Along with population aging, geriatric syndromes have become a major healthcare problem worldwide. Sarcopenia is one of the most challenging geriatric syndromes with multiple contributing factors. It has been described as an age-related decline in skeletal muscle mass as well as muscle function, which could lead to a decrease in physical capability, falls, disability, and higher mortality in older people (Cruz-Jentoft et al., 2010). On the other hand, chronic heart failure (CHF) remains one of the most important healthcare problems, with high costs and poor outcomes. The prevalence of heart failure (HF) is more than 10% among people aged ≥70 years. Sarcopenia is a common complication of CHF patients and the prevalence of sarcopenia in CHF patients was nearly 20% (Fulster et al., 2013). The prognosis of HF with sarcopenia is worse than that of patients without sarcopenia (Narumi et al., 2015). A prospective cohort study revealed that sarcopenia was significantly linked with a cardiac event in the New York Heart Association Class II–IV group (Zhang et al., 2021). In addition, a multicenter prospective cohort study indicated that sarcopenia was an independent predictor of 1-year mortality in both ejection fraction preserved and reduced HF patients (Konishi et al., 2021).

More than 1000 different bacterial species are observed in the gut. The diversity of the bacterial species plays a major role in maintaining homeostasis (Przewlocka et al., 2020). The composition of gut microbiota is proven to be dynamic due to dietary changes, age, disease, and so on (Marti et al., 2017). The gut microbiome is being increasingly recognized as a modulator of atherosclerosis, hypertension, atrial fibrillation, and myocardial fibrosis and contributes to the development of these diseases (Peng et al., 2018). Accumulating evidences suggest that gut microbiota has a significant impact on skeletal muscle metabolism and is related to the development of HF (Branchereau et al., 2019; Lahiri et al., 2019). Gut microbiota-derived micronutrients and metabolites such as lipopolysaccharide, trimethylamine N-oxide, short-chain fatty acids (SCFAs), and secondary bile acids can reach and act on muscle (Liu et al., 2021). Gut microbiome affects HF by generating bioactive metabolites that can impact host physiology (Tang et al., 2019). Numerous studies have demonstrated the existence of the gut microbiome-muscle axis and heart-gut microbiome axis (Liao et al., 2020; Madan and Mehra, 2020). Germ-free mice had less skeletal muscle mass than pathogen-free mice when fed the same food (Lahiri et al., 2019). Besides, gut microbiota influenced HF mainly by affecting immunity and inflammation (Yuzefpolskaya et al., 2020). Modulating the microbiota through dietary intervention, probiotics or prebiotics supplements, may be a novel strategy against muscle aging and HF.

SCFAs including acetate, propionate, butyrate, isovalerate, valerate, and caproate, are produced by microbial fermentation of fiber and prebiotics in the colon and mediate the interaction among diet, microbiota, and the host (Kimura et al., 2014). A study found that treating germ-free mice with SCFAs partially reversed muscle atrophy induced by dexamethasone (Lahiri et al., 2019). Professional athletes had relatively increased SCFAs compared with more sedentary subjects (Barton et al., 2018). SCFAs influence HF by regulating T-cell proliferation and exerting anti-inflammatory effects (Mamic et al., 2021) and proved to be an efficient energy source during pathological stress in the failing heart (Carley et al., 2021). Meanwhile, SCFAs were reported to have a positive impact on reducing cardiac hypertrophy and pressure overload (Pakhomov and A. Baugh, 2021).

Emerging evidences have shown the association between gut microbiota and sarcopenia. Sarcopenia may accelerate the progression of HF and increase the mortality of patients with HF. However, there has no standard treatment for slowing muscle loss in patients with HF. It is not clear whether alterations in gut microbiota and metabolites are related to sarcopenia in HF patients. This study is the first to explore the changes of gut microbiota composition and SCFAs levels in HF patients with or without sarcopenia.

In this study, we first presented the composition of gut microbiota, SCFA levels, and their relationship in HF patients with and without sarcopenia and controls. We found that overall microbial diversity (alpha‐diversity) and community structure (beta‐diversity) were significantly different between the control individuals and HF patients with or without sarcopenia, while no difference between the HF patients with sarcopenia and HF patients without sarcopenia. The Nocardiaceae, Pseudonocardiaceae, Leuconostocaceae, Alphaproteobacteria, and Slackia were found to be more abundant in HF individuals without sarcopenia. Conversely, the Synergistetes showed a higher abundance in HF patients with sarcopenia. In addition, the levels of isobutyric acid, isovaleric acid, and valeric acid were lower in HF patients with sarcopenia compared with that in the HF patients without sarcopenia and control group but has no significant differences.

Microbiota diversity has been proposed as a health biomarker. Diversity analyses indicated a difference in gut microbiota composition between the control group and HF patients with or without sarcopenia in the current study. Loss of gut flora biodiversity is associated with HF patients with and without sarcopenia. Based on a metagenomics study of patients with sarcopenia (Ticinesi et al., 2020), we expected that alpha-diversity and beta-diversity would be reduced in HF patients with sarcopenia compared to HF patients without sarcopenia, but the results exhibited that there were no significant differences between these two groups in our study population.

The main bacterial phyla in the gut are Firmicutes, Bacteroidetes, Actinobacteria, and Proteobacteria, which constitute the vast majority of the dominant human intestinal flora (Arumugam et al., 2011). The results were the same in our study. Some studies have examined gut microbiome differences in HF patients compared to control individuals (Sun et al., 2021). Likewise, we found significant differences in the composition of gut microbiome between control and HF patients with or without sarcopenia. In line with the study by Elena et al (Gutierrez-Calabres et al., 2020), Firmicutes and Bacteroidetes were the two most abundant phyla in control individuals. Proteobacteria are gram-negative bacteria, with the outer membrane mainly composed of lipopolysaccharide (LPS). The majority of the Proteobacteria phylum are pathogenic bacteria, it is thought that they serve as a microbial signature of dysbiosis in gut microbiota (Shin et al., 2015). An elevated level of Actinobacteria in cardiovascular diseases has been reported (Khan et al., 2022). Consistent with these findings, the relative abundance of Proteobacteria and Actinobacteria were higher in HF patients with and without sarcopenia than that in control individuals.

Differential abundances of certain bacterial taxa were observed in HF patients without sarcopenia compared with the control. Specifically, in line with previous studies, the abundance of Nocardiaceae which is associated with steroid hormone synthesis (Sherman et al., 2018), was found to be increased in HF patients without sarcopenia in our study. Pseudonocardiaceae, Slackia, and Alphaproteobacteria belong to the phylum Actinobacteria and Proteobacteria, respectively. Proteobacteria and Actinobacteria have an impact on the prognosis of patients with HF by influencing the production of trimethylamine-N-oxide (Bin-Jumah et al., 2021). The increased abundance of Proteobacteria and Actinobacteria was also discovered in HF patients without sarcopenia in our study. Based on LEfSe analyses, Synergistetes were found abundant in the HF patients with sarcopenia. Synergistetes was correlated with infection and enriched in HF patients with preserved ejection fraction (Huang et al., 2021; Zhu et al., 2022). Increasing evidence demonstrated that Synergistetes is associated with periodontal diseases, which is prevalent in sarcopenia patients (Belibasakis et al., 2013; Hatta and Ikebe, 2021). It may be a biomarker of HF patients with sarcopenia that influences the progression of sarcopenia in HF patients. Clostridia, Faecalibacterium, Peptostreptococcaceae, and Prevotellaceae were believed to be probiotic species that enriched the fecal microbiomes of control.

Changes in the microbiota of those suffering from various diseases have been associated with reduced diversity of bacteria and the amount of SCFAs in the feces (Machiels et al., 2014; Wang et al., 2014). SCFAs are produced by the gut microbiota metabolizing dietary fiber and undigested carbohydrates. Alterations in fecal SCFAs may lead to dysbiosis of the intestinal microbiota and inflammatory changes. Muscle mass and strength were increased in germ-free mice fed acetate, propionate, and butyrate (Lahiri et al., 2019). SCFAs, particularly butyric acid, can improve muscle atrophy during the aging process (E Walsh et al. (2015)). Our data suggested that there were no significant differences in SCFAs in fecal samples among the three groups. This was in contrast with our hypothesis. Treatment-related confounders in the HF patients with and without sarcopenia cannot be entirely ruled out.

Correlation analysis showed a positive correlation between SCFAs and SCFA-producing bacteria. Different SCFAs are known to be produced by various bacteria. For example, Bacteroides spp. produced acetate and propionate (Koh et al., 2016). The abundances of the Verrucomicrobia were increased in mice feeding with the butyrate and SCFA mix water (Lee et al., 2022). Metabolism and function of skeletal muscle are susceptible to changes in the gut microbiota, this association appears to be partially mediated by the generation of SCFAs. SCFAs have been proven to influence carbohydrate, lipid, and protein metabolism in skeletal muscle tissues both in vitro and in vivo (Frampton et al., 2020). Meanwhile, SCFAs inhibit systemic inflammation by binding to G-protein receptors on the surface of the cells and enhance myocardial energy metabolism, which plays a cardioprotective role (Borchers and Pieler, 2010). Moreover, a study on older Koreans found a positive correlation between sarcopenia and bone mineral content (Kim et al., 2014). Lower bone mass may have effects on falls and fracture risk in sarcopenia patients (Gandham et al., 2021). In our study, bone mineral content was positively correlated with SMI. HF patients with sarcopenia had also significantly lower bone mineral content compared with HF patients without sarcopenia.

There are some limitations in our study, including the small sample size, and the lack of detailed information about dietary intake and physical activity. Although all participants were from the same region and had similar dietary habits, we were still unable to fully rule out the influence of diet on gut microbiota and SCFAs. Furthermore, this is a single-center clinical study and may have a selection bias. In addition, a cross-sectional research is difficult to determine the causal relationships. Larger cohort studies are needed to explore the effect of gut flora on sarcopenia in HF patients and whether modulating the gut microbiota and metabolites can alter the natural course of sarcopenia in HF patients.

In summary, the preliminary study suggests that HF patients with and without sarcopenia differ from control subjects in intestinal microbial composition. Nocardiaceae, Pseudonocardiaceae, and the Alphaproteobacteria, Slackia were significantly enriched in HF patients without sarcopenia. Synergistetes may be biomarkers of HF patients with sarcopenia. Modulating the gut microbiota may be a new target for the prevention and treatment of sarcopenia in heart failure patients.

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can contact the corresponding author. The data presented in the study are deposited in the NCBI repository, accession number PRJNA930609.

The study involving human participants was reviewed and approved by Ethics Committee of the Second Xiangya Hospital of Central South University. The patients/participants provided their written informed consent to participate in this study.

JP: Writing-Original Draft, Investigation, Methodology. HG: Visualization, Methodology. XL: Project administration, Funding acquisition. YL: Software, Date Curation. SL: Conceptualization, Validation. ST: Funding acquisition, Software. LD: Resources, Supervision. XZ: Conceptualization, Funding acquisition, Writing-Reviewing, and Editing. All authors contributed to the article and approved the submitted version.