Previous studies have demonstrated significant differences in gut microbiota composition between individuals with sarcopenia and their healthy counterparts (21). Dysbiosis of the gut microbiota and its metabolites may contribute to distinct clinical complexities observed in frail elderly individuals (22). Specifically, the colonization of the gut microbiota in sarcopenia patients undergoing maintenance hemodialysis (MHD) has shown a diminished abundance of Akkermansia in the intestines of mice, indicating a potential role of altered gut microbiota in the development of skeletal muscle disorders in MHD patients (23). Particularly, reduced diversity and altered abundance of specific bacterial taxa have been observed in the gut microbiota of patients with sarcopenia (24,25). These changes include a decrease in beneficial taxa, such as Akkermansia and Lactobacillus, which play vital roles in maintaining the gut barrier function and regulating immune responses. Harmful bacteria, including Clostridium and Proteobacteria, tend to be more prevalent in the gut of patients (26–28). Metabolites produced by these abnormal bacterial populations may negatively affect the muscle health. These findings suggest that dysbiosis of the gut microbiota significantly contributes to the onset and progression of sarcopenia (Fig. 2). Thus, patients with sarcopenia exhibit specific gut microbiota characteristics. Reduced diversity, decreased abundance of beneficial taxa and increased levels of harmful bacteria collectively suggest the involvement of gut microbiota dysbiosis in the pathogenesis and progression of sarcopenia.

Although the association between gut microbiota imbalance and sarcopenia has been extensively reported, further exploration is required to establish a causal relationship. Current research has provided evidence from animal models and clinical trials. For instance, transplanting gut microbiota from healthy individuals into mice with muscle wasting demonstrated significant improvements in the muscle mass and function, indicating the therapeutic potential of gut microbiota restoration for treating muscle wasting (29,30). Moreover, supplementation with specific probiotics and prebiotics was reported to enhance the muscle mass and function in patients with sarcopenia, further supporting the role of gut microbiota in sarcopenia (31,32). Nonetheless, additional longitudinal studies and randomized controlled trials are necessary to elucidate the precise mechanisms underlying the gut microbiota imbalance in sarcopenia.

Gut microbiota can modulate the epigenetic status of the host either directly or indirectly through the production of various metabolites, including SCFAs (73,74). These metabolites can enter the bloodstream and affect distant tissues, including muscle cells (75). Fecal butyrate levels have been reported in older individuals with low muscle mass, suggesting a potential role for altered gut microbiota in the development of sarcopenia. These findings highlight the potential of gut microbial features and fecal butyrate as biomarkers for the early detection of sarcopenia (76), making them valuable diagnostic and intervention strategies. For instance, butyric acid, an SCFA, inhibits histone deacetylases, leading to increased histone acetylation and subsequent alterations in gene expression (77). Epigenetic regulation can influence the differentiation and regeneration capacity of muscle cells, thereby affecting the muscle health and function (78).

Furthermore, the gut microbiota modulates host gene expression by regulating the expression of microRNAs (miRNAs). miRNAs are a class of non-coding RNA molecules that regulate gene expression by inhibiting translation or promoting the degradation of specific mRNA targets (79). Studies have indicated that changes in the gut microbiota composition are associated with altered expression patterns of specific miRNAs, which may be involved in regulating muscle metabolism and processes associated with muscle atrophy (Fig. 3; Table II) (80–95). Circulating miRNAs (c-miRNAs), including miR-21, miR-126, miR-146a and miR-222, have been identified as potential biomarkers for sarcopenia (81). The upregulation of miR-141-3p in ovariectomized mice contributes to mitochondrial dysfunction by inhibiting FKBP prolyl isomerase 5 and Fibin, indicating that targeting miR-141-3p may be a promising therapeutic strategy for mitigating obesogenic sarcopenia (82). The expression profiles of miR-1, miR-133a/b, miR-206, miR-208b and miR-499 in 109 non-sarcopenic and 109 sarcopenic individuals were analyzed. These results revealed that sarcopenia and malnutrition frequently coexist in elderly individuals, suggesting that lower levels of miR-133b and miR-206 are associated with sarcopenia. The relationship between miR-133b and sarcopenia is mediated by the nutritional status, indicating the potential role of nutrition in modulating age-related muscle decline (83). The downregulation of miR-532-3p, which is associated with inflammation, regulates the apoptotic pathway during the development of sarcopenia by targeting BCL2 antagonist/killer 1 (84). Acupuncture has the potential to alleviate sarcopenia by regulating mitochondrial function and suppressing chronic inflammation through the miR-146a/interleukin 1 receptor associated kinase 1/TNF receptor associated factor 6/NF-kB signaling pathway, thus potentially decreasing the muscle wastage (85). Severe malnutrition and sarcopenia are strongly associated with poor surgical and oncological outcomes in patients with cancer. Decreased psoas muscle mass index (PMI) is an independent prognostic factor for overall survival, disease-free survival and metastasis in patients with colorectal cancer (CRC). Serum miR-21 expression, which is associated with PMI, may serve as a potential biomarker of sarcopenia in patients with CRC (86). miR-33a serves as a clinical prognostic marker for sarcopenia and glioma by targeting FOS-like 1, AP-1 transcription factor subunit and engrailed homeobox 2 (87). The plasma levels of miR-29b, miR-181a and miR-494 were detected in a cohort of 93 individuals with sarcopenia. The results revealed a significant downregulation of plasma miR-29b in elderly individuals with sarcopenia and cardiovascular risk factors, including diabetes, hypertension and dyslipidemia (88).

Epigenetics serve a pivotal role in the development of sarcopenia, with DNA methylation, histone modifications and non-coding RNA regulation being the most extensively studied. Alterations in DNA methylation patterns in patients with sarcopenia can lead to the dysregulation of gene expression associated with muscle growth and repair (96). For instance, genes such as myogenic differentiation 1 and myocyte enhancer factor 2, which are crucial for muscle development, have promoter regions susceptible to changes in the methylation status that can affect their activity (97). Histone modifications also serve a critical role in sarcopenia, particularly in the imbalance between histone acetylation and deacetylation, which affects the muscle fiber-type conversion and energy metabolism (98). Non-coding RNAs, particularly miRNAs and long non-coding RNAs (lncRNAs), have emerged as key regulators of muscle atrophy and regeneration. These molecules modulate the muscle mass and function by targeting multiple signaling pathways, such as insulin-like growth factor 1/AKT/mTOR and TGF-β/SMAD pathways (99,100).

Currently, the diagnosis of gut microbiota relies heavily on high-throughput sequencing technologies, such as 16S ribosomal RNA gene sequencing and metagenomic analysis (101). Although these methods offer detailed information about the diversity and abundance of the gut microbiota, they have few limitations. Firstly, they often require expensive equipment and specialized knowledge, which limits their widespread application in clinical practice (102). Secondly, data interpretation can be complex and influenced by sample processing and analysis platforms (103). Furthermore, these techniques do not provide information on the microbial activity and function, which is crucial for understanding the relationship between gut microbiota dysbiosis and sarcopenia.

To overcome the limitations of the current diagnostic techniques, researchers are exploring new approaches for monitoring and diagnosing gut microbiota dysbiosis. One promising method is metabolomic analysis, which assesses microbial activity by detecting small molecular metabolites in blood, urine or fecal samples (102,104). Metabolomics not only reflects the functional state of the microbial community, but also reveals interactions between the host and microbiota (105). Moreover, the development of bioinformatics tools in recent years has enabled improved interpretation of complex datasets and the identification of disease-related biomarkers (106). Another emerging field is microbiome editing technologies, such as the CRISPR-Cas system, which provide a potential means of modulating specific microbial members to correct dysbiosis (107,108). Finally, portable devices and rapid testing platforms are under development, potentially allowing gut microbiota monitoring in the home or primary healthcare settings in the future (109).

The application of probiotics and prebiotics has emerged as an important strategy for modulating gut microbiota balance and impacting host health. In the context of sarcopenia treatment, probiotics can positively influence muscle metabolism by improving gut microbiota composition, enhancing intestinal barrier function and attenuating inflammatory responses (110). For instance, specific strains of lactic acid bacteria have been shown to increase the production of SCFAs in the gut, which are vital for maintaining the muscle function and promoting muscle synthesis (111). Furthermore, prebiotics, as non-digestible food ingredients, promote the growth of beneficial bacterial communities such as Bifidobacteria and Lactobacilli, which indirectly affect muscle health through the production of metabolites such as SCFAs (112). However, the clinical application of probiotics and prebiotics requires further randomized controlled trials to validate their efficacy and safety.

The development of drugs targeting gut microbiota represents a promising therapeutic strategy to address the connection between gut microbiota dysbiosis and sarcopenia. These drugs regulate specific microbial communities or their metabolites to restore the gut microbiota balance and improve muscle function (113). For example, the administration of antibiotics or specific antimicrobial peptides can inhibit detrimental bacterial communities and alleviate their detrimental effects on host health (114). Additionally, research is exploring the utilization of prebiotics, invertase inhibitors and other approaches to modulate the activity and metabolic pathways of specific bacterial communities. Although these methods have potential, precise targeting and dose control are required to avoid adverse effects on microbial communities.

FMT is a method for restoring the gut microbiota balance in the recipient's intestines by transplanting the gut microbiota of healthy donors. Although research on the use of FMT for the treatment of sarcopenia is still in its early stages, some encouraging findings have been reported. An animal study demonstrated that FMT transplantation of the gut microbiota of a healthy donor significantly improved the muscle atrophy caused by gut microbiota dysbiosis (115). Additionally, FMT positively affects muscle health by restoring gut microbiota diversity, enhancing intestinal barrier function and reducing inflammation (116). Despite the potential of FMT, further verification of its safety, efficacy and long-term effects in clinical applications is required.

In addition to direct interventions using probiotics, prebiotics or medications, lifestyle modifications are effective approaches for modulating the gut microbiota and treating sarcopenia. Dietary habits have a significant impact on gut microbial diversity and function. Consumption of a high-fiber diet promotes the growth of beneficial bacterial communities and increases the production of SCFAs, which are advantageous for maintaining muscle health. Moreover, moderate exercise has been shown to improve gut microbiota composition and enhance beneficial functions for overall health (117). Therefore, combining dietary adjustments with appropriate physical activity may represent a comprehensive and sustainable strategy for improving gut health and preventing or treating sarcopenia.