The connection of the gut microbiota with human health and diseases, including the gut–muscle axis and its role in sarcopenia, has attracted growing interest. The gut–muscle axis represents the bidirectional intricate crosstalk between the gut microbiota and skeletal muscles. Both the gut and skeletal muscles are recognized as having a signaling function, with skeletal muscle recently being shown to produce and release various myokines that have the potential to interact with distant organs or tissues (Hawley, 2020; Severinsen and Pedersen, 2020).

Skeletal muscle tissue is recognized as a protein reservoir in the human body, with muscle cells densely packed with contractile proteins in the cytoplasm (Sartori et al., 2021). This structural characteristic implies the critical impact of protein synthesis and degradation, which constantly turnover, on muscle mass and function. Specifically, alterations in muscle myofibrillar proteins directly influence changes in muscle mass. Maintaining the optimal balance between protein synthesis and breakdown is essential for muscle homeostasis. An excess of protein synthesis over breakdown may lead to muscle hypertrophy, contributing to increased muscle mass and improved muscle function (Sartori et al., 2021). Conversely, an imbalance favoring protein breakdown over synthesis may result in muscle atrophy, contributing to a loss of muscle mass and a decline in muscle function (Sartori et al., 2021). The balance between the synthesis and degradation of skeletal muscle proteins is vital for the mass and function of skeletal muscle, and multiple complex networks are involved (Schiaffino et al., 2013; Sartori et al., 2021). Several factors, such as exercise, nutrition, inflammation, and hormones, are well documented to impact this balance, while the gut microbiota and derived metabolites also have been demonstrated to affect the molecular pathways related to the skeletal muscle protein balance (Lahiri et al., 2019; Mancin et al., 2023).

A previous animal study using mice raised in a germ-free environment without gut microbiota showed muscle atrophy and the reduced expression of genes associated with skeletal muscle growth (Lahiri et al., 2019). In contrast, the transplantation of fecal material from pathogen-free mice to germ-free mice resulted in an increase in skeletal muscle mass and a decrease in markers of muscle atrophy (Lahiri et al., 2019). To gain insights into the signaling pathways involved in muscle atrophy in mice without gut microbiota, key genes associated with muscle atrophy were examined. The results indicated an increase in the expression of Atrogin-1 and Murf-1, which encode E3 ubiquitin ligases. These genes are known to be regulated by Forkhead box O (FoxO) transcription factors, and mice without gut microbiota exhibited elevated expression of FoxO3 (Sandri et al., 2004; Lahiri et al., 2019). Additionally, an increase in the phosphorylation of the catalytic domain of adenosine 5′-monophosphate-activated protein kinase (AMPK), which plays a critical role in controlling muscle fiber size by activating the FoxO-mediated protein degradation pathway, was observed (Greer et al., 2007; Lahiri et al., 2019). These studies suggest that the activation of the AMPK–FoxO3–Atrogin cascade could serve as a potential signaling pathway that partially elucidates muscle atrophy in mice without gut microbiota. Consistent with the findings from Lahiri’s study on mice lacking gut microbiota, research in humans has demonstrated the connection between muscle atrophy and a notable change in gut microbiota, specifically in the order Clostridiales and the family Lachnospiraceae (Jollet et al., 2021). Importantly, the family Lachnospiraceae has the capability to produce SCFAs and metabolize primary bile acids, which are initially synthesized in the liver, into secondary bile acids in the intestine (Vacca et al., 2020). While new insights that coordinate the gut–muscle axis and its involvement in maintaining skeletal muscle mass and function as well as the development of sarcopenia continue to evolve, one key mechanism through which the gut microbiota influence skeletal muscle is through the production of metabolites. Through these related metabolites and pathways, the compositional change of the gut microbiota can potentially lead to skeletal muscle atrophy (Mancin et al., 2023).

The intricate relationship between the gut microbiota and skeletal muscle underscores the impact of its compositional disruption, known as gut dysbiosis, on muscle health and disorders, including sarcopenia in the elderly. Extensive studies in experimental animals have provided evidence supporting the close relationship between the gut microbiota and characteristic changes in muscle mass and function associated with sarcopenia (Liu et al., 2021). Wu et al. (2020) observed that Ghrelin-null (Ghrl −/−) mice exhibited microbial dysbiosis during their youth and decreased muscle mass in old age. In another study, decreased skeletal muscle mass and function were found to be linked to an altered composition of gut microbiota in mice (Lahiri et al., 2019). Additionally, the same study demonstrated that the depletion of gut microbiota in germ-free mice directly triggered muscle atrophy (Lahiri et al., 2019). Conversely, Bacteroides fragilis gnotobiotic mice showed a significantly enhanced muscle mass and function in comparison with germ-free mice (Lahiri et al., 2019). Various animal studies have utilized microbiome-transplanted models to explore the direct correlation between the gut microbiota and muscle, and most of the findings indicated a similar grip strength and muscle mass in recipient mice when compared to their donors, although certain studies have reported inconsistent results with no discernible differences in muscle function or mass following microbiome transplantation (Liu et al., 2021).

Human studies also have examined the link between the gut microbiota and characteristic changes associated with sarcopenia like muscle mass/function by comparing elderly individuals with and without sarcopenia. Observational studies have revealed a strong correlation between variations in the relative abundance of the gut microbiome and age-related muscle loss as well as diminished physical performance (Picca et al., 2019; Castro-Mejía et al., 2020; Ghosh et al., 2022). For example, Picca et al. conducted a study comparing the gut microbiota and inflammation levels as well as physical frailty in older individuals with and without sarcopenia (Picca et al., 2019). The study revealed altered gut microbiota compositions, with a decreased abundance of Barnesiellaceae and Christensenellaceae and an increased abundance of Oscillospira and Ruminococcus microbial taxa in older individuals with sarcopenia and physical frailty compared to those without these conditions (Picca et al., 2019). Moreover, older individuals with physical frailty and sarcopenia exhibited higher systemic inflammation levels compared to those without these conditions (Picca et al., 2019). Furthermore, the individuals with a higher muscle mass displayed a greater gut microbiota diversity (Castro-Mejía et al., 2020).

As discussed earlier in this review, previous studies have noted a connection between gut microbiota and sarcopenia, particularly in the elderly population. However, a definitive causal relationship, its mediators, and the underlying mechanisms have yet to be fully elucidated. In a recent study by Zhao et al., Mendelian randomization analysis, a widely used method to establish causal relationships between risk factors and outcomes, was conducted to investigate the potential causal association between gut microbiota and sarcopenia-related traits, such as a low HGS and appendicular lean mass (Zhao et al., 2023). The study, utilizing the Mendelian randomization approach, identified significant compositional changes in the gut microbiota at the family and genus levels (Zhao et al., 2023). Specifically, Alcaligenaceae at the family level (a group of Gram-negative bacteria within the class Betaproteobacteria, encompassing genera like Alcaligenes, Bordetella, and Achromobacter), Family XIII at the genus level (specifically the genus Family XIII AD3011 group), and Paraprevotella at the genus level (a bacterial genus commonly present in the human gut microbiota within the family Lachnospiraceae, characterized by anaerobic, Gram-positive, and nonspore-forming properties) were found to be significantly positively associated with the risk of a low HGS (all p < 0.05); in contrast, Streptococcaceae at the family level (a group of bacteria belonging to the phylum Firmicutes) showed a negative association with a low HGS (p < 0.05; Zhao et al., 2023).

Moreover, eight bacterial taxa (Actinomycetaceae, Actinomycetales, Bacteroides, Bacteroidaceae, Marvinbryantia, Phascolarctobacterium, Prevotellaceae, and Porphyromonadaceae) were linked to an increased risk of appendicular lean mass (p < 0.05), while the Eubacterium fissicatena group exhibited a negative association with the appendicular lean mass (p < 0.05; Zhao et al., 2023). These findings from the Mendelian randomization analysis suggest a causal link between specific compositional changes in the gut microbiota at the family and genus levels and traits related to sarcopenia. Furthermore, eight bacterial taxa (Actinomycetaceae, Actinomycetales, Bacteroides, Bacteroidaceae, Marvinbryantia, Phascolarctobacterium, Prevotellaceae, and Porphyromonadaceae) were significantly linked to a higher risk of appendicular lean mass (p < 0.05), with the Eubacterium fissicatena group displaying a negative association with the appendicular lean mass (p < 0.05; Zhao et al., 2023). These results from the Mendelian randomization analysis suggest a causal association of gut microbiota compositional changes at the family and genus levels with sarcopenia-related traits (Zhao et al., 2023), while factors that mediate the causal relation remain unexplored. Therefore, understanding how gut dysbiosis contributes to primary sarcopenia is crucial for developing new interventions.

The significant alterations in gut microbiota associated with sarcopenia make them potentially valuable as noninvasive markers for this skeletal muscle disorder. Currently, research on the development of gut microbiota-based markers/predictive models for sarcopenia in the elderly is in its infancy. Nevertheless, recent years have witnessed advancements in this research area (Wang et al., 2022; He et al., 2023; Zhou et al., 2023; Guo et al., 2024). Accordingly, we have compiled a summary of potential gut microbiota-based biomarkers/predictive models and their performance for sarcopenia in Table 1. While the gut microbiota-based predictive models presented in Table 1 have achieved relatively high area under the receiver operating characteristic curve (AUC) values, indicating a good ability to discriminate between sarcopenia and nonsarcopenia, especially in population-based studies as reported by Wang et al. (2022) with an AUC of 0.852 in a predictive model based on differentially abundant gut microbiota species between sarcopenia and nonsarcopenia individuals (Wang et al., 2022), there are notable limitations. These limitations include a relatively small sample size and the lack of validation with external samples, among others. Further studies are necessary before translating these preliminary findings into clinical applications.

The findings on the role of gut microbiota in the metabolism of skeletal muscle, muscle mass, and strength/function, along with the underlying mechanisms, have significant implications for managing primary sarcopenia. Direct microbiota-related interventions, such as probiotic supplementation and fecal transplantation, whether used alone or in combination with nonpharmacological approaches, have been investigated. Probiotics, which are nonpathogenic living organisms, are well known for their beneficial effects on host health and disease prevention, leading to a consensus statement on the appropriate use of probiotics (Hill et al., 2014). Recent research has explored various nutritional strategies, including probiotic supplementation (e.g., Bacillus coagulans GBI-30 and Bacillus subtilis), to enhance muscle mass and function (Jäger et al., 2016; Toohey et al., 2020). In addition, studies have demonstrated that probiotic supplementation can effectively enhance muscle mass and function in experimental animal models (Giron et al., 2022). In the context of age-related sarcopenia, specific strains of probiotics, such as lactobacilli and bifidobacteria, have shown promise in mitigating age-related muscle loss in various mouse models (Ni et al., 2019; Chen et al., 2022). Several animal studies in mice or rats also have investigated the potential benefits of probiotic supplements, either alone or in conjunction with exercise, on muscle mass, growth, or function (Chen et al., 2016; Chen et al., 2019; Ni et al., 2019; Soares et al., 2019; Huang W. C. et al., 2020; Lee et al., 2020; Chen et al., 2022). The probiotic supplements examined include Lactobacillus plantarum TWK10 (LP10) (Chen et al., 2016), Bifidobacterium longum BL986 and Lactobacillus casei LC122 (Ni et al., 2019), Lactobacillus paracasei PS23 (Chen et al., 2019), Saccharomyces boulardii (Soares et al., 2019), Lactobacillus salivarius SA-03 (Lee et al., 2020), and Bifidobacterium longum OLP-01 (Huang W. C. et al., 2020). Moreover, the beneficial effects of probiotic supplements on muscle growth were demonstrated by Ni et al. (2019) and Chen et al. (2016), and Chen et al. (2019), while their impact on muscle function was shown by Ni et al. (2019), Soares et al. (2019), Chen et al. (2016), Chen et al. (2019), Lee et al. (2020), and Huang W. C. et al. (2020). Given the promising results from animal studies, it would be worthwhile to assess the beneficial effects of these probiotic supplements, either alone or in combination with exercise and anti-inflammatory agents, in elderly individuals with sarcopenia.

SCFA-producing gut microbes are influenced by various substances in foods and supplements (Cronin et al., 2021; Fusco et al., 2023). Specifically, non-starch polysaccharides, resistant starch, and resistant oligosaccharides in high-fiber diets, as well as supplementary fiber, inulin, and fructooligosaccharides in prebiotic supplements, have been shown to directly promote these gut microbiomes, leading to increased SCFA production (Cronin et al., 2021; Fusco et al., 2023). These findings suggest that maintaining a well-balanced diet rich in fiber and prebiotics is generally beneficial for supporting SCFA-producing gut microbes and enhancing SCFA production, potentially exerting beneficial effects on sarcopenia.

However, translating these findings from animal studies to human applications poses challenges due to the limited number of studies and the complexities involved in accurately and consistently assessing muscle mass and function in older individuals (Liu et al., 2021). Currently, several clinical trials have evaluated the effects of prebiotics, probiotics, or symbiotics on sarcopenia parameters in the elderly (Neto et al., 2013; Buigues et al., 2016; Huang et al., 2019). For example, Buigues et al. conducted a randomized placebo-controlled trial, demonstrating that supplementation with a prebiotic formulation (Darmocare Pre®), comprising a combination of inulin and fructooligosaccharides (targeting microbiota), improved two aspects of frailty syndrome—time to exhaustion and grip strength—in older participants (aged 65 years and above) (Buigues et al., 2016). Similarly, young healthy adults consuming Lactobacillus plantarum TWK10 daily experienced a dose-dependent enhancement in antifatigue capacity as well as an increased muscle mass (Huang et al., 2019). These two clinical trials consistently supported the beneficial effects of probiotics and prebiotics on muscle mass and strength (Buigues et al., 2016; Huang et al., 2019). In contrast, a small-scale clinical study involving only 17 participants found that the long-term use of a synbiotic (consisting of fructooligosaccharides, Bifidobacterium lactis, and Lactobacillus strains) did not enhance the grip strength or fat-free mass in the elderly (Neto et al., 2013). Recent randomized controlled trials investigating the beneficial effects of probiotic supplements on sarcopenia parameters and a meta-analysis of seven studies are summarized in Table 2 (Ford et al., 2020; Karim et al., 2022a; Karim et al., 2022b; Nistor-Cseppento et al., 2022; Rondanelli et al., 2022; Prokopidis et al., 2023; Shokri-Mashhadi et al., 2023; Qaisar et al., 2024).

Analysis of the randomized controlled trials revealed that probiotic supplementation enhanced muscle strength (handgrip strength) and physical performance and function (gait speed), indicating a beneficial impact on overall sarcopenia parameters in older adults (Prokopidis et al., 2023; Besora-Moreno et al., 2024). While the evidence for the efficacy of prebiotics remains scarce, a randomized clinical trial demonstrated a significant enhancement of handgrip strength, a key parameter of sarcopenia, in frail older individuals aged 65 and above, following the consumption of a prebiotic product consisting of inulin and fructooligosaccharides compared to a placebo (Buigues et al., 2016). Additionally, the beneficial effects of a certain probiotic supplement, Bifidobacteria, on sarcopenia parameters have been observed in Asian older adults but not in European populations, suggesting a potential specificity of these effects (Prokopidis et al., 2023). Therefore, further randomized clinical trials are needed to assess the effects of prebiotics, identify the more efficacious probiotic strains, and explore the potential synergistic effects of combining prebiotics and probiotics for better management of sarcopenia in older adults.

Despite the rapid progress in understanding the role of gut microbiota in primary sarcopenia, potentially through their metabolites, and observing the beneficial effects of probiotics, either alone or in combination with nonpharmacological approaches, on improving sarcopenia indices in animal and human studies, there are limitations and challenges that need to be addressed by future studies. (1) Standardized diagnostic criteria for primary sarcopenia have not been universally agreed upon. Various international groups, such as IWGS, AWGS, EWGSOP, and FNIH, have each established their own diagnostic criteria and definitions for sarcopenia. These varying criteria may impact both research and treatment strategies for sarcopenia. In research, heterogeneous criteria are associated with different outcomes, affecting study consistency and comparability (Han et al., 2018). Treatment strategies are also influenced, as differences in diagnostic criteria may affect early identification, treatment initiation, and monitoring. Tailoring treatments based on specific criteria is crucial for optimal outcomes, including exercise interventions, and physical or nutritional therapy (Ooi and Welch, 2024; Han et al., 2018). Therefore, the absence of a universally uniform definition and diagnostic criteria for sarcopenia will require standardization. (2) Sarcopenia is more prevalent in males than in females (Cruz-Jentoft and Sayer, 2019). Given the sex-specific differences in the gut microbiota composition (Kim et al., 2020), future research should explore the impact of sex hormones and their interplay with the gut microbiota. These sex-specific differences in the gut microbiome might contribute to the sex dimorphism in sarcopenia. In addition, further investigations might help to elucidate the intricate pathological mechanisms underlying the sex disparity in primary sarcopenia, particularly the higher prevalence in males compared to females. Moreover, it would also be worthwhile to explore the potential role of hormone therapy in the elderly for the prevention or treatment of sarcopenia in the elderly. (3) In a recent study by Zhao et al., a Mendelian randomization analysis was conducted to investigate the potential causal association between the gut microbiota and sarcopenia-related traits, including appendicular lean mass and low HGS (Zhao et al., 2023), indicating the definitive causal relationship between the gut microbiota and sarcopenia. While this study indicated a definitive causal relationship between the gut microbiota and sarcopenia, the mediators and underlying mechanisms remain incompletely elucidated, necessitating further research in future studies. (4) The existing evidence suggests that key metabolites of the gut microbiota, including SCFAs and secondary bile acids, can mediate their effects on the metabolism of skeletal muscle and, consequently, the indices of sarcopenia. For example, the beneficial effects of SCFAs on muscle mass and function have been demonstrated in animal models of sarcopenia. Clinical studies also have shown associations between the gut microbiota composition, SCFA levels, and sarcopenia in elderly individuals. However, further investigation is needed to establish the direct causal relationship between gut microbiota-derived SCFAs and the development of primary sarcopenia through well-designed longitudinal studies and intervention trials. Gut microbiota-derived SCFAs have emerged as potential novel therapeutic agents for enhancing muscle mass (Liu et al., 2021). Furthermore, future human studies are crucial for confirming the promising results from experimental cell culture or animal studies, as this validation is essential for facilitating the translation of these findings into potential treatments or interventions. (5) An integrated approach, combining probiotics with nonpharmacological strategies like high-protein intake, exercise, and an anti-inflammatory diet, merits exploration in future research. Dietary modifications, exercise, and fecal microbiota transplantation represent diverse methods to rebalance the gut microbiota and to alleviate the effects of dysbiosis on skeletal muscle. Tailored interventions should be guided by individual microbiota profiles to enhance treatment effectiveness for sarcopenia in the elderly. (6) A key focus for future research is to identify gut bacteria or their metabolites that are unique to sarcopenia in the elderly, with the potential to serve as biomarkers for distinguishing older individuals with or without sarcopenia.