Impact of Diet on Gut Microbiota Composition and Microbiota-Associated Functions in Heart Failure: A Systematic Review of In Vivo Animal Studies

Heart failure (HF) represents a cardiovascular disease with high mortality and morbidity. The latest evidence shows that changes in the composition of the gut microbiota might play a pivotal role in the prevention and management of HF. This systematic review aims at assessing the potential associations between the diet, gut microbiota, and derived metabolites with the outcomes of HF. A systematic literature search was performed up to July 2022 on the PubMed, Web of Science, and Scopus databases. The PRISMA guidelines were followed when possible. The risk of bias was assessed with the SYRCLE and ARRIVE tools. A total of nine pre-clinical studies on animal models, with considerable heterogeneity in dietary interventions, were included. High-fiber/prebiotic diets (n = 4) and a diet rich in polyphenols (n = 1) modified the gut microbiota composition and increased microbial metabolites’ activities, linked with an improvement in HF outcomes, such as a reduction in systolic blood pressure, cardiac hypertrophy, and left ventricular thickness. A high-fat diet (n = 2) or a diet rich in choline (n = 2) induced an increase in TMAO and indole derivative production associated with a decrease in cardiac function, systemic endotoxemia, and inflammation and an increase in cardiac fibrosis and cardiac remodeling. Although results are retrieved from animal studies, this systematic review shows the key role of the diet—especially a high-fiber and prebiotic diet—on gut microbial metabolites in improving HF outcomes. Further studies on human cohorts are needed to identify personalized therapeutic dietary interventions to improve cardiometabolic health.


Introduction
The gut microbiota represents the most abundant community of microorganisms living in the human gastrointestinal tract [1]. Indeed, more than 1000 different bacterial species, with a few dominant phyla-Bacteroidetes, Firmicutes, Actinobacteria, and Proteobacteria-regulate essential host functions such as the maintenance of intestinal barrier integrity, nutrient absorption, and immunity homeostasis [2]. In humans, Firmicutes and Bacteroidetes are the most dominant phyla, with more than 90% of the total bacteria [3]. At the genus and species levels, the taxa diversity and microbial richness, as well as the microbiome functions, characterize the gut microbial signature, which is unique for each individual [4]. Throughout human life, several environmental factors (infancy factors, use of medication, diet, socioeconomic factors, etc.) influence the bidirectional relationships between the gut microbiota (in terms of composition and functions) and human health and diseases [5].
Dysbiosis, which is defined as an alteration of gut microbiota composition and function, seems to play an important role in the pathogenesis and progression of cardiovascular diseases, including heart failure (HF) [6][7][8][9][10][11][12][13][14]. HF is a complex clinical syndrome with symptoms and signs caused by structural and/or functional cardiac abnormality [15], representing a major clinical and public health problem. Indeed, worldwide, around 64.3 million people have been diagnosed with HF [16,17]. Underlying causes of HF can be various, and often, in an individual, it is not possible to identify a single major factor, because, especially in the chronic setting, multiple causes co-exist [18]. HF is characterized by typical anatomical alterations resulting in gut edema, congestion, and impaired intestinal permeability [19]. This leads to intestinal bacterial translocation, immune activation, and consequently low-grade systemic inflammation that adversely affects the course of the disease [20]. In the last year, microbial sequencing approaches and computational analyses have highlighted the key role of the gut microbiota and its derived metabolites in the host regulation of both inflammatory and fibrotic responses and cardiac remodeling [21,22]. Moreover, microbial metabolites, including short-chain fatty acids (SCFA), trimethylamine N-oxide (TMAO), lipopolysaccharide (LPS), and others, may exert different essential effects on the incidence and development of HF [23].
SCFAs include acetate, propionate, and butyrate, which are produced through the gut bacterial fermentation of dietary fiber [24]. TMAO is a metabolite produced through the action of gut microbial trimethylamine (TMA) lyase from choline-or carnitine-or betainerich foods contained in egg yolk, red meat, and certain seafoods [25]. Some in vitro studies support that TMAO promotes vascular inflammation and is associated with enhanced atherosclerosis and thrombosis [26,27]. In a study from Savi et al., it was demonstrated that TMAO affected myocardial contractility, interfering with calcium dynamics [28]. LPS are endotoxins primarily found in the outer layer of Escherichia genera, which are associated with increased host inflammatory responses [29]. Recently, the therapeutic potential of the gut microbiota and its microbial metabolites has been demonstrated in HF through different approaches, such as dietary/prebiotic supplementation [30]. Prebiotics are nutrients that induce the growth or activity of beneficial gut bacteria in the host [31]. The number of studies on the role of the gut microbiota in the pathogenesis of HF is growing.
In this context, we chose to conduct a systematic review to assess the impact of dietary interventions on gut microbiota composition and microbiota-associated functions in HF.

Methods
This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [32]. The PRISMA checklist is detailed in Table S1.

Inclusion Criteria
The inclusion criteria are presented according to the PICOS criteria ( Table 1). The exclusion criteria were the following: (1) non-English articles; (2) in vitro and human models; (3) review articles; (4) not fulfilling the PICOS criteria.

Data Sources and Search Strategy
The search was carried out using three electronic databases, MEDLINE (via PubMed), ISI Web of Science, and Scopus. Multiple search terms were used, including diet, food fiber, ketogenic, vegetarian, mediterranean, vegan, low protein diet, plant-based diet, low phosphate diet, high sulfur amino acid diet, high pral diet, alkalin diet, western diet, gluten free, protein free, high protein diet, gut microbiota, microflora, gut bacteria, microbiome, SCFA, butyrate, acetate, proprionate, TMAO, trimethylamine N-oxide indole, phenol indoxyl sulfate indole, acetic acid, LPS, lipolysaccharide, gut barrier. The search string for each database is described in Table S2. Hand searching of eligible studies was done to identify studies that may not have been found in the databases.

Study Selection
Titles and abstracts were screened for eligibility based on inclusion criteria. Two reviewers independently selected studies. All titles assessed as ineligible were excluded. Disagreements were resolved by consensus between these two authors and, if necessary, discussed by two additional authors.

Data Extraction and Reporting
After full-text analysis, the following information was extracted from the included articles: first author, year of publication, country, animal type, age, sample size, diet intervention type, duration of diet intervention, significant compositional changes in gut microbiota (compared with control groups), significant effects on microbiota-associated functions (compared with control group), significant effects on heart failure outcomes. Data were reported using an Excel© (Microsoft Office, Redmond, WA, USA) spreadsheet specifically developed for this study. Each full-text article was retrieved, and any ineligible articles were excluded from the reasoning reported. Differences in judgment between two reviewers were settled by discussion and consensus.

Quality Assessment
The SYRCLE's risk of bias tool for animal studies [33] and the ARRIVE tool [34] were used to assess the risk of bias. The risks of bias data were extracted by four different authors and all disagreements were resolved by consensus by the remaining authors.

Study Selection
The flow diagram in Figure 1 displays the results of the literature search and study selection process. A total of 2110 studies were initially identified. After duplicate removal, 1722 studies remained for title and abstract screening. Thirty-four studies were selected and, after full-text analysis, twenty-five studies were excluded for the following reasons: review (n = 6), editorial (n = 4), no gut microbiota outcomes (n = 4), no diet intervention (n = 11). Nine studies [35][36][37][38][39][40][41][42][43] were identified for inclusion in the systematic review. ineligible articles were excluded from the reasoning reported. Differences in judgment between two reviewers were settled by discussion and consensus.

Quality Assessment
The SYRCLE's risk of bias tool for animal studies [33] and the ARRIVE tool [34] were used to assess the risk of bias. The risks of bias data were extracted by four different authors and all disagreements were resolved by consensus by the remaining authors.

Study Selection
The flow diagram in Figure 1 displays the results of the literature search and study selection process. A total of 2110 studies were initially identified. After duplicate removal, 1722 studies remained for title and abstract screening. Thirty-four studies were selected and, after full-text analysis, twenty-five studies were excluded for the following reasons: review (n = 6), editorial (n = 4), no gut microbiota outcomes (n = 4), no diet intervention (n = 11). Nine studies [35][36][37][38][39][40][41][42][43] were identified for inclusion in the systematic review.

Study Characteristics
Nine studies were included: three from China [36,42,43], two from the USA [39,40], two from Australia [35,38], one from the United Kingdom [41], and one from Russia [37]. Nutritional interventions differed across studies and included a high-fiber diet/prebiotic

Impact of Diet Rich in Fiber on Gut Microbiota Composition and Functions in HF
A total of three studies [35][36][37] showed the effect of a high-fiber diet on the gut microbiota and HF outcomes.
Jama et al. showed, irrespective of mice type (wild-type or mice with dilated cardiomyopathy), significant compositional variations in mice receiving a high-fiber diet (for 7 weeks) compared with a control diet, with a significant increase in Bacteroidetes and Bacteriodales abundance [35]. Zhang et al. found, in healthy mice fed with a high-fat diet + oral Lycium Barbarum (100 mg/kg once a day for 2 months), an increase in the abundance of Gordonibacter, Parabacteroides, Anaerostipes, Blautia, Hungatella, and Marvin bryantia compared with mice fed with a high-fat diet or healthy mice [36]. In rats with HF fed with fermented wheat bran and inactivated Saccharomyces cerevisiae culture for 7 days, a reduction in the levels of Pretovella spp., Fusobacterium spp., Helicobacter pylori, Lactobacillus spp., Enterococcus spp., and Actinomyces and an increase in the levels of Bifidobacterium spp., Propionibacterium spp., and Eubacterium spp. were observed compared with rats with HF fed a control diet [37].
All three studies found a positive effect of a high-fiber diet on gut microbial activities in HF mice or rats. There was a significant expansion in splenic T reg cells in mice with dilated cardiomyopathy fed with a high-fiber diet compared with wild-type mice (p = 0.009) [35]. Zhang et al. assessed, in healthy mice fed with a high-fat diet + oral Lycium Barbarum (100 mg/kg once a day for 2 months), a reduction in intestinal permeability and an increase in indole derivatives (indole-3-acrylic acid, methyl indole-3-acetate) compared with mice fed with a high-fat diet or healthy mice [36].
Two studies demonstrated the beneficial effect of a high-fiber diet and SCFA supplementation on cardiac function and remodeling [36,38]. Zhang et al. reported noticeable improvements in respect to systolic function and diastolic relaxation, as well as cardiac remodeling [36]. Similar results were obtained by Marquez et al., who demonstrated that a high-fiber diet and SCFA supplementation can counteract cardiac alteration induced by DOCA surgery in mice [38]. In particular, in the intervention groups, authors observed reduced blood pressure, limited cardiac hypertrophy, and lower ventricular chamber dilatation [38]. On the other hand, Jama et al. showed no significant changes in cardiac hypertrophy, lung congestion, and blood pressure in response either to a high-fiber diet or acetate supplementation in model mice with severe dilatated cardiomyopathy [35].

Impact of Choline Diet on Gut Microbiota Composition and Functions in HF
Two studies analyzed the effects of a choline diet and of a diet supplemented with choline metabolite TMAO on the gut microbiota metabolites and heart function [39,40]. In both studies, HF was induced in mice surgically using transverse aortic constriction (TAC). Analysis of plasma from mice was performed, respectively, at 12 weeks [39] and 17 weeks [40] after TAC. Both studies showed that plasma levels of TMAO were significantly higher when animals were fed with a diet containing 0.12% TMAO added to the standard rodent chow compared with controls [39,40]. Interestingly, it was evidenced that, even after TMAO withdrawal, at 6 weeks, plasma levels of this metabolite remained elevated compared with controls [40]. Moreover, in mice fed with TMAO, a significant increase in plasma betaine levels was observed [39]. A diet containing 1 or 1.2% choline equally determined a significant rise in TMAO levels in the blood, demonstrating that choline is effectively converted into TMAO by intestinal microbes [39,40]. The use of iodomethylcholine, a small molecule that inhibits the gut microbial conversion of choline, given orally, has been demonstrated to be effective in avoiding the elevation of circulating TMAO [40].
In both trials, cardiac function was evaluated via echocardiography at 3-week intervals following baseline echocardiography studies at 1 week before TAC surgery for 12 [39] and 17 weeks [40]. Circulating BNP was measured at the end of the observation period in each group as an indicator of HF severity. Moreover, to further evaluate cardiac remodeling, histological and immunochemical analysis was performed to detect and quantify fibrosis [39,40]. Myocardial and pulmonary tissue weight were measured to investigate cardiac enlargement and pulmonary edema as the main consequences of HF [39,40].
The TMAO and choline group experienced a significant worsening of cardiac function in comparison with the control diet. Notably, in these experimental arms, echocardiography showed an increased LV dimension, abnormal IVSd, poorer LVFS, and lower LVEF [39,40]. Importantly, it was observed that TMAO withdrawal, as well as the use of iodomethylcoline, attenuated the pathological actions of the dietary intervention and all measured endpoints improved [40]. Similarly, BNP levels significantly increased in intervention groups and decreased after TMAO withdrawal or with the administration of a choline trimethylamine lyase inhibitor [39,40].
In one study, after 12 weeks of TMAO or choline diet, enhanced collagen and fibrosis were observed in the hearts of mice [39]. In the other study, although dietary TMAO did not directly affect cardiac fibrosis, it was associated with the increased expression of profibrotic genes in the heart [40]. An increase in total kidney fibrosis was observed in both intervention groups [39,40].
In one study, cardiac enlargement and pulmonary edema were evident from the direct observation of hearts taken from mice fed with TMAO and choline [39], but these results were not fully confirmed in a later study [40].

Impact of Western/Obesogenic Diet on Gut Microbiota Composition and Functions in HF
Two studies reported the consequences of high calories and a high-fat diet on microbiota and HF [41,42]. Kein et al. investigated the changes in microbial composition in young and aging mice after two months of nutrition with a calorie-dense obesogenic diet (OBD): a single fatty-acid-enriched diet (10% safflower oil) that mimicked a standard Western diet [41].
Microbiome analysis of fecal samples demonstrated important differences in gut microbiome composition between mice fed with STD versus OBD. In both young and old mice, the consumption of OBD was associated with an increase in actinobacteria, and the genus Allobactulum was the most represented [41]. On the other hand, Bacteroides S24-7 was the most abundant in mice fed with STD [41].
It was observed that mice fed with WD for 8 weeks had significantly higher levels of plasma TMAO compared with the control diet. The use of DMB, an inhibitor of trimethylamine formation, reduced TMAO levels not only in WD-fed mice but also in the control group [42]. Microbiome composition seemed to influence systemic inflammation. Indeed, OBD-fed young mice revealed an increased neutrophil to lymphocyte ratio [41]. As for aging mice, both the STD and the OBD group showed an elevation in neutrophil populations, reflecting the fact that age is the most influential factor [41]. Additionally, OBD impacted splenic leukocytes, resulting in a reduction in immune-responsive F4/80+ and CD169+ macrophages in aging mice [41]. Moreover, the blood dosage of isoprostanoids was indicative of increased lipid peroxidation and oxidative stress in OBD-fed mice regardless of age [41].
Only one of the two studies directly analyzed the effects of WD on cardiac function [42]. In this study, echocardiography was performed at baseline and after 8 weeks of diet, showing that WD correlated with poorer cardiac function [42]. The authors evidenced a decrease in LVEF (around 19%) and increases in LVICT, LVIRT, and MPI. DMP has been able to prevent the development of these alterations [42].
Through histological analysis, it was observed that interstitial fibrosis was remarkably increased in the hearts of mice fed with WD relative to controls [42]. Moreover, WD was associated with decreased levels of anti-inflammatory cytokines (IL-10) and elevated levels of pro-inflammatory cytokines (TNFα, IL β), which promote cardiac fibrosis [42].

Impact of Polyphenols on Gut Microbiota Composition and Functions in HF
One study observed the potential benefits of a diet containing polyphenols on HF, in particular analyzing doxorubicin-induced heart failure. The authors evaluated a fourweek treatment with purified polyphenols from Arctium Iappa L. (ALPP) at the dosages of 50 mg/kg (ALPP1) and 150 mg/kg (ALPP2) [43].
Important variations in microbial composition were observed. In the DOX group, there was a reduction in the richness and alpha diversity of the gut microbiota, as shown by the reductions in the Ace, Chao, and Shannon indexes [43]. Stool samples from mice with DOX-induced heart failure indicated an abundance of Proteobacteria and reduction in Firmicutes, with the upregulation of the Bacteroide/Firmicutes ratio. Notably, ALPP acted as a modulator of microbiota and could reverse the alteration induced by HF [43]. The heat map showed no significant difference between the control and ALPP groups. On the contrary, in the DOX group, a loss of some beneficial bacteria was observed (for example, Roseburia and Lactobacillus), together with the proliferation of some pathogens (such as Enterococcus and Escherichia, Shigella) [43].
Changes in microbial composition induced by HF and polyphenols clearly influenced the formation of specific gut microbiota metabolites. In the DOX group, there was high production of TMAO compared with the ALPP + DOX group [43]. ALPP treatment promoted the production of short-chain fatty acids (SCFAs), which positively modulate the immune system and inflammatory response and are essential for the health of colonocytes and to preserve the integrity of the gut barrier.
Polyphenols could counteract DOX-induced changes in the heart. Indeed, pretreatment with ALPP counteracted the loss of body weight and decreased the heart and kidney indices in a dose-dependent manner [43]. The histological analysis showed that heart tissue in HF was characterized by the infiltration of inflammatory cells, hypertrophy of myocardiocytes, and focal areas of necrosis. Interestingly, ALPP reduced these pathological lesions, as well as NO and pro-inflammatory cytokine secretion [43]. Moreover, serum CK and LDH were elevated in DOX-induced HF as signs of myocardial ischemia, but treatment with polyphenols has been effective in reducing the levels of these two markers, with a clearly dose-dependent effect [43].

Quality Assessment
Tables S3 and S4 summarize the quality assessment results. The ARRIVE guidelines were used to assess the quality of the nine included animal studies. All included animal articles adequately provided an accurate title and abstract, a structured and thorough introduction, an ethical statement for mammalian studies, and an adequate study design, except for one study [37], where the ethical statement was not indicated. None of the studies calculated the sample size; thus, a too small number of experimental animals may lead to a non-significant statistical analysis. All studies described statistical methods. Baseline characteristics (body weight, age, and gender) at baseline were reported in all studies. All studies reported outcomes in terms of analyzed numbers, adverse events, interpretation, and generalizability.
The SCYRCLE tool was also used to assess the risk of bias of the included studies. As regards sequence generation, in eight studies, the animals were randomly distributed into different groups, except for one study [37]. Indeed, Vlasov et al. did not specify how animals were allocated to different groups. Regarding allocation concealment, the concealment was not clear for all studies, except for one study [40]. Indeed, Organ et al. explicated the concealed procedure and blinded the investigators to randomization until the end of the study. All included studies had an unclear risk of performance bias. Indeed, the animals were not randomly housed but, in most of the studies, animals were placed in a single cage. Moreover, in all studies, it was not clear whether the investigators selected animals at random for outcome assessment. As regards data and outcome reporting, the risk of bias was low for all studies, since the outcome data reported in each study were completed for each outcome. Finally, the studies did not report other limitations, resulting in an unclear risk of bias for other sources of bias.
Overall, the quality of each study could be improved due to the unclear randomization of housing, unclear blinding outcome assessment, and absence of sample calculation. However, the animal population for all studies was homogenous. All studies had a control group with similar characteristics to the experimental groups. The reporting of outcomes (complete outcome data reporting, adequate outcome reporting) was acceptable for all studies.

Discussion
This systematic review highlighted the gut-modulatory activity of different dietary interventions in animals with HF. All included animal studies demonstrated a complex association between diet intervention, gut microbiota composition and functions, and HF outcomes. Thus, as one of the important modulators in the gut microbiota, a highfiber diet, prebiotic diet, and diet rich in polyphenols positively modify the microbial composition (increase in gut microbial diversity and richness) and microbial metabolite activity (reduction in endotoxemia, reduction in intestinal permeability, increase in SCFA production), which were linked with an improvement in HF outcomes, such as a reduction in systolic blood pressure, cardiac hypertrophy, and left ventricular thickness [36][37][38]43]. On the contrary, Western diets such as a high-fat diet or diet rich in choline negatively modify the gut microbial composition, inducing an increase in TMAO and indole derivative production, a decrease in cardiac function, systemic endotoxemia, inflammation, gut barrier dysfunction, and an increase in cardiac fibrosis and cardiac remodeling [36,[39][40][41][42].
It is well known that fiber has a prebiotic effect that selectively promotes intestinal eubiosis. Indeed, several studies have demonstrated that HF is associated with an altered gut microbiota and that these changes can influence disease progression in both animals and humans [44][45][46]. Modifications of the gut microbiome are strictly linked to HF due to the anatomical disorders that occur at the level of the gut barrier [47]. Thus, a high-fiber diet can be a powerful tool in HF therapy and prevention. In line with our results, Dietary Approaches to Stop Hypertension (DASH) and the Mediterranean diet appeared to be promising strategies for the prevention of HF in humans. The potential benefit is linked to the fact that these diets are rich in fiber and micronutrients (such as polyphenols and other antioxidants).
Polyphenols are compounds, naturally found in fruits, vegetables, and cereals, that have antioxidant properties. We know that dietary polyphenols exert an improving effect on several cardiovascular risk factors, such as blood pressure, endothelial function, and plasma lipids [48]. One of the well-known polyphenols is resveratrol, largely found in grapes. Studies on mice suggested that this compound may improve cardiac remodeling, diastolic cardiac function, and cardiac glucose metabolism in an HF mice model [49]. Moreover, it may increase exercise capacity, counteracting fatigue, which is clearly one of the main signs of HF [49]. What emerged from our review is that polyphenols are important modulators of the microbiota. They can influence the production of SCFAs, with a beneficial effect on the gut barrier and systemic inflammation [43].
One of the most-studied gut microbiota metabolites in HF is TMAO. It was demonstrated that TMAO levels led to a higher long-term mortality risk in HF patients [50]. The levels of this metabolite rely on the gut microbiota composition and diet content. Choline, betaine, and L-carnitine are the main precursors of TMAO. Chronic consumption of red meat increases plasma TMAO levels, while a vegan diet is effective in reducing its levels [51,52]. The studies reported in this review highlighted the fact that a diet rich in choline is responsible for a significant elevation in TMAO levels in mice, and this leads, as a consequence, to the impairment of cardiac function [39,40]. A similar alteration occurred with the consumption of a Western diet, rich in saturated fat and sucrose [42]. Thus, an obesogenic diet and Western diet appear to be detrimental in this setting [39,40,42].
Other types of dietary approaches should be evaluated, such as dietary carbohydrate restriction [53]. In a recent study, a low-carbohydrate diet reduced the progression of pathological hypertrophy in HF through ketone body production and the inhibition of underlying signaling mechanisms, such as mTOR [54]. Moreover, some evidence supported the fact that, in HF, the failing heart progressively loses its capacity for the use of fatty acids and glucose oxidation as an energy source and shifts to ketone bodies as a fuel source for ATP production [55]. In this context, ketosis may have a therapeutic role, even if results are limited and myocardial ketone use seems to be only adaptative [56]. Notably, a short-term ketogenic diet (KD) has a beneficial effect on glucose control and weight loss and thus can be effective in reducing cardiovascular risk. However, a recent animal study showed an increase in inflammation-inducing Enterobacteria and a reduction in SCFA levels in the cecum in a carbohydrate-restricted diet group compared with a control group [57]. Even in humans, KD seemed to negatively affect the intestinal microbiota [58]. Thus, the effect of a low-carbohydrates diet in preventing or reversing the progression of heart failure remains to be clarified and the gut microbiota should be analyzed.
Helicobacter pylori (H. pylori) is one of the most-studied bacteria in the gastrointestinal tract. Chronic infection is linked to peptic ulcer disease and gastric cancer and it is responsible for a state of persistent inflammation that is associated with other extra-intestinal diseases. In the literature, many studies have highlighted the connection between H. pylori positivity and cardiovascular risk [59,60]. Indeed, the role of H. pylori infection in HF patients can be of interest.
This systematic review has some limitations. First, no human studies assessing the associations between diet intervention, gut microbiota, and HF outcomes were found. Secondly, although all included studies enrolled rodent models, the animal sample size, the type of diet intervention, and their exposure duration differed between studies and this does not allow clear results. Thus, although all studies found a significant impact on gut microbiota and HF outcomes, it remains difficult to reach firm conclusions. Further animal homogeneous studies are needed to evaluate the impact of different dietary patterns as promising therapeutic approaches. The impact of a high-fiber diet and prebiotic diet on the gut microbiota in animals and humans with HF should be further evaluated. However, the results of the studies analyzed in this review suggest that HF is often associated with an altered gut microbiota composition, with a prevalence of Enterococcus and Clostridium spp., a reduction in the abundance of Bifidobacterium spp., and thus an increased Firmicutes/Bacteroidetes ratio (F/B). Indeed, a Mediterranean diet rich in fiber and antioxidants, and low in saturated fat and animal protein, can be of great benefit in HF patients.
As a conclusion, this systematic review suggests a strong correlation between HF and gut microbiota metabolites, and specific associations between diet interventions, microbiota, and gut microbiota metabolites and progression. Although these results need to be confirmed by larger studies, they aim at considering diet strategies toward regulating the gut microbiome and using its metabolic pathways to treat HF, potentially improving prognostic outcomes.

Conflicts of Interest:
The authors declare no conflict of interest.