Weixuan Chew1,2
Yen Peng Lim3,4
Wee Shiong Lim1,2,3
Edward S. Chambers5
Gary Frost6
Sunny Hei Wong1,2,7
Yusuf Ali1,2,8,9*†- 1Nutrition, Metabolism and Health Programme, Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore, Singapore
- 2Centre for Microbiome Medicine, Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore, Singapore
- 3Institute of Geriatrics and Active Aging, Tan Tock Seng Hospital, Singapore, Singapore
- 4Department of Nutrition and Dietetics, Tan Tock Seng Hospital, National Healthcare Group, Singapore, Singapore
- 5Section for Nutrition Research, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, United Kingdom
- 6Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London, London, United Kingdom
- 7Department of Gastroenterology and Hepatology, Tan Tock Seng Hospital, National Healthcare Group, Singapore, Singapore
- 8Singapore General Hospital, Singapore Eye Research Institute (SERI), Singapore, Singapore
- 9Clinical Research Unit, Khoo Teck Puat Hospital, National Healthcare Group, Singapore, Singapore
Our gastrointestinal system functions to digest and absorb ingested food, but it is also home to trillions of microbes that change across time, nutrition, lifestyle, and disease conditions. Largely commensals, these microbes are gaining prominence with regards to how they collectively affect the function of important metabolic organs, from the adipose tissues to the endocrine pancreas to the skeletal muscle. Muscle, as the biggest utilizer of ingested glucose and an important reservoir of body proteins, is intricately linked with homeostasis, and with important anabolic and catabolic functions, respectively. Herein, we provide a brief overview of how gut microbiota may influence muscle health and how various microbes may in turn be altered during certain muscle disease states. Specifically, we discuss recent experimental and clinical evidence in support for a role of gut-muscle crosstalk and include suggested underpinning molecular mechanisms that facilitate this crosstalk in health and diseased conditions. We end with a brief perspective on how exercise and pharmacological interventions may interface with the gut-muscle axis to improve muscle mass and function.
Introduction
The gut-muscle axis describes how the gut microbiota can impact muscle mass, muscle quality and muscle function. The gut consists of trillions of microbial cells, which plays an important role in many aspects of human health and can influence muscle health through dietary fiber, proteins and metabolic by-products (1). The gut microbiota ferments non-digestible substrates such as dietary fibers to produce short chain fatty acids (SCFA) which have important regulatory functions. Emerging evidence suggests a relationship between gut microbiota and sarcopenia, which is the age-related loss of skeletal muscle mass and function. The spectrum of parameters implicated in muscle health ranges from muscle quantity which is typically measured via the appendicular lean mass using dual energy X-ray absorptiometry (DXA) or bioelectrical impedance analysis (BIA); muscle quality which refers to the amount of fat infiltration into muscle; and muscle function which measures the components of strength and physical performance.
Muscle health is important because skeletal muscles are major sites of insulin stimulated glucose uptake, and thus play a key role in glucose homeostasis and whole-body metabolism. Furthermore, low skeletal muscle mass is often associated with frailty in older adults which increases their susceptibility to adverse outcomes and negatively affects their quality of life. It is also associated with many metabolic diseases such as Type 2 Diabetes Mellitus (T2DM). If it turns out that the gut microbiome does indeed strongly influence muscle health via the gut-muscle axis, it can create new avenues of treatment to improve muscle health through direct means such as probiotics or indirectly via dietary interventions or prebiotic supplementation. In this article, we summarize recent animal and human studies that suggest the role of gut microbiota in influencing muscle health, and on how gut microbes may in turn be altered during certain muscle disease states. Insofar, the aim is not to provide a systematic review but rather to give a perspective based on existing evidence that exercise and pharmacological interventions provide benefit by impinging on the gut-muscle axis.
Associations between gut microbiome and muscle
Animal studies reveal interesting insights about the gut-muscle axis. In a study on mice, it was found that germ free (GF) mice lacking in gut microbiota displayed reduced skeletal muscle weight, as compared to conventional or specific pathogen free (SPF) mice which have an intact gut microbiota and immune system (2). Upon histological examination of the tibialis anterior and gastrocnemius, fewer but larger muscle fibers could be seen. In the muscles of the GF mice, there was reduced expression of the succinate dehydrogenase (Sdh) gene and reduced activity of the mitochondrial SDH enzyme. The amount of mitochondrial DNA content also reduced and there was evidence of dysfunctional mitochondrial biogenesis and oxidative capacity of the soleus (oxidative) and extensor digitorium longus (glycolytic). Reduced expression of glycolytic genes was observed in these muscle groups. However, despite a possible reduction in oxidative metabolic capacity, the GF mice performed as well as SPF mice when challenged till exhaustion, suggesting the involvement of other compensatory pathways especially during the endurance phase. Importantly, upon treatment with SCFA, the muscle strength of GF mice increased as compared to the untreated GF mice, suggesting that SCFAs may be an important link between gut microbiota and muscle function. Transplantation of gut microbiota from SPF mice to GF mice helped to restore muscle mass and mitochondrial DNA content in GF mice muscle. This suggests that modulation of microbiota could potentially be used in humans as a way to treat conditions such as sarcopenia. When similar experiments were repeated in piglets, the results were largely similar to what was observed in mice (3). The GF piglets exhibited a lower growth rate as compared to control piglets with normal microbiota. A group of GF piglets was treated with fecal microbiota transplantation (FMT) from healthy adult pigs and the average body weight of piglets receiving FMT increased by ~1.4-fold compared to that of the GF piglet. Although the FMT did not completely restore growth of the GF piglet, they showed improved body conditioning and physiological traits as compared to the GF piglets. As for underpinning mechanism, the lower proportion of slow twitch muscle fibers of the GF piglets correlated with reduced SCFA contents pointing toward a role of gut microbes, specifically butyrate-producers in influencing slow-twitch muscle fiber development. In addition, the blood concentrations of triglycerides (TG), glucose and growth hormones in the FMT piglet were also significantly higher than that of the GF piglet suggesting that the introduction of gut microbes improved whole-body metabolic homeostasis in GF piglets.
In another study, when three different antibiotic regimens (1. cefoperazone, 2. enrofloxacin/ampicillin, 3. a four-drug regimen of neomycin, vancomycin, metronidazole and ampicillin) were administered to mice, there was a decrease in mass of the gastrocnemius-soleus complex of the mice (4). However, when the antibiotics were administered to GF mice, they did not lose any muscle mass as compared to the control suggesting that the effects of antibiotics on muscle mass is likely modulated through its impact on the microbiome. This could be due to the concurrent alteration of the gut microbiota, the composition of which depended on antibiotics administered. An intact gut microbiome has also been shown to be important for skeletal muscle adaptation to exercise (5). Mice treated with antibiotics to disrupt gut microbiome showed a blunted soleus and plantaris muscle fiber-type specific hypertrophy in response to progressive weighted wheel running as compared to those without antibiotics treatment. Mice which were colonized with gut bacteria through FMT from high functioning human donors had a 5.4% increase grip strength as compared to those which received FMT from low functioning human (6). While animal studies help with mechanistic underpinnings of phenotypic observations, it is also important to assess how much of these findings translate to the human setting.
It is worth noting that there are also studies the suggest negative associations between gut microbiota and whole-body lean mass. In one study when GF mice were colonized by fecal samples from age matched, conventionally raised mice, the whole-body lean mass decreased by 7–9% with a 57% increase in total body fat content. It was also associated with increased plasma leptin, fasting glucose and fasting insulin levels (7).
In another study, mice treated with pulsed antibiotic treatment (PAT) either using amoxicillin or tylosin phosphate developed larger bones with increased lean and fat mass as compared to controls. It trended toward increased bone in amoxicillin-treated mice and increased fat in tylosin-treated mice (8) and this was corroborated in antibiotic treated piglets. In tylosin phosphate-treated piglets, myofiber density and expression of genes related to type I and type IIb myofibers as well as fatty acid uptake in longissimus muscle was observed to be increased, together with gut microbe changes where the ratio of Firmicutes to Bacteroidetes was increased, while Prevotella and Campylobacter were decreased in the cecum (9).
Given its highly complex and multi-dimensional nature, the microbiota that evolve with different antibiotics and FMT regimens can exert different corresponding phenotypes. While gut microbiota does have affect muscle mass and function, these discrepant findings do suggest the need for more studies to determine the causality, functionality and directionality of the microbiota and its constituent members.
Human studies associate gut microbe changes with metabolic- and age-related muscle loss
Patients with low muscle mass or sarcopenia, in the context of organ failure or cancer, were observed to have alterations in their gut microbiome. It was reported that patients with chronic liver disease who had lower muscle mass possessed a lower Firmicutes/ Bacteroidetes ratio than those with normal muscle mass (10). The levels of Coprobacillus, Catenibacterium and Clostridium were also lower while Bacteroides was higher comparing between muscle sub-groups. There was also a high relative abundance of Gram-negative bacteria and corresponding lipopolysaccharides (LPS) suggesting a possible link between gut microbes, inflammation and changes to muscle mass. There are cross-sectional human association studies that compare patients with cirrhosis-related sarcopenia with control subjects. The principal alteration in age-related sarcopenia and cirrhosis-related sarcopenia was a reduction in SCFA-producing bacteria. Lachnospiraceae family, consisting of Lachnospira, Fusicatenibacter, Roseburia, and Lachnoclostridium, significantly decreased in age-related sarcopenia.
Interestingly, in a study involving nursing-home residents aged 65 years or older, with increasing frailty, residents had lower levels of butyrate producing organisms, higher levels of known dysbiotic species, and higher LPS and peptidoglycan (PGN) biosynthesis. Amongst the residents, with increasing age, there was a reduction in mucin-degrading Akkermansia muciniphila and butyrate-producing Ruminococcus bromii likely due to a change in diet. With increasing malnourishment, there is increased abundance of LPS-producing Ruminococcus gnavus and deceased butyrate-producing Lachnospiracae and Ruminococcaceae (11). In a separate study on stool samples from frail old people, Lactobacilli, F. prausnitzii, and Bacteroides / Prevotella ratio declined sharply and Enterobacteriaceae increased (12). Such changes in gut microbial species may alter the inflammatory tone as Lactobacilli, F. prausnitzii are largely anti-inflammatory while Enterobacteriaceae induces pro-inflammatory effects. It has been suggested that age dependent changes in gut microbiota may be the initiator of frailty symptoms facilitated by chronic inflammation, since probiotic rescue reduces inflammation and muscle atrophy (13–15).
Admittedly, metabolic dysregulation and aging are complex conditions that encompass differences in nutritional intake, digestion and assimilation, drug use treatments (usually involving multiple drugs) and background physiology and inflammation, all of which may profoundly confound microbiome changes and muscle health. Mechanistic studies are key to elucidating how the microbiome, and its metabolites, influence muscle metabolism and survivability. Furthermore, the gut microbiota diversity may also be affected by protein intake. Briefly, in a study with professional athletes from an international rugby union squad compared against healthy male controls, there was a significant increase in gut microbiota diversity and this association also correlated with protein intake and plasma creatine kinase values (16). Greater microbiota α-diversity has been reported in athletes in associations with dietary patterns and protein consumption (16, 17).
Involvement of gut microbiota in cancer-related muscle loss
In patients with advanced gastric cancer, cachexia was associated with intestinal barrier dysfunction (i.e., greater intestinal permeability) with a higher degree of bacterial translocation, as compared to patients with gastric cancer but without cachexia (18). Levels of Interleukin-6 (IL-6), Tumor Necrosis Factor α (TNF-α), and Interferon γ (IFNγ) correlated with bacterial translocation in patients with cachexia and these inflammatory cytokines may drive myocyte cell death (19).
Mechanistically, there are a number of gut bacteria that have been singled out as gut barrier function disabling and inflammatory promoting. In lung cancer patients with cachexia, while gut α-diversity was not significantly perturbed when compared to patients without cachexia, a few bacteria species were significantly different. For example, a lower abundance of Prevotella copri was observed in patients with cachexia and this correlated with reduced plasma levels of postulated myogenic branched chain amino acids (BCAAs) isoleucine and leucine. Lower levels of Faecalibacterium prausnitzii, a gut bacterium with known anti-inflammatory effects (20), was also observed in cancer patients with cachexia and this may tip the balance to a more proinflammatory state in patients with cachexia. Inversely significantly higher levels of Klebsiella oxytoca, a bacterium associated with reduced gut barrier function (21), was seen in lung cancer patients with cachexia, and together with reduced gut barrier function, bacterial translocation and inflammatory cytokines may drive cachexia in patients with cancer (22).
Underpinning mechanisms for gut microbiome and muscle crosstalk
Most published mechanistic studies leverage on the pathophysiology of small animals. Altered patterns of microvillus formation and reduced cell renewal were observed in mice depleted of gut microbiota. Since microvilli are involved in absorption of both macro- and micro-nutrients, pathologies affecting the microvilli may impact overall metabolism including muscle mass and function (23, 24). In a study, GF mice had low levels of 25-hydroxyvitamin D (25D), 24,25-dihydroxyvitamin D (24,25D) and 1,25-dihydroxyvitamin D, and were hypocalcaemic. After 8 commensal bacteria were introduced, the levels of 25D and 24,25D increased to the same extent as conventionalisation. Fibroblast growth factor (FGF)23 was initially high in GF mice, but eventually reduced and normalized the vitamin D and calcium levels (25). GF mice also exhibited increased bone mass due to reduced number of osteoclast per bone surface, and it normalized with colonization by normal gut microbiota (26). However, associations between alterations in gut microbiota and changes in muscle function could also be mediated by gut-derived metabolites such as SCFAs, which play an important role in modulating lipid, carbohydrate and protein metabolism in skeletal muscle. Although SCFAs are formed in the gut, effective concentrations can be found circulating in the body (27). SCFAs are formed from the fermentation of fibers such as non-digestible carbohydrates, and they include acetate, propionate, and butyrate. These SCFAs are critical for maintaining the integrity of the epithelial barrier, the loss of which compromises barrier permeability and increases the risk of bacteria or bacterial antigen translocation. This in turn triggers the inflammatory cascade which may underpin chronic inflammation observed in obesity and insulin resistance (28).
Butyrate, of which higher levels are found in older adults with normal compared to low muscle mass, has been shown to promote mitochondria biogenesis (29, 30). When female mice were given a dietary supplement containing butyrate throughout the gestation and lactation phases, mitochondrial biogenesis was correspondingly enhanced in the offspring, evident by increased ATP content, mitochondrial DNA-encoded gene expression and uncoupling protein 3 (UCP3) in the gastrocnemius muscle of the offsprings (30). Separately, high functioning sedentary older adults had higher levels of Barnesiella and Prevotella genera, including the species Barnesiella intestinihominis, as compared to their low functioning sedentary counterparts. Notably, Barnesiella and Prevotellaceae were shown to be gut producers of SCFA (31, 32). Among older persons with low functional muscle strength, those with higher levels of SCFAs correlated with greater muscle strength, suggesting that SCFAs may contribute to the observed enhanced muscle strength (33).
When circulating SCFAs were significantly reduced in plasma of antibiotic treated mice, exercise endurance in these mice correspondingly dropped, which was again restored with acetate infusion. Caecal acetate, propionate, and butyrate were eliminated in antibiotic treated mice, suggesting that gut microbe derived SCFAs, especially acetate, may be an important energy substrate during endurance exercise (34). Besides its effects on mitochondria, SCFAs also affects muscle health by altering nuclear gene expression.
Administration of dexamethasone to C2C12 myotubes resulted in increased Atrogin-1 expression. This effect on Atrogin-1 expression was reduced when the C2C12 myotubes were treated with a cocktail of SCFAs, similar to those generated from fermentation of dietary polysaccharides. In addition, treatment of GF mice reduced the expression of Atrogin-1 in the tibialis anterior and increased the expression of MyoD (2).
Diversified effects of microbial biomolecules for the muscle
Indoxyl sulfate is a gut microbiome derived uremic toxin and is known for its pro-inflammatory properties in chronic kidney disease (CKD) patients (35). Administration of indoxyl sulfate was observed to reduce muscle mass in mice. It significantly increased intracellular ROS production in C2C12 myoblast cells, which plays an important role for skeletal muscle atrophy through various mechanisms (36). Also, indoxyl sulfate caused an increase in expression of myostatin (Mstn) and Atrogin-1 mRNA through the arylhydrocarbon receptor (AHR) pathway, inhibiting cell proliferation and myotube formation (37). Another way in which gut microbiome could negatively affect muscle health is through LPS. LPS is potent endotoxin present in the outer membrane of Gram negative bacteria and is known for its pro-inflammatory properties. Disrupted intestinal barrier may cause translocation of these bacterial components into systemic circulation which may in turn result in inflammation, via the Toll-like Receptor 4 (TLR4) pathway, resulting in muscle atrophy (38, 39). This is also seen in chronic diseases where pro-inflammatory factors appear to be the unifying factor of muscle atrophy (40). It was found that LPS decreased the formation of multi-nucleated myotubes and inhibited myogenic differentiation in vitro (41) suggesting that changes in gut permeability may allow leakage of bacterial derived glyco-peptides into the circulation which then affects the function of distal tissues such as skeletal muscle.
Muscle function in common gastrointestinal diseases
Diseases of the gastrointestinal tract such as inflammatory bowel diseases (IBD) and celiac disease (CD) are associated with a decline in muscle function and cachexia (42). Studies have shown that the gut microbiota in IBD patients were significantly altered from that of healthy individuals, and that dysbiosis of gut microbiota accompanied by disruption of diet-microbe interactions, results in damage to intestinal microbial barrier. For instance, in Crohn's Disease, over 50% of patients presented with adherent-invasive E. coli colonization in intestinal mucosa (43). Dysbiosis, defined as a disease associated imbalance in the gut microbial community, was reported for IBD. Decreased Firmicutes and Bacteroides, and increased Enterobacteriaceae, were observed in IBD. This microbe diversity shift disrupted the intestinal barrier integrity through increased abundance of mucolytic bacteria facilitating increased penetration of pathogens into intestinal tissue (44). Furthermore, it has been reported that more than a third of IBD patients suffer from sarcopenia. Similar to what was observed in the frail population, there was a reduction in F. prausnitzii, a SCFA producer with significant anti-inflammatory function (45). This raises the possibility that the decrease in anti-inflammatory gut microbiota with disruption of the epithelial barrier function in IBD may trigger the inflammatory cascade with release of proinflammatory cytokines such as TNF-α and IL-6 affecting muscle mass and function.
Exercise as a potential modulator of intestinal microbiome composition
While physical exercise directly benefits muscle function, either anatomically through maintenance of muscle sarcomere density or metabolically through increase of myocyte energetics, it has also been suggested have indirect benefits on the muscle through for example the modulation of gut commensals. Physical activity performed continuously at low doses can increase the abundance of health promoting gut bacteria such as Bifidobacterium spp, R. hominis, A. muciniphilia and F. parusnitzii (46). However, the relationship between gut microbiota and muscle health remains complex. In addition to diet, exercise is a positive modulator of gut microbiota biodiversity and this has been reviewed extensively (47, 48). Conversely, frailty, as determined using the Rockwood Frailty Index, had a negative correlation with gut microbiota α-diversity (49). The microbiota, especially those that produce metabolites such as SCFA, are important to endurance athletes, because they can supply around 10% of the energy needed by the host (50). With regular physical activity, muscle fibers release myokines such as IL-6, contributing to an overall systemic anti-inflammatory tone (51, 52). In turn, this may help to protect the microbiota from changes caused by inflammatory conditions such as IBD and T2DM (53). High-fat diet fed (i.e., pre-diabetic) mice which received fecal microbiota transplantation (FMT) from actively exercising mice showed improved metabolic parameters such as insulin sensitivity, suggesting that microbes obtained from a physically active host contributes positively to overall metabolic function (54).
While exercise is associated with numerous health benefits, intense exercise can result in acutely increased gut permeability, and reduced mucus production, allowing pathogens such as LPS in ultra-endurance runners to enter the bloodstream and causing inflammation (55, 56). Exercise-induced gut barrier disruption is observed with an acute rise in inflammatory markers, such as plasma TNF-α (57). These changes were however found to be reversible and thus may not outweigh the benefits of exercise. Separately, in a 6-week intervention study amongst older adult males who participated in twice weekly resistance training, resistance training did not alter much of their gut microbiome composition (58). Although a subsequent in silico analysis revealed a paradoxical increase in mucin synthesis, the study stopped short of validating changes to bacterial translocation and systemic inflammation (47). Taken together, more studies with prospective follow-up are required to better understand the longitudinal impact of these cross-sectional associations of exercise and nutrition with gut microbes and systemic inflammation. These studies also point to the judicious use of antibiotics because inappropriate or excessive use of broad-spectrum antibiotics is a major iatrogenic contributor to a deranged gut microbiome.
Other forms of interventions involving the gut microbiome
Besides physical exercise, alterations either through microbiome depletion/ reconstitution, FMT, diet interventions or pre-/probiotics supplementation may offer a new approach to address the problem of frailty by targeting the gut-muscle axis (59). Probiotics refer to defined viable microorganisms, sufficient amounts of which reach the intestine in an active state and thus exert positive health effects. Prebiotics, on the other hand, refer to selectively fermented ingredients that allow specific changes, both in composition and/or activity in the gastrointestinal microflora that confers benefits upon host wellbeing and health, such as non-digestible oligosaccharides (60).
Since increased gut permeability is seen in cachexic mice and patients, supplementation with probiotics may restore gut barrier dysfunction thereby lowering pathogen leakage and systemic inflammation. Supplementation with Lactobacillus and Bifidobacillus has the potential to reduce age-induced and cancer induced muscle loss, while supplementation with lactobacillus is suggested to ameliorate muscle wasting via increasing butyrate production and decreasing gut permeability.
Most recently, two studies have revealed interesting insights. The SAMP8 mouse is commonly used as a pre-aging animal model because it starts to display an aging phenotype from 4 months of age. Probiotic supplementation of Lactobacillus casei Shirota (1 × 108 or 1 × 109 CFU/mouse/day by oral gavage) decreased the senescent scores and increased muscle mass in SAMP8 mice. Furthermore, it helped to maintain muscle strength in the aged mice, as seen from the higher grip force. It also reduced age related increases in inflammation by down regulating the proinflammatory cytokine TNF- α and upregulating the anti-inflammatory cytokine IL-10. In contrast to the fall in SCFAs usually seen in aging, Lactobacillus casei Shirota helped to maintain the butyrate levels in the aged mice (61). This study involved a small case series of six non-agenarian older adults (mean age: 90.8 ± 5.4 years) with sarcopenia who were administered the prebiotic 1-kestose (10 g/day for 2 weeks), there was an increase in the intestinal Bifidobacterium longum population along with increased skeletal muscle mass index and reduced body fat percentage (62). This study provided proof-of-concept evidence regarding the potential clinical benefit of prebiotic supplementation even in the oldest-old age group. Although treatment with prebiotics and probiotics may be promising in improving the gut microbiota (63), there are too limited studies at the moment to associate, let alone validate, whether its gut microbe effect carries on to muscle health amongst people with frailty syndrome.
Conclusion
In this perspective, we start with a brief overview on how gut microbiota can influence muscle health through various mechanisms and on how various microbes can be altered in certain muscle disease states. We discuss recent experimental and clinical evidence in support of microbiome impacting muscle mass, with an overall consensus that gut microbes impact muscle mass, either positively or negatively, depending on the microbe strain. This is supported by evidence that microbiome manipulation through either FMT or antibiotic administration can reverse phenotypes in GF and SPF mice, respectively. Meanwhile, human studies are beginning to show that microbiome composition is associated with muscle mass and function, paralleling changes in inflammatory markers in patients with frailty and other cachexic conditions. We looked into as many relevant papers as possible without bias or application of any exclusion criteria (i.e., not a systemic review) when gathering evidence for this perspective, but in doing so may have inadvertently missed a few relevant papers. This remains a limitation of this piece. Nevertheless, while much remains unknown about how microbiome interacts with muscle, this emerging field of research holds promise for improving our understanding of sarcopenia and other age-related muscle loss. Information on human, and animal, gut-muscle axis are now compiled into a single table (Table 1). Importantly, clinical studies will be needed to determine whether microbiome modulation via diet modification or pre/probiotic supplements can improve muscle health in humans. With continued research, we may 1 day be able to use microbiome manipulation to combat sarcopenia and other disorders of muscle loss.
Table 1. List of human and animal studies that relate gut microbes to muscle and its related phenotype.
Data availability statement
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.
Author contributions
WC, WL, SW, and YA wrote the manuscript. YL, EC, GF, and YA edited the manuscript. All authors contributed to the article and approved the submitted version.
Funding
This work was supported by the Ministry of Education Singapore (MOE2018-T2-1-085 and MOE-T2EP30221-0003) (YA) and Tier 1 (2019-T1-001-059) (YA). This work is also partly supported by the LKC Medicine Healthcare Research Fund (Diabetes Research), established through the generous support of alumni of Nanyang Technological University, Singapore, the NTU Start Up Grant (021337-00001) (SW) and Wang Lee Wah Memorial Fund for the support of this work.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher's note
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References
1. Guinane CM, Cotter PD. Role of the gut microbiota in health and chronic gastrointestinal disease: understanding a hidden metabolic organ. Therap Adv Gastroenterol. (2013) 6:295–308. doi: 10.1177/1756283X13482996
2. Lahiri S, Kim H, Garcia-Perez I, Reza MM, Martin KA, Kundu P, et al. The gut microbiota influences skeletal muscle mass and function in mice. Sci Transl Med. (2019) 11:eaan5662. doi: 10.1126/scitranslmed.aan5662
3. Qi R, Sun J, Qiu X, Zhang Y, Wang J, Wang Q, et al. The intestinal microbiota contributes to the growth and physiological state of muscle tissue in piglets. Sci Rep. (2021) 11:11237. doi: 10.1038/s41598-021-90881-5
4. Bongers KS, McDonald RA, Winner KM, Falkowski NR, Brown CA, Baker JM, et al. Antibiotics cause metabolic changes in mice primarily through microbiome modulation rather than behavioral changes. PLoS ONE. (2022) 17:e0265023. doi: 10.1371/journal.pone.0265023
5. Valentino TR, Vechetti IJ, Mobley CB, Dungan CM, Golden L, Goh J, et al. Dysbiosis of the gut microbiome impairs mouse skeletal muscle adaptation to exercise. J Physiol. (2021) 599:4845–63. doi: 10.1113/JP281788
6. Fielding RA, Reeves AR, Jasuja R, Liu C, Barrett BB, Lustgarten MS. Muscle strength is increased in mice that are colonized with microbiota from high-functioning older adults. Exp Gerontol. (2019) 127:110722. doi: 10.1016/j.exger.2019.110722
7. Backhed F, Ding H, Wang T, Hooper LV, Koh GY, Nagy A, et al. The gut microbiota as an environmental factor that regulates fat storage. Proc Natl Acad Sci USA. (2004) 101:15718–23. doi: 10.1073/pnas.0407076101
8. Nobel YR, Cox LM, Kirigin FF, Bokulich NA, Yamanishi S, Teitler I, et al. Metabolic and metagenomic outcomes from early-life pulsed antibiotic treatment. Nat Commun. (2015) 6:7486. doi: 10.1038/ncomms8486
9. Yan H, Yu B, Degroote J, Spranghers T, Van Noten N, Majdeddin M, et al. Antibiotic affects the gut microbiota composition and expression of genes related to lipid metabolism and myofiber types in skeletal muscle of piglets. BMC Vet Res. (2020) 16:392. doi: 10.1186/s12917-020-02592-0
10. Yamamoto K, Ishizu Y, Honda T, Ito T, Imai N, Nakamura M, et al. Patients with low muscle mass have characteristic microbiome with low potential for amino acid synthesis in chronic liver disease. Sci Rep. (2022) 12:3674. doi: 10.1038/s41598-022-07810-3
11. Haran JP, Bucci V, Dutta P, Ward D, McCormick B. The nursing home elder microbiome stability and associations with age, frailty, nutrition and physical location. J Med Microbiol. (2018) 67:40–51. doi: 10.1099/jmm.0.000640
12. van Tongeren SP, Slaets JP, Harmsen HJ, Welling GW. Fecal microbiota composition and frailty. Appl Environ Microbiol. (2005) 71:6438–42. doi: 10.1128/AEM.71.10.6438-6442.2005
13. Bindels LB, Beck R, Schakman O, Martin JC, De Backer F, Sohet FM, et al. Restoring specific lactobacilli levels decreases inflammation and muscle atrophy markers in an acute leukemia mouse model. PLoS ONE. (2012) 7:e37971. doi: 10.1371/journal.pone.0037971
14. Bindels LB, Neyrinck AM, Claus SP, Le Roy CI, Grangette C, Pot B, et al. Synbiotic approach restores intestinal homeostasis and prolongs survival in leukaemic mice with cachexia. ISME J. (2016) 10:1456–70. doi: 10.1038/ismej.2015.209
15. Britton RA, Irwin R, Quach D, Schaefer L, Zhang J, Lee T, et al. Probiotic L. reuteri treatment prevents bone loss in a menopausal ovariectomized mouse model. J Cell Physiol. (2014) 229:1822–30. doi: 10.1002/jcp.24636
16. Clarke SF, Murphy EF, O'Sullivan O, Lucey AJ, Humphreys M, Hogan A, et al. Exercise and associated dietary extremes impact on gut microbial diversity. Gut. (2014) 63:1913–20. doi: 10.1136/gutjnl-2013-306541
17. Barton W, Penney NC, Cronin O, Garcia-Perez I, Molloy MG, Holmes E, et al. The microbiome of professional athletes differs from that of more sedentary subjects in composition and particularly at the functional metabolic level. Gut. (2018) 67:625–33. doi: 10.1136/gutjnl-2016-313627
18. Mi L, Lin J, Zheng H, Xu X, Zhang J, Zhang D. Bacterial translocation contributes to cachexia from locally advanced gastric cancer. Hepatogastroenterology. (2012) 59:2348–51. doi: 10.5754/hge11810
19. Jiang Y, Guo C, Zhang D, Zhang J, Wang X, Geng C. The altered tight junctions: an important gateway of bacterial translocation in cachexia patients with advanced gastric cancer. J Interferon Cytokine Res. (2014) 34:518–25. doi: 10.1089/jir.2013.0020
20. Martin R, Miquel S, Chain F, Natividad JM, Jury J, Lu J, et al. Faecalibacterium prausnitzii prevents physiological damages in a chronic low-grade inflammation murine model. BMC Microbiol. (2015) 15:67. doi: 10.1186/s12866-015-0400-1
21. Potgens SA, Brossel H, Sboarina M, Catry E, Cani PD, Neyrinck AM, et al. Klebsiella oxytoca expands in cancer cachexia and acts as a gut pathobiont contributing to intestinal dysfunction. Sci Rep. (2018) 8:12321. doi: 10.1038/s41598-018-30569-5
22. Ni Y, Lohinai Z, Heshiki Y, Dome B, Moldvay J, Dulka E, et al. Distinct composition and metabolic functions of human gut microbiota are associated with cachexia in lung cancer patients. ISME J. (2021) 15:3207–20. doi: 10.1038/s41396-021-00998-8
23. Yu LC, Wang JT, Wei SC Ni YH. Host-microbial interactions and regulation of intestinal epithelial barrier function: from physiology to pathology. World J Gastrointest Pathophysiol. (2012) 3:27–43. doi: 10.4291/wjgp.v3.i1.27
24. Schneeberger K, Roth S, Nieuwenhuis EES, Middendorp S. Intestinal epithelial cell polarity defects in disease: lessons from microvillus inclusion disease. Dis Model Mech. (2018) 11:dmm031088. doi: 10.1242/dmm.031088
25. Bora SA, Kennett MJ, Smith PB, Patterson AD, Cantorna MT. The gut microbiota regulates endocrine vitamin D metabolism through fibroblast growth factor 23. Front Immunol. (2018) 9:408. doi: 10.3389/fimmu.2018.00408
26. Sjogren K, Engdahl C, Henning P, Lerner UH, Tremaroli V, Lagerquist MK, et al. The gut microbiota regulates bone mass in mice. J Bone Miner Res. (2012) 27:1357–67. doi: 10.1002/jbmr.1588
27. Morrison DJ, Preston T. Formation of short chain fatty acids by the gut microbiota and their impact on human metabolism. Gut Microbes. (2016) 7:189–200. doi: 10.1080/19490976.2015.1134082
28. Cani PD, Bibiloni R, Knauf C, Waget A, Neyrinck AM, Delzenne NM, et al. Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes. (2008) 57:1470–81. doi: 10.2337/db07-1403
29. Han DS, Wu WK, Liu PY, Yang YT, Hsu HC, Kuo CH, et al. Differences in the gut microbiome and reduced fecal butyrate in elders with low skeletal muscle mass. Clin Nutr. (2022) 41:1491–500. doi: 10.1016/j.clnu.2022.05.008
30. Huang Y, Gao S, Jun G, Zhao R, Yang X. Supplementing the maternal diet of rats with butyrate enhances mitochondrial biogenesis in the skeletal muscles of weaned offspring. Br J Nutr. (2017) 117:12–20. doi: 10.1017/S0007114516004402
31. Tao F, Xing X, Wu J, Jiang R. Enteral nutrition modulation with n-3 PUFAs directs microbiome and lipid metabolism in mice. PLoS ONE. (2021) 16:e0248482. doi: 10.1371/journal.pone.0248482
32. Yao W, Gong Y, Li L, Hu X, You L. The effects of dietary fibers from rice bran and wheat bran on gut microbiota: an overview. Food Chem X. (2022) 13:100252. doi: 10.1016/j.fochx.2022.100252
33. Louis P, Flint HJ. Formation of propionate and butyrate by the human colonic microbiota. Environ Microbiol. (2017) 19:29–41. doi: 10.1111/1462-2920.13589
34. Okamoto T, Morino K, Ugi S, Nakagawa F, Lemecha M, Ida S, et al. Microbiome potentiates endurance exercise through intestinal acetate production. Am J Physiol Endocrinol Metab. (2019) 316:E956–E66. doi: 10.1152/ajpendo.00510.2018
35. Yang CY, Tarng DC. Diet, gut microbiome and indoxyl sulphate in chronic kidney disease patients. Nephrology. (2018) 23:16–20. doi: 10.1111/nep.13452
36. Enoki Y, Watanabe H, Arake R, Sugimoto R, Imafuku T, Tominaga Y, et al. Indoxyl sulfate potentiates skeletal muscle atrophy by inducing the oxidative stress-mediated expression of myostatin and atrogin-1. Sci Rep. (2016) 6:32084. doi: 10.1038/srep32084
37. Powers SK, Smuder AJ, Judge AR. Oxidative stress and disuse muscle atrophy: cause or consequence? Curr Opin Clin Nutr Metab Care. (2012) 15:240–5. doi: 10.1097/MCO.0b013e328352b4c2
38. Ghosh SS, Wang J, Yannie PJ, Ghosh S. Intestinal barrier dysfunction, LPS translocation, and disease development. J Endocr Soc. (2020) 4:bvz039. doi: 10.1210/jendso/bvz039
39. Londhe P, Guttridge DC. Inflammation induced loss of skeletal muscle. Bone. (2015) 80:131–42. doi: 10.1016/j.bone.2015.03.015
40. Perry BD, Caldow MK, Brennan-Speranza TC, Sbaraglia M, Jerums G, Garnham A, et al. Muscle atrophy in patients with type 2 diabetes mellitus: roles of inflammatory pathways, physical activity and exercise. Exerc Immunol Rev. (2016) 22:94–109. Available online at: https://pubmed.ncbi.nlm.nih.gov/26859514/
41. Ono Y, Sakamoto K. Lipopolysaccharide inhibits myogenic differentiation of C2C12 myoblasts through the Toll-like receptor 4-nuclear factor-kappaB signaling pathway and myoblast-derived tumor necrosis factor-alpha. PLoS ONE. (2017) 12:e0182040. doi: 10.1371/journal.pone.0182040
42. Klein GL, Petschow BW, Shaw AL, Weaver E. Gut barrier dysfunction and microbial translocation in cancer cachexia: a new therapeutic target. Curr Opin Support Palliat Care. (2013) 7:361–7. doi: 10.1097/SPC.0000000000000017
43. Shawki A, McCole DF. Mechanisms of intestinal epithelial barrier dysfunction by adherent-invasive Escherichia coli. Cell Mol Gastroenterol Hepatol. (2017) 3:41–50. doi: 10.1016/j.jcmgh.2016.10.004
44. Lee M, Chang EB. Inflammatory bowel diseases (IBD) and the microbiome-searching the crime scene for clues. Gastroenterology. (2021) 160:524–37. doi: 10.1053/j.gastro.2020.09.056
45. Nardone OM, de Sire R, Petito V, Testa A, Villani G, Scaldaferri F, et al. Inflammatory bowel diseases and sarcopenia: the role of inflammation and gut microbiota in the development of muscle failure. Front Immunol. (2021) 12:694217. doi: 10.3389/fimmu.2021.694217
46. Bressa C, Bailen-Andrino M, Perez-Santiago J, Gonzalez-Soltero R, Perez M, Montalvo-Lominchar MG, et al. Differences in gut microbiota profile between women with active lifestyle and sedentary women. PLoS ONE. (2017) 12:e0171352. doi: 10.1371/journal.pone.0171352
47. Clauss M, Gerard P, Mosca A, Leclerc M. Interplay between exercise and gut microbiome in the context of human health and performance. Front Nutr. (2021) 8:637010. doi: 10.3389/fnut.2021.637010
48. Aya V, Florez A, Perez L, Ramirez JD. Association between physical activity and changes in intestinal microbiota composition: a systematic review. PLoS One. (2021) 16:e0247039. doi: 10.1371/journal.pone.0247039
49. Jackson MA, Jeffery IB, Beaumont M, Bell JT, Clark AG, Ley RE, et al. Signatures of early frailty in the gut microbiota. Genome Med. (2016) 8:8. doi: 10.1186/s13073-016-0262-7
50. Bergman EN. Energy contributions of volatile fatty acids from the gastrointestinal tract in various species. Physiol Rev. (1990) 70:567–90. doi: 10.1152/physrev.1990.70.2.567
51. Leal LG, Lopes MA, Batista ML. Physical exercise-induced myokines and muscle-adipose tissue crosstalk: a review of current knowledge and the implications for health and metabolic diseases. Front Physiol. (2018) 9:1307. doi: 10.3389/fphys.2018.01307
52. Xing Z, Gauldie J, Cox G, Baumann H, Jordana M, Lei XF, et al. IL-6 is an antiinflammatory cytokine required for controlling local or systemic acute inflammatory responses. J Clin Invest. (1998) 101:311–20. doi: 10.1172/JCI1368
53. Guo Y, Wang B, Wang T, Gao L, Yang ZJ, Wang FF, et al. Biological characteristics of IL-6 and related intestinal diseases. Int J Biol Sci. (2021) 17:204–19. doi: 10.7150/ijbs.51362
54. Lai ZL, Tseng CH, Ho HJ, Cheung CKY, Lin JY, Chen YJ, et al. Fecal microbiota transplantation confers beneficial metabolic effects of diet and exercise on diet-induced obese mice. Sci Rep. (2018) 8:15625. doi: 10.1038/s41598-018-33893-y
55. Morishima S, Aoi W, Kawamura A, Kawase T, Takagi T, Naito Y, et al. Intensive, prolonged exercise seemingly causes gut dysbiosis in female endurance runners. J Clin Biochem Nutr. (2021) 68:253–8. doi: 10.3164/jcbn.20-131
56. Oktedalen O, Lunde OC, Opstad PK, Aabakken L, Kvernebo K. Changes in the gastrointestinal mucosa after long-distance running. Scand J Gastroenterol. (1992) 27:270–4. doi: 10.3109/00365529209000073
57. Shing CM, Peake JM, Lim CL, Briskey D, Walsh NP, Fortes MB, et al. Effects of probiotics supplementation on gastrointestinal permeability, inflammation and exercise performance in the heat. Eur J Appl Physiol. (2014) 114:93–103. doi: 10.1007/s00421-013-2748-y
58. Moore JH, Smith KS, Chen D, Lamb DA, Smith MA, Osburn SC, et al. Exploring the effects of six weeks of resistance training on the fecal microbiome of older adult males: secondary analysis of a peanut protein supplemented randomized controlled trial. Sports. (2022) 10:65. doi: 10.3390/sports10050065
59. Liu C, Cheung WH Li J, Chow SK Yu J, Wong SH, et al. Understanding the gut microbiota and sarcopenia: a systematic review. J Cachexia Sarcopenia Muscle. (2021) 12:1393–407. doi: 10.1002/jcsm.12784
60. de Vrese M, Schrezenmeir J. Probiotics, prebiotics, and synbiotics. Adv Biochem Eng Biotechnol. (2008) 111:1–66. doi: 10.1007/10_2008_097
61. Chen LH, Chang SS, Chang HY, Wu CH, Pan CH, Chang CC, et al. Probiotic supplementation attenuates age-related sarcopenia via the gut-muscle axis in SAMP8 mice. J Cachexia Sarcopenia Muscle. (2022) 13:515–31. doi: 10.1002/jcsm.12849
62. Tominaga K, Tsuchiya A, Nakano O, Kuroki Y, Oka K, Minemura A, et al. Increase in muscle mass associated with the prebiotic effects of 1-kestose in super-elderly patients with sarcopenia. Biosci Microbiota Food Health. (2021) 40:150–5. doi: 10.12938/bmfh.2020-063
63. Tsai YL, Lin TL, Chang CJ, Wu TR, Lai WF, Lu CC, et al. Probiotics, prebiotics and amelioration of diseases. J Biomed Sci. (2019) 26:3. doi: 10.1186/s12929-018-0493-6
64. Claesson MJ, Jeffery IB, Conde S, Power SE, O'Connor EM, Cusack S, et al. Gut microbiota composition correlates with diet and health in the elderly. Nature. (2012) 488:178–84. doi: 10.1038/nature11319
65. Kang L, Li P, Wang D, Wang T, Hao D, Qu X. Alterations in intestinal microbiota diversity, composition, and function in patients with sarcopenia. Sci Rep. (2021) 11:4628. doi: 10.1038/s41598-021-84031-0
66. Ley RE, Turnbaugh PJ, Klein S, Gordon JI. Microbial ecology: human gut microbes associated with obesity. Nature. (2006) 444:1022–3. doi: 10.1038/4441022a
67. Turnbaugh PJ, Hamady M, Yatsunenko T, Cantarel BL, Duncan A, Ley RE, et al. A core gut microbiome in obese and lean twins. Nature. (2009) 457:480–4. doi: 10.1038/nature07540
68. Larsen N, Vogensen FK, van den Berg FW, Nielsen DS, Andreasen AS, Pedersen BK, et al. Gut microbiota in human adults with type 2 diabetes differs from non-diabetic adults. PLoS ONE. (2010) 5:e9085. doi: 10.1371/journal.pone.0009085
69. Qin J, Li Y, Cai Z, Li S, Zhu J, Zhang F, et al. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature. (2012) 490:55–60. doi: 10.1038/nature11450
70. Picca A, Ponziani FR, Calvani R, Marini F, Biancolillo A, Coelho-Junior HJ, et al. Gut microbial, inflammatory and metabolic signatures in older people with physical frailty and sarcopenia: results from the biosphere study. Nutrients. (2019) 12:65. doi: 10.3390/nu12010065
71. Morita E, Yokoyama H, Imai D, Takeda R, Ota A, Kawai E, et al. Aerobic exercise training with brisk walking increases intestinal bacteroides in healthy elderly women. Nutrients. (2019) 11:868. doi: 10.3390/nu11040868
72. Bjorkhaug ST, Aanes H, Neupane SP, Bramness JG, Malvik S, Henriksen C, et al. Characterization of gut microbiota composition and functions in patients with chronic alcohol overconsumption. Gut Microbes. (2019) 10:663–75. doi: 10.1080/19490976.2019.1580097
73. Munukka E, Ahtiainen JP, Puigbo P, Jalkanen S, Pahkala K, Keskitalo A, et al. Six-week endurance exercise alters gut metagenome that is not reflected in systemic metabolism in over-weight women. Front Microbiol. (2018) 9:2323. doi: 10.3389/fmicb.2018.02323
74. Carey RA, Montag D. Exploring the relationship between gut microbiota and exercise: short-chain fatty acids and their role in metabolism. BMJ Open Sport Exerc Med. (2021) 7:e000930. doi: 10.1136/bmjsem-2020-000930
75. Liang R, Zhang S, Peng X, Yang W, Xu Y, Wu P, et al. Characteristics of the gut microbiota in professional martial arts athletes: a comparison between different competition levels. PLoS ONE. (2019) 14:e0226240. doi: 10.1371/journal.pone.0226240
76. Xu Y, Wang Y, Li H, Dai Y, Chen D, Wang M, et al. Altered fecal microbiota composition in older adults with frailty. Front Cell Infect Microbiol. (2021) 11:696186. doi: 10.3389/fcimb.2021.696186
77. Barger K, Langsetmo L, Orwoll ES, Lustgarten MS. Investigation of the diet-gut-muscle axis in the osteoporotic fractures in men study. J Nutr Health Aging. (2020) 24:445–52. doi: 10.1007/s12603-020-1344-1
78. Buigues C, Fernandez-Garrido J, Pruimboom L, Hoogland AJ, Navarro-Martinez R, Martinez-Martinez M, et al. Effect of a prebiotic formulation on frailty syndrome: a randomized, double-blind clinical trial. Int J Mol Sci. (2016) 17:932. doi: 10.3390/ijms17060932
79. Ley RE, Backhed F, Turnbaugh P, Lozupone CA, Knight RD, Gordon JI. Obesity alters gut microbial ecology. Proc Natl Acad Sci USA. (2005) 102:11070–5. doi: 10.1073/pnas.0504978102
80. Chen YM, Wei L, Chiu YS, Hsu YJ, Tsai TY, Wang MF, et al. Lactobacillus plantarum TWK10 supplementation improves exercise performance and increases muscle mass in mice. Nutrients. (2016) 8:205. doi: 10.3390/nu8040205
81. Everard A, Lazarevic V, Derrien M, Girard M, Muccioli GG, Neyrinck AM, et al. Responses of gut microbiota and glucose and lipid metabolism to prebiotics in genetic obese and diet-induced leptin-resistant mice. Diabetes. (2011) 60:2775–86. doi: 10.2337/db11-0227
82. Meijers BK, De Preter V, Verbeke K, Vanrenterghem Y, Evenepoel P. p-Cresyl sulfate serum concentrations in haemodialysis patients are reduced by the prebiotic oligofructose-enriched inulin. Nephrol Dial Transplant. (2010) 25:219–24. doi: 10.1093/ndt/gfp414
83. Taki K, Takayama F, Niwa T. Beneficial effects of Bifidobacteria in a gastroresistant seamless capsule on hyperhomocysteinemia in hemodialysis patients. J Ren Nutr. (2005) 15:77–80. doi: 10.1053/j.jrn.2004.09.028
84. Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C, Bastelica D, et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes. (2007) 56:1761–72. doi: 10.2337/db06-1491
85. Cani PD, Neyrinck AM, Fava F, Knauf C, Burcelin RG, Tuohy KM, et al. Selective increases of bifidobacteria in gut microflora improve high-fat-diet-induced diabetes in mice through a mechanism associated with endotoxaemia. Diabetologia. (2007) 50:2374–83. doi: 10.1007/s00125-007-0791-0
86. Matsumoto M, Inoue R, Tsukahara T, Ushida K, Chiji H, Matsubara N, et al. Voluntary running exercise alters microbiota composition and increases n-butyrate concentration in the rat cecum. Biosci Biotechnol Biochem. (2008) 72:572–6. doi: 10.1271/bbb.70474
87. Goker M, Gronow S, Zeytun A, Nolan M, Lucas S, Lapidus A, et al. Complete genome sequence of Odoribacter splanchnicus type strain (1651/6). Stand Genomic Sci. (2011) 4:200–9. doi: 10.4056/sigs.1714269
88. Blanton LV, Charbonneau MR, Salih T, Barratt MJ, Venkatesh S, Ilkaveya O, et al. Gut bacteria that prevent growth impairments transmitted by microbiota from malnourished children. Science. (2016) 351:aad3311. doi: 10.1126/science.aad3311
Keywords: gut microbes, muscle function, metabolites, cytokines, sarcopenia
Citation: Chew W, Lim YP, Lim WS, Chambers ES, Frost G, Wong SH and Ali Y (2023) Gut-muscle crosstalk. A perspective on influence of microbes on muscle function. Front. Med. 9:1065365. doi: 10.3389/fmed.2022.1065365
Received: 09 October 2022; Accepted: 20 December 2022;
Published: 09 January 2023.
Edited by:
Ming Yang, West China Hospital, Sichuan University, ChinaReviewed by:
Nazarii Kobyliak, Bogomolets National Medical University, UkraineLiang-Yu Chen, Taipei Veterans General Hospital, Taiwan
Siti Setiati, University of Indonesia, Indonesia
Copyright © 2023 Chew, Lim, Lim, Chambers, Frost, Wong and Ali. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Yusuf Ali, 
yusuf.ali@ntu.edu.sg
†ORCID: Yusuf Ali orcid.org/0000-0002-0681-1125