling through NF-κB [35] and by inhibiting histone deacetylase (HDAC) to increase the number of Foxp3 + T regulatory (Treg) cells, enhancing their anti-inflammatory effect and ameliorating inflammatory responses [36]. SCFAs play a role in the maintenance of the intestinal epithelial barrier by directly activating the G-protein-coupled-receptors (GPCRs) GPR41, GPR43, and GPR109A, and they also serve as energy substrates for gut microbiota and intestinal epithelial cells [37, 38]. The SCFA propionate lowers blood pressure through GPR41 signaling [39]. Butyrate promotes the proliferation and differentiation of intestinal epithelial cells, and enhances the repair and integrity of damaged intestinal mucosa by enhancing oxygen consumption that stabilizes hypoxia-inducible factor (HIF), a transcription factor involved in maintaining a healthy gut barrier and decreasing inflammation caused by pathogenic microbes [40]. SCFAs can serve as fuel for the heart in HF and improve heart functionality [41] and also have protective properties against systemic hypertension and left-sided cardiac pathology [42].

Bile Acids

Primary bile acids (cholate and chenodeoxycholate) are synthesized from cholesterol and conjugated using taurine or glycine by the hepatocytes and stored in the gallbladder [43]. The gut microbiota converts them to secondary bile acids lithocholate, ursodeoxycholateonce, and deoxycholate once secreted by the gallbladder into the duodenum following ingestion of fatty food [43]. Ninety-five percent of bile acids are reabsorbed in the ileum and the remainder are lost in the feces [44]. Bile acids bind to nuclear farnesoid X receptor (FXR) in the ilium to induce the expression of fibroblast growth factor (FGF15/19), which in turn is transported to the liver to bind to hepatocyte receptors and repress bile synthesis by inhibiting the main regulatory enzyme for primary bile synthesis, cholesterol 7α-hydroxylase (CYP7A1) [45–47]. Interestingly, FXRs are also expressed by cardiac cells, where they modulate physiological function of heart tissue. Thus, elevated serum bile acids can contribute to cardiac dysfunction [48]. The vasculature also expresses FXRs [49]. Elevated levels of bile acids are associated with electrical conductance defects in the heart, cardiac hypertrophy, and apoptosis and reduced heart contractility via FXR stimulation [48]. However, the exact mechanisms remain unknown. FXR is therefore a potential target in ameliorating cardiac dysfunction and promoting myocardial remodeling [50, 51]. There is a close link between increased levels of secondary bile acids generated by gut microbiota and congestive HF, as demonstrated in one prospective study [52].

Salt Modulates the Gut Microbiome, Contributing to Heart Failure

Increased salt intake is associated with increased risk for development of hypertension, HF, and other CVDs and death [53]. The World Health Organization recommends < 5 g of salt per day (~ 2 g of sodium) to prevent CVD [5••]. Increased salt intake alters gut microbiota diversity [54], as demonstrated in mice fed with high salt which tend to have lower Bacteroidetes and Lactobacillus and higher Firmicutes, Corynebacteriaceae, Lachnospiraceae, and Ruminococcus compared to those fed with a low salt diet [54, 55]. A high Firmicutes/Bacteroidetes ratio is associated with increased risk for CVD and obesity [56, 57]. Increased dietary salt not only contributes to HF indirectly via dysbiosis but also directly, by increasing the fluid load in the cardiovascular system that results in increased cardiac workload [58]. Although high dietary salt suppresses the renin–angiotensin–aldosterone system (RAAS) to avoid the pressor effect of RAAS, salt increases oxidative stress in the vasculature increasing cardiac remodeling [59]. Oxidative stress in the brain then activates sympathetic tone and the local RAAS and induces RAAS activation in the kidney to promote resorption of sodium and potentiate a high blood pressure effect [59].

A recent study by Yan et al. demonstrated the effect of high salt on the microbiota composition as a contributor to hypertension using murine models. They found that high salt reduced the levels of Bacteroides fragilis and arachidonic acid in the intestine, which increased intestinal-derived corticosterone production, thereby elevating blood pressure [60••]. Further, transplantation of fecal microbiota from salt induced hypertensive rats promoted development of hypertension in healthy rats while fecal microbiota transplantation from healthy rats, had a lowering effect on blood pressure. This effect has been reported in another recent study [61•]. This study by Yan et al. suggests a novel hormonal mechanism of salt-gut microbiota effect on blood pressure independent of immune activation/inflammation. High salt intake has also been shown to immediately decrease the prevalence of Lactobacillus species and types that produce indole-3-lactic acid, which inhibits the polarization of pro-inflammatory T_h17 cells [62]. This results in production of IL-17A and induction of hypertension by this subset of activated CD4 + cells [62]. High sodium intake was associated with decreased microbial diversity and a shift in the composition of microbiomes and hypertension in humans [61•]. Mice fed a high-salt diet exhibited increased intestinal, mesenteric arterial arcade and aorta inflammation due to dendritic cell activation resulting in hypertension [61•]. These studies highlight the role of dietary salt in modulating the gut microbiota and inducing hypertension, an effect that may exacerbate or increase the risk of HF.

In addition, the gut expresses the epithelial sodium/hydrogen exchanger isoform 3 (NHE3) which is important for nutrient absorption and maintenance of gut microbiota homeostasis [54]. NHE3 is a member of the solute carrier family 9 (SLC9A3) and is expressed on apical membranes of epithelial cells of the kidney and the gut [63]. High salt diets increase the expression of NHE3 at the apical or basolateral membranes in the gut [5••], increasing salt absorption and the risk for hypertension. The pathogenic bacteria Escherichia coli and Clostridium difficile inhibit NHE3 expression and function in the murine and human gut [64–66], while commensal Lactobacillus acidophilus upregulate NHE3 expression and function [63]. This suggests that NHE3 is modulated by pathogenic and commensal bacteria in disease and may therefore be an important player in HF. However, there is still scarcity of data on the role of NHE3’s in HF.

Salt and Heart Failure Mechanisms

Dietary salt may worsen HF via several mechanisms [4] briefly described here and summarized in Fig. 4.

Fig. 4.

Salt-related mechanisms in heart failure. NHE3, sodium-hydrogen exchanger 3; ROS, reactive oxygen species; MEF2, myocyte enhancer factor; NFAT, nuclear factor of activated T cell; SIK1, salt-inducible kinase 1; SGK1, glucocorticoid kinase 1

Dietary salt can directly stimulate sympathetic activity and increase blood pressure [67]. High salt intake also promotes aortic stiffness, resulting in decreased systemic resistance and increased blood pressure that may worsen HF [68•].

Increased salt intake reduces erythrocyte sodium buffering capacity potentiating extravascular accumulation of salt in the interstitial space [69]. Increased salt in the interstitial tissue and skin activates innate immune cells such as monocytes and dendritic cells that activate T cells, leading to increased production of IL-17A, TNF-α, and interferon-gamma, which in turn mediate kidney damage, endothelial dysfunction, and increase blood pressure [70–72]. This effect has deleterious effects on HF. Further, increased salt induces expression of vascular cell adhesion molecule (VCAM-1), leading to increased cell activation and release of inflammatory cytokines that result in cardiac remodeling [73], as well as alteration in transient receptor potential cation channel subfamily C member 3 (TRPC3) expression and calcium influx that induce oxidative stress and inflammation in cardiac cells of hypertensive patients and increase systolic blood pressure [74].

High salt is also associated with increased cardiac expression of beta myosin heavy chain (β-MHC) and a decrease in the α/β-MHC ratio resulting in poor myocardial mechanical performance [75]. In one study, increased intracellular sodium increased the transcriptional activity of the myocyte enhancer factor (MEF)2/nuclear factor of activated T cell (NFAT) to activate salt-inducible kinase 1 (snflk-1, SIK1) via calcium signaling [76]. The two transcription factors MEF2 and SIK1 are important in cardiac cell health. MEF2 activates a genetic program that promotes chamber dilation, dilated cardiomyopathy and contractile dysfunction in calcineurin-induced HF [77]. SIK1 promotes pathologic cardiomyocyte remodeling by phosphorylating and stabilizing histone deacetylase 7 (HDAC7) protein during cardiac stress [78••]. SIK1 expression also mediates activation of MEF2/NFAT and genes associated with left ventricular hypertrophy [76]. Finally, high salt intake activates innate immune cells such as dendritic cells and enhances M2 macrophage polarization and activation of T-cells toward the proinflammatory Th17 phenotype [79, 80]. High salt also induces glucocorticoid kinase 1 (SGK1) expression, which promotes IL-23R expression that in turn enhances T_H17 cell differentiation and production of inflammatory cytokines [81]. SGK1 is a serine-threonine kinase highly expressed in heart that mediates inflammation and cell death in the heart [82]. Infiltration of heart with activated cells and inflammatory cytokines (IL-6, TNF-α) initiate or worsen HF development [83].

A few recent studies highlighting cross talks between salt and/or gut microbiota and HF are summarized in Table 1.

Table 1.

Major recent clinical studies reporting salt, gut microbiota, and HF

Author	Design/method	Significant findings
Romano et al. [84••]	Clinical study involving humans and experimental using cultured cells and animal model An initial discovery US cohort, n = 3256 and a validation European cohort, n = 829	Circulating gut microbiota-dependent metabolite phenylacetylglutamine were dose-dependently associated with HF and indices of severity (reduced ventricular ejection fraction, elevated N-terminal pro-B-type natriuretic peptide) independent of traditional risk factors and renal function in both cohorts
Awoyemi et al. [85•]	Multicenter, prospective randomized open label, blinded end-point trial, comparing 3 months treatment with the probiotic yeast Saccharomyces boulardii or the antibiotic rifaximin in HF patients with left ventricular ejection fraction	Treatment with Saccharomyces boulardii or rifaximin on top of standard of care had no significant effect on left ventricular ejection fraction, microbiota diversity, or the measured biomarkers
Moludi et al. [86•]	Single-center double-blind clinical study. Forty-four subjects with myocardial infarction (MI) who underwent percutaneous coronary intervention (PCI) to evaluate the effects of probiotics administration on attenuating cardiac remodelling	Significant decreases were seen in serum transforming growth factor beta (TGF-β) concentrations (− 8.0 ± 2.1 vs. − 4.01 ± 1.8 pg/mL, p = 0.001) and trimethylamine N-oxide (TMAO) levels (− 17.43 ± 10.20 vs. − 4.54 ± 8.7 mmol/L, p = 0.043), and there were no differences were seen in matrix metallopeptidase 9 (MMP-9) (− 4.1 ± 0.12 vs. − 4.01 + 0.15 nmol/mL, p = 0.443) and procollagen III levels (− 1.35 ± 0.70 vs. 0.01 + 0.3 mg/L, p = 0.392) subsequent to probiotics supplementation compared with the placebo group
Yan et al. [60••]	Experimental study using healthy and hypertensive rats. Study uses 16S rRNA gene sequencing, untargeted metabolomics, selective bacterial culture, and fecal microbiota transplantation techniques	Fecal microbiota of healthy rats dramatically lowered blood pressure (BP) of hypertensive rats, whereas the fecal microbiota of salt–induced hypertensive rats had opposite effects. High-salt diet reduced the levels of B fragilis and arachidonic acid in the intestine, which increased intestinal-derived corticosterone production and corticosterone levels in serum and intestine, thereby promoting BP elevation

Potential Interventions

Antibiotics

Antibiotic usage kills most healthy gut microbiota and renders the gut susceptible to colonization by pathogens, as it takes several weeks to reestablish and regrow the gut microbiota [87]. The effect of antibiotics such as ciprofloxacin and duration of reestablishment of normal gut microbiota are heterogenous among individuals and recovery of some microbiota species can take more than 6 months [87]. However, antibiotics are also beneficial in restoring healthy gut microbiota during dysbiosis in HF [88–90]. Using rat models, Riba et al. demonstrated that doxycycline improved left ventricular systolic function and reduced the severity of HF by ameliorating cardiomegaly, cardiac remodeling and fibrosis [91]. Whether this effect is reproducible in humans remains unknown. More studies are required to evaluate the potential benefits of using antibiotics in HF to avoid inducing microecological dysfunction and antibiotic drug resistance [92, 93].

Prebiotics and Probiotics

Prebiotics are specialized non-digestible fibers that stimulate the growth of healthy gut microbiota while probiotics are live microorganisms such as Lactobacillus and Bifidobacterium that promote healthy gut and increase biodiversity [94, 95]. Yeasts such as Saccharomyces boulardii are also used as probiotics which function through multiple mechanisms to improve gut barrier function, to exclude pathogens by competitive growth, production of antimicrobial peptides, modulating the immune system, as well as having trophic effects [96]. In one randomized double-blind, placebo-controlled pilot trial, HF patients with left ventricular ejection fraction had decreases in serum creatinine and inflammatory markers associated with Saccharomyces boulardii supplementation [97, 98]. In a separate study using C57BL/6 mice, Saccharomyces boulardii ameliorated Citrobacter rodentium-induced colitis by inhibiting secretion and translocation of the pathogen’s receptor for bacterial intimin effector protein, the translocated intimin receptor (Tir), and the translocator protein EspB which are virulent components of the bacteria, reducing bacterial attachment to host intestinal epithelial cells and gut barrier disruption [99]. Saccharomyces boulardii also decreased the inflammatory response in the gut mucosa [99]. Saccharomyces boulardii has been shown to secrete proteins that bind to and block endotoxins secreted by Clostridium difficile, Escherichia coli, and Vibrio cholerae and thus ameliorate inflammation, fluid secretion, mucosal permeability and intestinal epithelial injury [100–106]. However, the exact mechanisms of action remain unclear. In general, probiotics produce antimicrobial compounds such as acteriocins, hydrogen peroxide, diacetyl, or amines, which inhibit growth of pathogenic bacteria [98] and thus protect HF patients from induced microbial translocation and resultant systemic inflammation.

Dietary Interventions

Dietary interventions, such as the Dietary Approaches to Stop Hypertension (DASH) and the Mediterranean diet consisting of fruits, vegetables, whole grains, and low-fat dairy foods have beneficial effects on CVDs, including HF [107–111]. The DASH diet has been reported to reduce blood pressure and the risk for HF [112, 113••], and to reduce arterial stiffness and oxidative stress in HF patients with preserved ejection fraction [114]. The Mediterranean diet, in particular, decreases TMAO levels [115], possibly through extra virgin oil’s 3,3-dimethyl-1-butanol (DMB) which lowers the production of TMAO [6]. This likely attenuates TMAO’s contribution to atherogenesis and hyperactivation of platelets that results in adverse CVD events such as stroke, heart attack and death [6]. Dietary interventions are effective in maintaining healthy microbiota and modulating disease [116–118]. A recent clinical trial found that use of a winery product grape pomace, which is rich in polyphenols and dietary fiber, modulates the gut microbiota and functional bacterial communities, mediating cardiometabolic effects such as lowering blood pressure and fasting blood sugar [119].

Reducing Dietary Salt

It is well established that reducing salt intake reduces blood pressure and attenuates the complications of HF and associated structural and functional derangements [120–124]. The DASH diet, which emphasizes limiting salt intake, was associated with lower incidence of HF in a prospective observational study of 36,019 participants who were followed for 7 years [125]. Reduced salt intake was associated with decreased B-type natriuretic peptide (BNP), aldosterone, plasma renin activity, TNF-α, IL-6 and increased levels of IL-10, an anti-inflammatory cytokine in patients with recently compensated congestive HF [126]. However, there is also established evidence against low sodium intake in HF [127]. Sodium restriction may lead to decreased renal perfusion, cardiac output and sodium delivery to renal tubules that may result in activation of the renin angiotensin aldosterone system (RAAS) and thus retention of water and sodium by renal tubules that may activate pro-oxidant and pro-inflammatory genes in endothelial cells and lead to cardiorenal syndrome and decompensated HF [4]. In addition, salt restriction is associated with decreased L-type Ca²⁺ channel protein levels, increased phospholamban expression, and reduced Na⁺/Ca²⁺ exchanger levels in the left ventricle, resulting in decreased sarcoplasmic reticulum Ca²⁺ overload and hence a decrease in the contractility index of myocytes [4, 128, 129]. Hence, salt restriction in HF requires caution and further study.

Future Directions

Clinical trials are needed to understand microbiota composition, interactions with high salt diets and their effects on the clinical course of HF.

Future studies should focus on demonstrating the amount of dietary salt that may be beneficial in managing HF patients. Since the DASH and Mediterranean diets are known to have beneficial effects in CVDs including HF, specific foods within these diets should be identified to be used as supplements in low- and middle-income countries where the cost of living forbids a balanced plant-based diet. Most robust studies on gut microbiota use mouse models. More human studies are required to further understand the role of the gut microbiota in modulating the clinical course of HF.

Conclusion

The composition of the gut microbiota is important in the course of HF. Dysbiosis worsens HF due to bacterial translocation and induction of inflammation. Dietary salt modulates the gut microbiota to indirectly worsen HF and directly increases cardiac load by increasing fluid retention through the RAAS. Thus, multiple complex mechanisms interact to increase the risk of or worsen the severity of HF.

What Is Known?

• Gut microbiota composition is associated with HF development and prognosis.

• Dietary salt contributes to HF indirectly and directly by inducing dysbiosis and increasing fluid retention in the vascular system

What Is New?

• Gut microbiota contribute to HF via several mechanisms, e.g., inducing a leaky gut via activation of MLCK, MAP kinase, JNK, and NF-κB signaling pathways

• Increase in Prevotella, Hungatella, Succinclasticum and reduction of Coriobacteriaceae, Erysipelotrichaceae, Bifidobactericeae, Ruminococcaceae, Blautia, Collinsella, Clostridium and Dorea are associated with HF.

• The gut-associated metabolite TMAO induces myocardial hypertrophy, cardiac mitochondrial dysfunction, decreased left ventricular pump function and fibrosis. The mechanisms involve activation of the NLRP3 inflammasome, SIRT3-SOD2-mtROS and the NF-kB pathway, leading to oxidative stress and increased inflammation.

• Increased bile acid contributes to HF by increasing FXR expression.

• High dietary salt contributes to HF through several mechanisms including increasing expression of NHE3 in the gut, increasing the cardiac expression of β-MHC, and activation of MEF2/NFAT and SIK1.