Gut Microbiota Interacts with HFpEF: Comparison
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Heart failure with preserved ejection fraction (HFpEF) is a disease for which there is no definite and effective treatment, and the number of patients is more than 50% of heart failure (HF) patients. Gut microbiota (GMB) is a general term for a group of microbiota living in humans’ intestinal tracts, which has been proved to be related to cardiovascular diseases, including HFpEF. In HFpEF patients, the composition of GMB is significantly changed, and there has been a tendency toward dysbacteriosis. Metabolites of GMB, such as trimethylamine N-oxide (TMAO), short-chain fatty acids (SCFAs) and bile acids (BAs) mediate various pathophysiological mechanisms of HFpEF. GMB is a crucial influential factor in inflammation, which is considered to be one of the main causes of HFpEF. The role of GMB in its important comorbidity—metabolic syndrome—also mediates HFpEF. Moreover, HF would aggravate intestinal barrier impairment and microbial translocation, further promoting the disease progression. In view of these mechanisms, drugs targeting GMB may be one of the effective ways to treat HFpEF. 

  • gut microbiota
  • HFpEF
  • barrier

1. Intestinal Barrier Dysfunction and Microbial Translocation

Intestinal barrier dysfunction is always observed in heart failure (HF) patients [1]. The intestinal barrier is composed of mechanical, chemical, immunological, and biological barriers. Normally, the GMB forms an important protective barrier against pathogens. When the stability of this biocoenosis is disrupted, intestinal colonization resistance is severely impaired, making invasion and colonization by potential pathogens (including conditionally pathogenic bacteria) easier in the gut. Much evidence supported the indication that patients with HFpEF have a gut microbial dysregulation in comparison with healthy people [2][3][4], meaning the risk of infection is increased after the onset of HFpEF. The chronic heart failure (CHF) population has a large number of pathogenic bacteria compared to healthy controls, such as Candida, Campylobacter, Salmonella, Shigella, and Yersinia enterocolitica [5]. Moreover, insufficient cardiac output in heart failure could lead to intestinal ischemia, edema, and inflammation, increasing the permeability of the bowel wall and aggravating the compromised epithelial barrier [6].
Bacterial translocation is defined as the penetration of a large number of tissues and organs outside the intestine by normal microbiota and their endotoxins, peptidoglycans, or metabolites that initially colonized in the intestine through the intestinal mucosal barrier [7]. It is often secondary to intestinal barrier dysfunction. Zhou et al. found that the blood flora composition of patients with cardiac dysfunction after acute myocardial infarction has apparently changed compared with healthy people or patients with stable coronary heart disease [8]. Plasma endotoxin and cytokine levels are also raised in CHF patients [9][10]. The levels of endotoxin in the hepatic veins was higher than in the left ventricle during acute HF, which directly suggested that the bacterium or endotoxin did translocate from intestine into bloodstream [11]. Endotoxin is one of the most important pro-inflammatory activators, and inflammation is a crucial part of the pathogenesis of HFpEF, so endotoxin could play an important role in this disease.

2. Inflammation

A lot of experimental and clinical evidence has demonstrated the critical role of inflammation in the occurrence and development of HEpEF by direct injury or from interacting with other pathophysiological changes. Regardless of the primary etiology, HF is related to both local and systemic inflammatory responses [12]. HFpEF patients showed higher levels of inflammation than HFrEF patients, and HFpEF is more affected by systemic inflammation, while the heart insult of HFrEF is mainly based on a local inflammatory reaction [13][14]. A subgroup of inflammatory cells expressing profibrotic growth factor transforming growth factor-β (TGF-β) can be found in endomyocardial biopsy samples from HFpEF patients [15]. In patients with HFpEF, the increase in plasma content of inflammatory indicators, including soluble interleukin (IL)-1 receptor-like 1, growth differentiation factor 15, soluble ST2, and pentraxin-3, is greater than in HFrEF or other conditions [16]. Chirinos et al. screened TNF-alpha, sTNFRI, and IL-6 as predictors of all-cause death or heart failure-related hospital admission risk by machine-learning [17].
High levels of inflammatory factors could lead to endothelial dysfunction, myocardial fibrosis or other pathological changes that then promote the progress of HFpEF [18][19][20][21]. For example, inflammatory mediators (inflammatory cytokines, chemokines, and growth factors) are related to the pathogenesis of cardiac fibrosis by directly activating fibroblasts, stimulating the recruitment and activation of fibrotic macrophages and lymphocytes, and triggering the fibrotic process in vascular cells and cardiac myocytes. Long-term chronic inflammation may lead to myocardial cell necrosis and cause fibrosis in the form of repair [22].
In addition, recent studies reported that the NLR family pyrin domain containing 3 (NLRP3) inflammasome may be critical for the systemic inflammatory response and cardiac remodeling of HFpEF. Activation of the NLRP3 inflammasome and secondary IL-1β/IL-18 overproduction were found in HFpEF mouse models [23][24]. NLRP3 inflammasome in endothelial cells will disrupt the tight connection between cells, resulting in endothelial dysfunction [25]. The NLRP3 inflammasome may also induce ventricular arrhythmias in HFpEF patients, leading to poor prognosis [26]. Inhibition of the NLRP3 inflammasome reduces inflammation and fibrosis and reverses cardiac remodeling [27].
GMB is associated with systemic inflammation levels. There is already evidence of an increase in the abundance of pro-inflammatory bacteria and a decline in anti-inflammatory bacteria in patients with HFpEF [2]. In addition, increased bacterial diversity is always accompanied by decreased levels of inflammatory markers [28], because the dysbacteriosis may break immune homeostasis, leading to the occurrence of inflammation. Both the structural components and metabolites of bacteria can enter the bloodstream through microbial translocation or be delivered to immune cells and trigger an inflammatory cascade [29]. Endotoxin is a typical pro-inflammatory component of bacteria, and pathophysiology-related endotoxin amounts have been shown to induce the release of multiple inflammatory factors in vitro or vivo of patients with HF [30][31]. It is mainly combined with Toll-Like receptor 4 (TLR4) on the heart to play an inflammatory role or impair the heart [32], and TLR4 expression was increased on the heart of patients with advanced HF [33]. Blocking its effect with the inhibition of TLR4 may benefit HFpEF patients. Moreover, GMB and its metabolites have regulatory effects on the NLRP3 inflammasome, and dysbacteriosis will cause activation of the NLRP3 inflammasome, which will further aggravate inflammation or myocardial fibrosis [34][35].
In conclusion, when intestinal immune homeostasis is disrupted, the inflammatory cascade triggered by GMB, especially its endotoxins, is a complex immune response system composed of intricate cytokine networks and has not been completely studied. If future studies could screen out the immune factors that play the key role in this network and carry out precise immune targeted therapy on them, it will have important therapeutic significance for systemic inflammation and HFpEF. Of course, targeting microbiota and endotoxins in the upstream of the cascade or NLRP3 is a relatively simple approach, so the effect of TLR4 inhibitors or NLRP3 inhibitors on HFpEF is worth studying.

3. Metabolites

3.1. Trimethylamine N-oxide (TMAO)

TMAO is an amine oxide, which naturally presents in our diets, such as in fish, or that can be generated from its metabolic precursors—food-derived choline, carnitine and other substances. The precursors must first be converted into trimethylamine (TMA) by TMA lyase derived from GMB, then TMA will enter the portal circulation and be oxidized to TMAO by hepatic enzyme flavin-containing monooxygenase 3 in the liver. Diet and endogenous TMAO can be released by the liver and absorbed by extrahepatic tissues or excreted with urine [36][37]. Firmicutes, Proteus, and Actinomycetes have been proven to be involved in this process [38]. In 2011, Wang et al. screened TMAO from more than 2000 small molecule metabolites and demonstrated that increased plasma levels of TMAO could predict the risk of several cardiovascular diseases in a large independent clinical cohort [39].
Patients with HFpEF have more TMAO in the plasma than healthy people [40]. This is not merely an independent hazard factor of HFpEF, but it is also associated with other risk factors such as blood urea nitrogen, creatinine, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) [41]. It is a prognostic predictor of HFpEF. Elevated TMAO was independently associated with an increase in the composite endpoints of HF readmissions and cardiac death in HFpEF patients and this effect was enhanced in patients with malnutrition status [42]. Moreover, it could be used as a marker of risk stratification for HFpEF; especially when BNP is not high, it could more sensitively reflect the prognosis [43].
TMAO may lead to cardiac diastolic dysfunction, which is the key hemodynamic change of HFpEF, and myocardial fibrosis is a significant reason for diastolic dysfunction. A prospective cohort study of 112 samples presented a positive correlation between TMAO and diastolic dysfunction indices, such as mitral E/septal Ea and LA volume index [44]. Chen et al. found an increased level of TMAO derived from a diet high in sugar and saturated fat contributed to inflammation and fibrosis of the heart and impaired diastolic function [45]. TMAO promotes TGF-β/SMAD3 expression. TGF-β activates fibroblasts through the second messenger SMAD and induces the secretion of type I collagen, which is the molecular basis of myocardial and pulmonary fibrosis [46]. Its effects could be blocked by SMAD3 inhibitor or TMA synthesis inhibitor [47]. It has also been demonstrated through in vitro and in vivo experiments that TMAO may aggravate pulmonary hypertension [48]. Furthermore, TMAO increased the expression of pro-inflammatory genes via the nuclear factor kappa-B (NF-κB) pathway and activated the NLRP3 inflammasome [49]. In short, TMAO derived from GMB intervenes in the development of HFpEF by inducing cardiac remodeling through promoting myocardial fibrosis and pro-inflammatory effects. Blocking its molecular pathway can be used as a drug therapy idea.

3.2. Short-Chain Fatty Acids

SCFAs are organic fatty acids containing less than six carbon atoms; acetic acid, propionic acid and butyric acid are more common in human bodies. SCFAs are products of the fermentation of various fiber substances in food by the GMB, after which they are taken by clonocytes or enter the portal vein and provide energy to the liver cells; a minor fraction of colon-derived SCFAs enters the systemic circulation and is taken advantage of by other tissues [50][51].
Most evidence suggests that SCFAs have a protective effect against HF. In the normal adult heart, energy is mainly derived from the oxidation of long-chain fatty acids (LCFAs). In failing hearts, however, LCFAs produce less ATP, while SCFAs normalize contractile function as an effective energy source [52][53]. Additionally, SCFAs play their physiological roles as antihypertension agents, for example, and by providing protective effects on endothelial function via G protein-coupled receptors (GPCRs) [54]. A high-fiber diet and acetate supplementation significantly reduced blood pressures, cardiac fibrosis, and left ventricular hypertrophy through the downregulation of early growth response 1 (Egr1) [55]. Butyrate alleviated pulmonary hypertension, reversed right ventricular hypertrophy, and preserved diastolic and systolic functions of the heart in rats [56][57]. SCFAs also play an important role in the regulation of immunity and inflammation by two main mechanisms: regulating the expression of inflammatory genes via GPCRs and its downstream NF-κB and MAPK pathways, or by going directly into the cell to inhibit histone deacetylase [58].
SCFAs also have positive effects on intestinal microbial homeostasis and barrier function. Small intestinal bacterial overgrowth (SIBO) is a common manifestation of microbial dysbiosis, which was found in some patients with HFpEF and which increased their risk of cardiovascular death [59]. Butyrate has a significant negative correlation with SIBO [60]. SCFAs could up-regulate tight junction protein claudin-1 transcription to enhance the intestinal epithelial barrier function [61]. In HFpEF patients, SCFAs producing microbiota is reduced [3], which weakens the protective effect of SCFAs on the gut and heart, and further aggravates the disease. Therefore, SCFAs not only improve cardiac function by ensuring the energy supply of the heart, reducing blood pressure, preventing ventricular hypertrophy, and controlling inflammation, but also stabilize the intestinal microbial environment and prevent further damage caused by GMB disorder in HFpEF.

3.3. Bile Acids (BAs)

BAs can be classified into primary bile acids (PBAs) and secondary bile acids (SBAs), according to their sources. PBAs are synthesized in the liver by cholesterol, then about 5–10% of them reach the colon and undergo biotransformations by certain microbiota and finally into SBAs such as deoxycholic acid, ursodeoxycholic acid (UDCA), and lithocholic acid (LCA) [62][63]. Moreover, BAs can be divided into hydrophilic and hydrophobic BAs by their molecular structures. Hydrophobic BAs are more toxic to cells due to their high affinity for lipids and have been found to be associated with an increased risk of cardiovascular diseases, while hydrophilic BAs are more beneficial to the heart. LCA has the strongest hydrophobicity, and UDCA has the strongest hydrophilicity [64][65]. UDCA has been proven to have an important cardioprotective effect and to provide a dose-dependent inhibition of myocardial fibrosis [66][67][68].
BAs bind to receptors like farnesoid X-receptor (FXR) and takeda G-protein-coupled receptor 5 (TGR-5), etc., to affect the heart [65]. For example, UDCA, as an agonist of FXR, degraded nitric oxide synthase inhibitors to improve the bioavailability of NO, which mediates calcium desensitization in myofilaments and myocardial relaxation via the PKG pathway, thereby reducing diastolic dysfunction and myocardial fibrosis [67][69]. TGR-5 activates pro-survival kinases and heat shock proteins which could protect cardiac cells in HF and enhances its adaptability to physiological, inotropic and hemodynamic stress in mice [70]. In contrast to TMAOs, BAs inhibit the NLRP3 inflammasome activation via TGR-5 signaling to exert anti-inflammatory effects [71].
BAs also modulate the stability of intestinal ecology. In fact, bile salts have a certain degree of antibacterial activity, which provides a selective pressure on the flora, thus regulating the composition of GMB [72]. PBAs promote the restoration of the microbiome after ecological dysregulation and prevent the overgrowth of pathogenic bacteria in the small intestine [73]. Increased bacteria levels in the ileum and an impaired intestinal barrier were found in mice lacking FXR; thus, FXR could inhibit the bacterial overgrowth and mucosal injury in the ileum [74]. TGR-5 null mice had a disarrayed molecular architecture of colonic tight junctions and a higher intestinal permeability [75].
In conclusion, BAs produce a marked effect, mainly through FXR and TGR-5, to protect cardiomyocytes, improve diastolic function, resist inflammation in HFpEF, and repair intestinal barrier. However, not all BAs have positive effects, such as hydrophobic BAs, so it is necessary to study the impact of different BAs on HFpEF.

3.4. Other Metabolites

In addition to TMAOs, SCFAs, and BAs, which have been extensively studied, new potential HFpEF-related metabolites are continually being discovered. For instance, polyphenols are plant-derived antioxidants. Dietary polyphenols are converted into low-molecular-weight, absorbable bioactive metabolites in the small intestine by specific enzymes derived from GMB [76]. In HF mouse models, polyphenols ameliorated HF-induced GMB disorders and protected cardiac function [77][78]. Polyphenols have antioxidant, anti-inflammatory, protective endothelial, and anti-myocardial fibrosis effects, which may be beneficial to HFpEF [76][79][80].
GMB has been shown to be correlated with amino acid (AA) metabolism. Microbes help the host to establish amino acid homeostasis, while AAs regulate the abundance and diversity of AA-fermenting microbiota [81]. The metabolic disorder of AAs is related to the pathophysiological mechanism of HFpEF. For example, HF patients with high plasma levels of phenylalanine have higher levels of C-reactive protein (CRP), inflammatory cytokines (IL-8, IL-10), and higher mortality [82], while glycine shows anti-inflammatory effects and protection of cells and heart [81]. The GMB metabolites of AAs also affect HFpEF. The fermentation product of tryptophan—indoxyl sulphate—increases expression of pro-inflammatory and pro-fibrotic signaling molecules and induces oxidative stress in animal experiments [83][84]. The levels of phenylacetylgutamine—a product of fermentation which has been proven to promote thrombosis—tracks with NT-proBNP levels in HFpEF patients, suggesting the potential correlation between them [84][85].
Timethyl-5-aminovaleric acid (TMAVA) is the metabolite of trimethylysine (TML) through GMB. TML is also the metabolic precursor of TMAO, and TML will be preferentially converted to TMAVA rather than TMAO in mice. Zhao et al. found the relationship between TMAVA and HF in 2022. In a cohort study involving 1647 patients, TMAVA was positively correlated with the risk of HF and the risk of death. In animal experiments, they found that TMAVA could inhibit the synthesis of carnitine, lead to the reduction of fatty acid oxidation, ultimately disrupt the myocardial energy metabolism, and induce the excessive accumulation of myocardial lipids, which is related to the decline of diastolic function [86].
The research on these newly discovered metabolites is still insufficient, and more experimental evidence is needed to verify their association with HFpEF. Of course, searching for new metabolites is an important part of intestinal microbiology and metabolomics. New technologies, like machine learning, can help to screen new metabolic markers.

4. Metabolic Syndrome (MetS), Heart Failure with Preserved Ejection Fraction and Gut Microbiota

MetS is a series of metabolic disorders including central obesity, insulin resistance, glucose intolerance, hypertension, and dyslipidemia [87]. GMB was found to be involved in MetS. Ridaura et al. transplanted the GMB from one obese twin and one thin twin into germ-free mice. The mice that received the obese twin microbiota significantly tended to become obese [88], proving an essential impact of GMB on obesity. People with low gut microbiota abundance were more likely to have obesity, dyslipidemia, and insulin resistance [89]. SCFAs, Bas, and inflammation also play a complex regulatory role between GMB and MetS [90]. The gut-centric view of MetS has been proposed because of these associations [91]. Meanwhile, MetS is a classical hazard factor of cardiovascular diseases, particularly as an important comorbidity of HFpEF. Among various cardiovascular diseases, obesity has the strongest correlation with HF and more significantly raises incidence rate and mortality of HFpEF compared with HFrEF [92][93]. From an epidemiological point of view, HFpEF patients are mainly elderly people, of which 84% have overweight/obesity, more than 60% have hypertension, and over 20% have type 2 diabetes [94]. In terms of pathophysiology mechanism, insulin resistance can induce endothelial dysfunction and myocardial energy failure, and eventually lead to diastolic dysfunction [95]. Metabolic inflammation and oxidative stress stimulate myocardial fibrosis in obese patients [96]. Thus, MetS is an important bridge for GMB to affect HFpEF. When GMB is disturbed, the direct consequence is more likely to be nutritional metabolism disorders such as fat accumulation and insulin resistance, which increases the probability of HFpEF. When MetS occurs, wresearchers could intervene early in the course of the disease by adjusting GMB to achieve the purpose of HFpEF prevention. So, the GMB therapy of MetS is also a research direction with important clinical significance.

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