Integrative Insights into the Gut-Muscle Axis: Unraveling Its Role in Sarcopenia Pathogenesis and Therapeutic Approaches

Sarcopenia, often referred to as a “Geriatric Giant,” is a progressive disorder of the skeletal muscles characterized by a decrease in muscle mass and function (Cruz-Jentoft and Sayer, 2019). This condition is linked to several negative outcomes, including a heightened risk of falls, functional decline, frailty, and increased mortality in older populations (Cesari et al., 2014; Cruz-Jentoft et al., 2019; Landi et al., 2012). The European Working Group on Sarcopenia in Older People (EWGSOP) outlines that the diagnosis of sarcopenia necessitates measuring muscle mass (through methods like mid-arm muscle circumference, dual energy X-ray absorptiometry, or bioelectrical impedance analysis), muscle strength (evaluated via hand grip), and physical performance (assessing mobility and balance). These measures help in determining the severity of the disease using established cut-off values (Cruz-Jentoft et al., 2019).

In the context of the underlying mechanisms of muscle wasting, chronic low-grade inflammation has been associated with the onset of sarcopenia, as it can initiate pathways that result in muscle wasting and decrease the synthesis of muscle protein (Marcell, 2003). Furthermore, Oxidative stress plays a role by damaging muscle cells and disrupting the equilibrium between muscle protein synthesis and breakdown (Marcell, 2003). Insulin resistance is another contributing factor, as it can diminish muscle protein synthesis and enhance muscle protein degradation, thus promoting muscle wasting (Cruz-Jentoft and Sayer, 2019; Marcell, 2003). Hormonal changes also influence sarcopenia, with older men experiencing reduced testosterone levels and older women experiencing decreased estrogen levels, both of which can lead to a reduction in muscle protein synthesis and an increase in muscle protein degradation (Marcell, 2003). Additionally, as aging progresses, the activation of muscle satellite cells becomes less efficient, which leads to a reduction in muscle repair and an escalation in muscle wasting. (Cruz-Jentoft and Sayer, 2019; Marcell, 2003).

The decline in human skeletal muscle mass with age, a key factor leading to sarcopenia, is attributed to a reduction in both the size and number of myofibers, including both fast and slow type myofibers. Notably, the loss of fast myofibers, which rely on glycolytic metabolism, typically begins earlier (Lexell et al., 1983). The nervous system, crucial for muscle strength, also deteriorates with age. This deterioration is due to factors like the loss of motoneurons, the demyelination of axons, and the retraction of nerve terminals from neuromuscular junctions (Chai et al., 2011; Ham et al., 2020). Furthermore, an important aspect of sarcopenia is the anabolic resistance of older skeletal muscle to protein nutrition. This resistance can be mitigated through resistance exercise and dietary supplementation (Farnfield et al., 2012; Narici and Maffulli, 2010).

There has been a growing body of research indicating a relationship between gut microbes and skeletal muscle metabolism. The condition of the gut microbiome may influence both the composition and functionality of skeletal muscle. Disorders in the intestinal microbiota can lead to health deterioration in patients and the elderly, impacting their quality of life. Consequently, it is imperative to identify effective intervention strategies by understanding the role of gut microbiota in skeletal muscle metabolism.

Recent pre-clinical studies have shown a significant correlation between the composition of the intestinal microbiome and the structure and metabolic indicators of skeletal muscle (Lahiri et al., 2019; Manickam et al., 2018). Experiments involving the transplantation of intestinal flora for skeletal muscle enhancement have been conducted. Certain gut microbiomes can produce metabolites that foster skeletal muscle anabolism. For instance, an optimally functioning gastrointestinal microbiome featuring microbiota like Propionibacteria and Lactobacillusreuteri has the capacity to generate substantial quantities of folate and vitamin B₁₂. These bioactive compounds are implicated in enhancing muscle anabolism and mitigating the adverse effects of hyperhomocysteinemia-induced oxidative stress and endothelial damage. Consequently, this could lead to an amelioration in muscle functionality (Kuo et al., 2007). Furthermore, the gut microbiota such as by Bacillus subtilis possesses the capability to biosynthesize specific amino acids, such as tryptophan, which serve as essential substrates for facilitating muscle protein anabolism (Lin et al., 2017). Further, short-chain fatty acids (SCFAs), produced by the intestinal microbiota, including Faecalibacterium, Succinivibrio, and Butyricimonas, can enter the systemic circulation and become assimilated by skeletal muscle cells. Within these cells, SCFA serve as ligands for free fatty acid receptors 2 and 3, which are recognized for their pivotal role in regulating glucose uptake and metabolism, as well as enhancing insulin sensitivity. (Kimura et al., 2014). Notably, experiments involving the transplantation of fecal material from malnourished children into mice resulted in altered growth patterns in the recipient mice. Conversely, transplantation of fecal microbiota from well-nourished children into mice did not exert any significant impact on growth. This underscores the concept that a healthy gut microbiota promotes anabolic processes, while a dysbiotic microbiota is linked to anabolic resistance or, in some cases, catabolism (Ticinesi et al., 2017). Mice made germ-free (GF) and then transplanted with feces from elderly individuals exhibited varying functions, with some showing increased lean mass and reduced fat mass (Fielding et al., 2019). In another study, the mice transplanted with feces from the physically high-functioning elderly demonstrated greater grip strength and a higher proportion of beneficial microbiota such as Prevotella and Barnesiella at the genus level (Ticinesi et al., 2017). GF mice typically had lower muscle mass and fewer muscle fibers, with increased markers of muscle atrophy, compared to pathogen-free mice. Remarkably, these effects were largely reversed following fecal transplantation and treatment with SCFA (Lahiri et al., 2019). Studies in animal models consistently reveal that alterations in gut microbiome composition can regulate the metabolic functions of skeletal muscle. Thus, understanding the intricate relationship between the gut microbiome and host physiology is crucial for developing lifestyle, nutritional, and pharmaceutical interventions to preserve and enhance skeletal muscle health.

Studies in humans have also identified a link between the composition of the gut microbiome in the elderly and skeletal muscle function. Alterations in the gut microbiome, often observed when older adults move to long-term care facilities, can impact bone and body composition. This transition seems largely attributable to dietary modifications, shifting from a fiber-rich, predominantly plant-based diet at home to one with lower fiber, increased fat, and greater sucrose levels in the facilities. Furthermore, elderly adults in these institutions frequently undergo prolonged antibiotic therapy and have coexisting medical conditions. They also live alongside other seniors, factors which collectively impact gut microbiota. Such changes can potentially contribute to conditions such as sarcopenia, osteoporosis, and obesity, consequently heightening fracture risks (Inglis and Ilich, 2015).

Currently, the role of the gut-muscle axis in maintaining muscle health during aging is supported by evidence from animal studies and human research. Nonetheless, the precise mechanisms at play are not fully elucidated. This study intends to thoroughly investigate the possible underlying mechanisms. These encompass factors such as protein metabolism, systemic chronic inflammation, metabolic resistance, mitochondrial dysfunction, and their impact on the expression of host genes. In older adults, the gut microbiota may impact their health by affecting aging-related sarcopenia. The reduction in muscle mass and strength observed in the elderly could be linked to changes in their gut microbiota. Studies have shown that individuals with sarcopenia, or those at risk of sarcopenia, exhibit notably lower microbial diversity compared to healthy controls. These individuals tend to have higher levels of Lactobacillus and lower levels of Lachnospira, Fusicantenibacter, Roseburia, Eubacterium, and Lachnoclostridium (Kang et al., 2021). In elderly patients with sarcopenic cirrhosis, there has been a significant increase in potentially pathogenic bacteria like Klebsiella and Eggerthella, while beneficial bacteria such as Akkermania and Prevotella have decreased, fostering a pro-inflammatory environment (Ponziani et al., 2021). Furthermore, Ticinesi et al. found that elderly sarcopenic patients, compared to non-sarcopenic controls, had a lower abundance of bacteria that produce SCFAs such as Faecalibacterium prausnitzii and Roseburia inulinivorans (Ticinesi et al., 2020). Analysis of the fecal metagenome in these individuals revealed a reduced representation of genes responsible for the synthesis of SCFAs, along with genes involved in the biotransformation of carotenoids and isoflavones, and those facilitating the interconversion of amino acids. These observations emphasize the significant relationship between the gut microbiota’s composition and the development of sarcopenia.

Several animal studies have investigated the link between intestinal microbiota and age-related sarcopenia in older mice and rats. Research by Siddharth et al. demonstrated that aging can modify the intestinal microbial composition in aged male rats, exemplified by changes in the ratio of Sutterella to Barneseilla, and the metabolic capabilities of the gut microbiota (Siddharth et al., 2017). Furthermore, GF mice, which lack intestinal microbiota, exhibited skeletal muscle atrophy, decreased levels of insulin-like growth factor-1, and lowered expression of genes related to the neuromuscular junction, specifically those encoding Rapsyn and Lrp4, in comparison to pathogen-free mice (Lahiri et al., 2019). These findings suggest that age-related alterations in intestinal microbiota may contribute to the deterioration of muscle function in older mice or rats.

Overall, the aforementioned studies provide initial evidence of a link between intestinal microbiota and muscle metabolism. However, further research is necessary to validate these initial findings. Future investigations should also focus on identifying specific bacterial markers associated with the development of sarcopenia, which could offer novel targets for therapeutic intervention.

A range of human studies and animal model research has delved into the potential mechanisms by which gut microbiota contributes to muscle loss. These studies have focused on various aspects, including protein anabolism, mitochondrial dysfunction, chronic inflammation and immune responses, as well as imbalanced metabolism.

Skeletal muscle quality is influenced by the balance between muscle protein synthesis (MPS) and muscle protein breakdown. Gut microbiota are capable of synthesizing certain essential amino acids, such as tryptophan, which are fundamental for MPS and metabolism (Lin et al., 2017). Tryptophan which can be synthesized by Bacillus subtilis plays a crucial role in stimulating the IGF-1/p70s6k/mTOR signaling pathway in muscle cells, which is essential for myofibril synthesis (Dukes et al., 2015; Lin et al., 2017). Conversely, gut microbiota imbalances, known as dysbiosis, are marked by reduced diversity, an increased presence of pathogenic bacteria, and compromised integrity of epithelial tight junctions, which may enhance intestinal permeability. This condition could enable the migration of microbial derivatives like lipopolysaccharide (LPS) into the bloodstream and diminish SCFA levels, leading to impaired protein metabolism and a decrease in MPS (Mesinovic et al., 2019; Ni Lochlainn et al., 2018). Therefore, an imbalanced gut microbiome can lead to lower protein absorption and availability, contributing to anabolic resistance and potentially causing sarcopenia. Investigating the role of gut microbiota in contributing to anabolic resistance and identifying ways to improve MPS are critical areas for future research.

In skeletal muscle, primary aging leads to mitochondrial energetics deficiency and muscle mass reduction (Cartee et al., 2016). It is suggested that ultrastructural modifications in the number and functionality of mitochondria caused reduced muscle protein synthesis (Marzetti et al., 2013, 2016; St‐Jean‐Pelletier et al., 2017). Interestingly, research has revealed a reciprocal interaction between gut microbiota and mitochondria. This exchange primarily occurs through signals sent from the gut microbiota to mitochondria and back, facilitated by endocrine, immune, and humoral connections (Mottawea et al., 2016). Key insights into the mitochondrial-microbiota relationship have emerged from studies focusing on mitochondrial functions and the tactics bacterial pathogens use to interfere with calcium homeostasis, redox state maintenance, and mitochondrial structure (Lobet et al., 2015). Additionally, recent investigations have shown that metabolites produced by the commensal gut microbiota, such as SCFAs and secondary bile acids, can impact mitochondrial activities related to energy generation, mitochondrial formation, redox equilibrium, and inflammatory pathways, suggesting their potential role in enhancing endurance (Circu and Aw, 2012; Den Besten et al., 2013; Mottawea et al., 2016). For instance, gut commensal microbiota reduce ROS production via SCFA such as N-butyrate (Mottawea et al., 2016). Therefore, a disruption of the relationship leads to dysfunctional mitochondria. It is worth noting that mitochondrial dysfunction may play a vital role to link the relation between chronic inflammation and age-related sarcopenia, and the gut microbiota dysbiosis may be a key role in the gut–muscle crosstalk (Picca et al., 2018). Consequently, any disruption of this intricate relationship can precipitate mitochondrial dysfunction.(Ni Lochlainn et al., 2018).

Sarcopenia’s progression is intimately linked to age-related systemic chronic inflammation (Grosicki et al., 2018; Ni Lochlainn et al., 2018). Disruptions in gut microbiota can compromise the integrity of the host’s intestinal barrier and disturb the balance between pro-inflammatory and anti-inflammatory cytokines, which in turn can lead to the development of sarcopenia (Ni Lochlainn et al., 2018; Picca et al., 2018). Beyond changes in microbial composition, microbial by-products like LPS can also contribute to sarcopenia by inducing systemic chronic inflammation and insulin resistance. Therefore, inflammaging – the chronic, low-grade inflammation associated with aging – plays a crucial role in both the development and persistence of sarcopenia (Livshits and Kalinkovich, 2019).

SCFAs, key by-products of the gut microbiota, play a significant role in altering muscle biology (Lahiri et al., 2019). SCFAs are known to aid in increasing muscle mass and enhancing physical function by boosting muscle glycogen levels (Fushimi and Sato, 2005; Lahiri et al., 2019). They also enhance the metabolic efficiency of muscle fibers by increasing ATP production (Leonel and Alvarez-Leite, 2012), and can improve lean muscle mass and cross-sectional area by inhibiting histone deacetylase activity (Walsh et al., 2015). As individuals age, changes in the microbiota are characterized by a reduction in microbial diversity and a rise in pathogenic bacteria, particularly Proteobacteria, along with a relative decline in advantageous bacteria like Bifidobacterium. In addition to shifts in microbial diversity, there is a significant decrease in the production of beneficial microbial metabolites, such as SCFAs which might be associated with the process of aging (Chen et al., 2019; Rampelli et al., 2013). In fact, a decrease in gut microbiota-derived SCFAs has been linked to subclinical chronic inflammation, which can lead to sarcopenia (Ticinesi et al., 2017). These findings underscore a strong correlation between gut microbiota, through its SCFA metabolites, and muscle mass.

Imbalances in gut microbiota can lead to the production of certain detrimental bacterial metabolites. For example, indoxyl sulfate, a metabolite of tryptophan derived from the gut microbiome and classified as a uremic toxin, is generated by certain gut bacteria including Escherichia coli, Clostridium species, and Bacteroides species. It has been demonstrated to stimulate increased activity in the pentose phosphate pathway and enhance glycolysis in C2C12 myoblasts. These metabolic processes are associated with the onset of sarcopenia. (Grosicki et al., 2018; Sato et al., 2016; Wikoff et al., 2009). Additionally, an increase in LPS levels as a by-product of gram-negative bacteria, resulting from a consequence of dysbiosis, can disrupt retinoic acid signaling. This disruption occurs through the generation of reactive oxygen species and affects antioxidant genes like Nrf2 and AKR1B10, thereby hindering the development of muscle progenitor cells (Song et al., 2020).

Collectively, a dysregulated gut microbiota can affect muscle mass and function through various mechanisms, such as inflammation, immune responses, protein metabolism, metabolism of SCFAs, and mitochondrial dysfunction. These interactions, whether direct or indirect, establish a connection with sarcopenia via the gut-muscle axis, thereby significantly impacting the physiological functions of the host.

Based on the understanding of the gut-muscle axis, numerous studies have proposed that modifying gut microbiota could be a potential therapeutic approach for managing age-related sarcopenia. There is a growing body of preclinical and human research that either directly or indirectly establishes a connection between gut microbiota and muscle mass/function. Several interventions targeting gut microbiota have been suggested, including the use of probiotics and/or prebiotics, SCFAs, dietary supplementation, and exercise, all of which have shown effectiveness in improving muscle mass and overall host function. The composition of the gut microbiota is influenced by dietary habits, which can lead to microbiota changes critical for organism function (Singh et al., 2017). Supplementing with prebiotics and/or probiotics has shown to be beneficial in improving intestinal homeostasis and enhancing skeletal muscle metabolism and synthesis (Salazar et al., 2017). Furthermore, exercise or physical activity also contributes to regulating the gut microbiota, showcasing its role in gut health and overall physiological function (Franko et al., 2016).

Protein supplementation is a commonly utilized approach for preventing and managing sarcopenia. It is well-established that increasing dietary protein intake can have a positive impact on both skeletal muscle mass and function. Furthermore, there is empirical evidence to suggest that adhering to a high-protein diet in accordance with recommended macronutrient distribution guidelines can be effective in alleviating the consequences of sarcopenia. (Ford et al., 2018). A study has demonstrated a positive correlation between protein intake and the diversity of gut microbiota (Singh et al., 2017). It appears that the source of protein may also play a role in this relationship. Additionally, research indicates that the supplementation of whey protein and leucine has the potential to enhance muscle mass and function (Bechshøft et al., 2016; Kobayashi, 2018). However, further investigation is required to establish a connection between the improvement in muscle mass and function achieved through high-protein diets and the modulation of gut microbiota.

An increasing number of both animal and human studies suggest that the use of prebiotics and/or probiotics can have beneficial effects on skeletal muscle. Prebiotics, which are non-digestible carbohydrates fermented in the lower part of the gut and selectively stimulate the growth and/or activity of specific bacteria, have been shown to have positive effects on the host (Delzenne and Cani, 2011). Some studies have explored the impact of prebiotics on skeletal muscle mass and strength by altering gut microbiota (Bindels and Delzenne, 2013). In one study involving elderly human subjects, a prebiotic supplement containing inulin and fructooligosaccharide, expected to promote a healthy microbiome, was administered. The subjects who consumed the prebiotic supplement exhibited greater hand strength and endurance compared to control subjects, although the effects on the microbiome were not reported (Y. Liu et al., 2016; Ni Lochlainn et al., 2021). Additionally, research by Cani et al. demonstrated the beneficial effects of prebiotic supplementation on the skeletal muscle of mice (Cani et al., 2009). Prebiotic intake modulated bacteria that produce SCFAs, which in turn altered skeletal muscle mass and function. SCFAs promoted the release of insulin-like growth factor-1 from the host, acting as an anabolic hormone to enhance skeletal muscle and reduce inflammation (Schroeder and Bäckhed, 2016; Ticinesi et al., 2017). Probiotics are live microorganisms that provide health benefits to the host when administered in adequate amounts (Delzenne and Cani, 2011). In a mouse model of acute leukemia, sarcopenia was attenuated through oral supplementation with specific Lactobacillus species as one of representative probiotics (Bindels et al., 2012). Furthermore, supplementation with Lactobacillusplantarum resulted in increased muscle mass and function In young adults, the consumption of TWK10 for a duration of six weeks resulted in improved endurance performance in a maximal treadmill running test (Huang et al., 2018). Furthermore, the intake of heat-killed Bifidobacterium breve B-3 had a significant positive impact on skeletal muscle mass and function. This effect was accompanied by enhanced mitochondrial biogenesis, indicated by increased phosphorylation of AMP-activated protein kinase, activation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha, and elevated cytochrome c oxidase activity in the rat soleus muscle (Toda et al., 2020).

Fecal microbiota transplantation (FMT) involves the introduction of a donor feces solution into patients (Van Nood et al., 2013). Several studies have suggested that FMT may have the potential to enhance skeletal muscle mass and function. For example, Yan et al. conducted an experiment in which they transferred gut microbiota from obese pigs to GF mice. Several studies have suggested that FMT may have the potential to enhance skeletal muscle mass and function. For example, Yan et al. conducted an experiment in which they transferred gut microbiota from obese pigs to germ-free (Yan et al., 2016). Similarly, a recent study investigated the role of intestinal microbial imbalances in sarcopenia in mice with chronic kidney disease (CKD) (Uchiyama et al., 2020). When the cecal bacteria from CKD mice were transplanted into GF mice, the GF mice developed features of sarcopenia observed in the CKD mice. However, their muscle function improved, and disease symptoms were alleviated, highlighting the potential of FMT in this context.

Exercise training, especially resistance training, has long been recognized as a highly promising method for enhancing muscle mass and strength in older individuals The majority of clinical trials have consistently demonstrated the positive impact of exercise in the prevention of sarcopenia (Beaudart et al., 2017). Exercise exerts a significant influence on the intestinal microbiome, with some studies indicating that it is associated with increased microbial diversity and the presence of taxa that offer beneficial metabolic functions (Bressa et al., 2017; Clarke et al., 2014; Ticinesi, Lauretani, et al., 2019). A reciprocal relationship between skeletal muscle and the gut microbiome has been postulated (Ni Lochlainn et al., 2018). a significant body of research indicates a synergistic effect in improving muscle performance when exercise is combined with protein supplementation (Bechshøft et al., 2016; Kobayashi, 2018; Ni Lochlainn et al., 2018). However, the results of implementing a combined approach that includes exercise and dietary protein supplements have displayed variations among different population groups, emphasizing the necessity for additional investigations (Dhillon and Hasni, 2017).