Sarcopenia, the age-related loss of muscle mass and strength, is a major contributor to frailty, disability and reduced quality of life in older adults(Reference Kirk, Cawthon and Arai1). With global populations ageing rapidly, the prevalence of sarcopenia is increasing, necessitating effective interventions to mitigate its impact. Recent research has highlighted the gut microbiome as a key modulator of systemic health, including skeletal muscle metabolism(Reference Liu, Cheung and Li2) through gut microbiota composition and function, and its metabolites, short-chain fatty acids (SCFAs; acetate, propionate, butyrate)(Reference Frampton, Murphy and Frost3). Probiotics (live microorganisms), prebiotics (non-digestible substrates that promote microbial growth), and synbiotics (combination of probiotics and prebiotics) have emerged as potential interventions to modulate the gut microbiome and potentially modify sarcopenia-related outcomes(Reference Barry, Farragher and Betik4,Reference Prokopidis, Giannos and Kirwan5) . Previous research has shown evidence between microbiota composition and muscle health, with faecal transplantation studies revealing promising results via microbial environments transferred from younger to older rodents(Reference Xie, Kim and Liu6–Reference Kim, Chung and Huh8), as well as faecal transplantation from high vs. low-functioning older adults(Reference Fielding, Reeves and Jasuja9). This manuscript provides an overview of the current state of research on probiotics, prebiotics, and synbiotics in counteracting sarcopenia, focusing on evidence from both animal and human models. It also discusses the challenges that may hinder the progress in this field, including inconsistencies in microbial assessments throughout trials, lack of dietary control and the influence of confounders such as multimorbidity, prescription medications, treatment parameters, and delivery methods.
The role of the gut microbiome in metabolic and muscle health
The gut microbiome, encompassing trillions of microorganisms, may profoundly influence host metabolism and immune function, with significant implications for skeletal muscle health. This relationship may be mediated by microbial metabolites, affecting immune signalling and nutrient sensing and absorption(Reference Dey10,Reference Zheng, Liwinski and Elinav11) . A primary mechanism involves the engagement of SCFAs, which are produced through microbial fermentation of dietary fibres (e.g. inulin, resistant starch). SCFAs may exert anti-inflammatory effects, enhance insulin sensitivity and improve mitochondrial function in skeletal muscle, supporting energy metabolism(Reference Frampton, Murphy and Frost3). The term ‘gut dysbiosis’, characterised by an imbalance in gut microbial composition, is associated with systemic inflammation(Reference Malicevic, Rai and Skrbic12) that could lead to muscle catabolism and increase sarcopenia risk(Reference Wang, Xiang and Wu13). Conversely, beneficial microbial taxa, including Bifidobacterium and Lactobacillus, may preserve intestinal epithelial tight junction integrity, thereby mitigating inflammation and subsequently protecting muscle health(Reference Zhu, Peng and Yang14,Reference Abdulqadir, Engers and Al-Sadi15) . In this context, the gut microbiome could also regulate nutrient metabolism, influencing the absorption and bioavailability of amino acids, vitamins, and other micronutrients(Reference Barone, D’amico and Brigidi16,Reference Rowland, Gibson and Heinken17) that may be essential for maintaining muscle health. These considerations have been instrumental in shaping the notion that gut microbiome-based therapies could have a fundamental impact on muscle health, having led to a series of experimental animal and human studies.
Evidence from animal models
Rodent studies have provided robust preliminary evidence for the potential of the gut-muscle axis. Previous work has shown that germ-free mice exhibit a decreased expression of neuromuscular junction genes Rapsyn and Lrp4. Particularly, transplanting gut microbiota from pathogen-free mice led to improved muscle mass, enhanced oxidative metabolism and restored Rapsyn and Lrp4 expression; SCFA treatment partially alleviated muscle impairments(Reference Lahiri, Kim and Garcia-Perez18). Furthermore, transferring microbiota from healthy young mice to older mice led to improvements in inflammatory profile, handgrip strength, and overall frailty score(Reference Mo, Shen and Cheng7,Reference Zhu, Huang and Wang19) , and exhibited better physical performance(Reference Mo, Shen and Cheng7,Reference Kim, Chung and Huh8) . These studies identified specific bacteria, such as Ruminococcus, Akkermansia, Lachnospiraceae_UCG-001, Lactococcus, and Lactobacillus, being positively correlated with muscle health, likely due to their role in SCFA production and modulation of inflammatory responses by reducing lipopolysaccharide (LPS), toll-like receptor 4 production (TLR4), trimethylamine n-oxide (TMAO), and muscle atrophy-related proteins [i.e. nuclear factor kappa-beta (NF-kB)]. In addition, faecal transplantation from high-functioning older adults to germ-free mice have led to handgrip strength improvements after 4 weeks compared to germ-free mice transplanted with faecal samples from a low-functioning age-matched group(Reference Fielding, Reeves and Jasuja9). In this study, some bacterial differences between the groups were identified at the family-level S24_7 and Prevotellaceae, genus-level Prevotella and Barnesiella and species-level Barnesiella intestinihominis. Similar findings have been observed recently via faecal transplantation from adults with vs. without sarcopenia, showing improved muscle mitochondria density, adenosine triphosphate (ATP) content, mitochondrial dynamics, and biogenesis proteins, as well as colon tight junction proteins in ageing mice(Reference Liu, Wong and Barua20). Interestingly, the gut microbiome may possess a key role in exercise-induced skeletal muscle adaptations (in mice). Specifically, antibiotic-induced dysbiosis did not affect running activity or inflammatory profile, although blunted soleus and plantaris muscle hypertrophy, fibre-type type I to II shift and myonuclei accretion in response to an 8-week progressive weighted wheel running(Reference Valentino, Vechetti and Mobley21). Regarding probiotic research, several studies have demonstrated a beneficial impact in rodent models, ameliorating sarcopenia, reducing inflammation, and muscle atrophy markers(Reference Jeong, Kim and Jung22–Reference Chen, Huang and Huang32). These animal studies reveal that the gut microbiome could be linked to muscle health and exercise adaptations, potentially mediating inflammation and neuromuscular gene expression, which could offer promising avenues to target sarcopenia in humans.
Evidence from human studies
Multiple observational and systematic review studies have reported associations between microbial diversity and physical performance and sarcopenia in older adults, with higher diversity linked to better overall muscle strength(Reference Lee, Song and Jung33–Reference Yan, Li and Xie39). A study investigating sarcopenia prevalence and gut microbiota changes in patients with haematological disorders before and after haematopoietic stem cell transplantation (HSCT) analysis via 16S rRNA sequencing revealed altered abundance of Enterococcus, Bacteroides, Blautia and Dorea post-HSCT(Reference Wang, Hu and Zhang40). Pre-HSCT, patients with sarcopenia exhibited lower Dorea and higher Phascolarctobacterium levels. Alpha and beta diversity analyses showed significant microbial diversity and composition changes post-HSCT. Alistipes, Rikenellaceae, Alistipes putredinis and Blautia coccoides were linked to pre-HSCT sarcopenia, with functional shifts in anaerobic and oxidative stress-tolerant functions, suggesting a potential therapeutic effect. Interestingly, a recent study(Reference Yang, Li and Wang41) found that sarcopenia remission may be more pronounced in older adults undergoing resistance training combined with faecal microbiota transplantation from younger adults. In particular, those receiving faecal transplants from younger donors demonstrated higher sarcopenia remission rates after 24 weeks compared to those undergoing resistance training alone(Reference Yang, Li and Wang41), showing promise through such strategies. However, it is worth noting that gut microbial composition, immune system function, host genetics, the amount of faecal material, number of infusions, delivery route (e.g. colonoscopy, capsules), and use of adjuvant treatments are factors to be additionally considered in determining the effectiveness of faecal transplantation(Reference Porcari, Benech and Valles-Colomer42). Additionally, causality remains difficult to establish due to ethical considerations in conducting clinical trials around the field, invasive sampling methods, complexity of human microbiota and confounding factors, such as diet, lifestyle, comorbidities, and medications(Reference Hou, Wu and Chen43).
Utilisation of probiotic supplementation has shown potential in alleviating sarcopenia. A meta-analysis(Reference Prokopidis, Giannos and Kirwan5) showed that adults receiving probiotics vs. placebo demonstrated improved appendicular lean mass and global muscle strength. Subgroup analyses revealed that muscle strength was profoundly improved in middle-aged-to-older adults (>50 years) and when duration was ≥12 weeks. However, it is worth highlighting that muscle strength in those ≥50 years was measured via handgrip strength, while the younger counterparts performed compound exercises such as squats, bench press and deadlifts, which may be harder to observe changes in. More recently, trials in older adults with a mean age > 60 years also demonstrated improvements in muscle strength (lower limb, handgrip strength)(Reference Lee, Hsu and Yang44–Reference Kang, Jung and Jung46), gait speed and quality of life (SarQoL)(Reference Qaisar, Burki and Karim45), but not muscle mass(Reference Lee, Hsu and Yang44) within 12–16 weeks. These changes seemed to correspond with reductions in inflammatory markers, plasma zonulin levels (a marker of intestinal leakage) and elevated follistatin concentrations(Reference Lee, Hsu and Yang44–Reference Kang, Jung and Jung46). The evidence is less clear in relation to prebiotics, considering that although increased handgrip strength have been demonstrated after 13 weeks, frailty score remained unaltered(Reference Buigues, Fernández-Garrido and Pruimboom47). Added to this, recently, the PROMOTe trial by Ni Lochlainn et al. (2024)(Reference Ni Lochlainn, Bowyer and Moll48) showed no changes in multiple sarcopenia indices from prebiotic supplementation for 12 weeks in adults ≥ 60 years. Finally, ongoing experimental trials may reveal further insights into the potential impact of synbiotics in sarcopenia measures(Reference Barry, Farragher and Betik4,Reference Jamshidi, Masoumi and Abiri49) .
Challenges in translating findings to clinical practice
Lack of consistency in microbial assessments
The lack of consistency in microbial assessments represents a critical gap in research exploring the gut-muscle axis in sarcopenia. Standardised baseline and post-intervention microbial assessments are essential for robust, reproducible findings(Reference Swann, Rajilic-Stojanovic and Salonen50), yet many studies fail to incorporate them. For instance, SCFAs may influence the gut microbiome and support muscle anabolism; however, without standardised sequencing methods (i.e. 16S rRNA, shotgun metagenomics) at baseline and follow-up, detecting these changes may not confer causal interpretations. The absence of comprehensive gut microbiota characterisation before and after interventions may hinder the identification of specific microbial taxa, functional profiles or metabolic pathways linked to sarcopenia outcomes. Hence, standardisation of microbial assessments could ensure detailed reporting and follow-up tracking throughout probiotic and nutrition-based interventions, providing more robust findings that may be utilised for targeted sarcopenia therapies and improved outcomes.
Diversity of assessment techniques
The gut microbiome is typically assessed using techniques such as 16S rRNA gene sequencing, shotgun metagenomics, metatranscriptomics and metabolomics. Each method provides different levels of resolution, which poses challenges in standardising and comparing results across studies(Reference McGuinness, Stinson and Snelson51). In probiotics and sarcopenia research, 16S rRNA sequencing limits precision by only identifying microbial taxa at the genus level, obscuring strain-specific effects from interventions on sarcopenia outcomes. Shotgun metagenomics may overcome this challenge by providing species-level resolution and functional gene profiles, enabling identification of probiotic strains and their metabolic pathways relevant to muscle health. However, its high cost and incomplete databases may restrict its use, potentially missing novel taxa or functions around skeletal muscle metabolism. Interestingly, the integration of metabolomics may also be critical for detecting microbial metabolites such as SCFAs, which may provide further insights on the specificity and involvement of each SCFA, yet inconsistent detection methods may challenge cross-study comparisons. These limitations highlight the need for standardised protocols as proposed by the Strengthening The Organisation and Reporting of Microbiome Studies (STORMS) checklist to ensure reliable microbial assessments(Reference Mirzayi, Renson and Consortium52).
Factors impacting interindividual variability in the gut microbiome
The gut microbiome may exhibit significant interindividual variability due to several factors including diet, (oldest of the old) age, genetics, lifestyle, comorbidities, and medications, all of which are particularly relevant in older adults with sarcopenia. This variability makes it challenging to establish consistent microbial signatures associated with sarcopenia or the effects of probiotics, prebiotics, or synbiotics. More specifically, although diet could profoundly influence microbial composition, most clinical trials fail to adequately control for dietary intake(Reference Vitolins and Case53), leading to confounding effects that may misestimate the true impact of microbiome-based interventions. Studies that have incorporated dietary control measures, such as standardised meal plans or dietary monitoring, could provide stronger evidence linking microbial changes to sarcopenia. Although dietary status may be assessed using food diaries (e.g. 3-or 7-day food records), 24-hour recalls, food frequency questionnaires, digital assessment methods or image analysis to estimate nutrient intakes automatically, they may be subject to recall and selection bias(Reference Mirmiran, Bahadoran and Gaeini54). Therefore, providing sufficient training from nutrition professionals is necessary for participants to maximise their utility, which may offer greater insights if applied consistently throughout studies. Furthermore, lifestyle factors, including physical activity or medication use (e.g. antibiotics) and comorbidities, could further diversify the microbiome, making it difficult to identify consistent microbial species linked to sarcopenia or therapeutic responses. Older adults often present multimorbidity, including conditions such as heart failure or diabetes, which may independently alter gut microbiota composition or vice versa (Reference Beale, O’Donnell and Nakai55,Reference Razavi, Amirmozafari and Navab-Moghadam56) . Additionally, these conditions are accompanied by different prescribed medications, which may disrupt microbial homeostasis. Accounting for comorbidities is critical in sarcopenia research, as diverse clinical cohorts may exhibit varying physiological and microbial profiles that may necessitate tailored gut microbiome-based interventions. For instance, the potential efficacy of probiotics, such as Lactobacillus or Bifidobacterium strains, in mitigating sarcopenia could differ significantly across populations due to concurrent health conditions. Metabolic conditions may influence microbial responses to probiotics, influencing their therapeutic impact in certain groups compared to other clinical or healthier cohorts. Without controlling for comorbidities, studies risk confounding results, thereby, rigorous study designs, incorporating stratified analyses or covariate adjustments for comorbidities, are deemed essential to ensure more robust findings.
Treatment parameters and delivery methods
The efficacy of probiotics, prebiotics and synbiotics in modulating the gut microbiome to potentially counteract sarcopenia may be influenced by their delivery method, consisting of capsules, whole foods, fermented foods or fortified products. Encapsulated probiotics and synbiotics offer precise dosing and enhanced viability by protecting microbes from gastric acid and bile salts, ensuring delivery to the gut(Reference Bu, Mcclements and Zhang57). However, these formulations often lack essential dietary components, such as fibre or micronutrients, which could be critical for sustaining microbial growth. In contrast, whole foods rich in prebiotics such as fruits, vegetables and whole grains, may provide a broad nutritional profile that could enhance microbial diversity and function but may be challenging for older adults to consume due to dietary restrictions, chewing and swallowing difficulties or reduced appetite, potentially limiting their therapeutic impact(Reference Nicklett and Kadell58). Fermented foods, including yogurt or kefir, may deliver live microbes that may positively influence microbial diversity and muscle health by SCFA production(Reference Valentino, Magliulo and Farsi59). However, their microbial content is highly variable, and processing methods such as pasteurisation, may reduce probiotic viability, compromising efficacy(Reference Tripathi and Giri60). Fortified products, such as protein bars, powders, gummies or beverages enriched with probiotics or prebiotics, may offer a convenient and targeted delivery method(Reference Yoha, Nida and Dutta61), particularly for adults with sarcopenia who may require greater protein intake to support muscle health. Yet, as previously mentioned, challenges persist, including probiotic instability during processing and storage and the potential of food matrix interactions, negating microbial benefits(Reference Wang, Dekker and Heising62,Reference Kawano, Edwards and Huang63) . The scarcity of studies comparing these delivery methods in sarcopenia research highlights a critical gap, necessitating rigorous investigations to optimise intervention strategies and improve clinical outcomes in ageing populations and/or those at risk of sarcopenia.
Mechanistic research
Although probiotic-based strategies have shown potential in enhancing muscle health, mechanisms underpinning these benefits in humans are warranted. In preclinical models, using gene expression data and tissue-specific genome-scale metabolic models, Mardinoglu et al. (2015)(Reference Mardinoglu, Shoaie and Bergentall64) compared conventionally raised and germ-free mice across multiple tissues, observing that gut microbiota may significantly affect host metabolism, validated by amino acid measurements in the hepatic portal vein. Fermented milk administration with Lactiplantibacillus plantarum Y44 reduced body weight and hepatic lipid accumulation in high-fat diet-fed C57BL/6 mice, which was accompanied by decreases in Firmicutes to Bacteroidetes ratio and unclassified_f_Lachnospiraceae, a notable increase in Oscillospiraceae and increased branched chain amino acid (BCAA) biosynthesis in the liver(Reference Gao, Mu and Tuo65). In addition, Lactobacillus plantarum CCFM405 administration in rotenone-induced Parkinson’s disease mice enhanced BCAA biosynthesis, corresponding to increased serum and faecal BCAA levels(Reference Chu, Yu and Li66). In pigs, Lactobacillus reuteri 1 supplementation vs. antibiotics for 6 months increased skeletal muscle concentrations of BCAAs, maintained higher levels of glutamine and modulated amino acid transport and ribosomal protein S6 kinase 1 (S6K1) genes(Reference Tian, Cui and Lu67). Furthermore, supplementation with Bifidobacterium animalis ssp. lactis Probio-M8 has shown enhanced probiotic properties of fermented milk in increasing BCAA levels(Reference Sun, Guo and Kwok68). Similarly, supplementation of Bifidobacterium animalis subsp. lactis BB-12 in cow and goat milk yogurt significantly increased BCAA compared to classical yogurt cultures(Reference Terzioğlu and Bakirci69). In humans, administration of fresh with live probiotics vs. pasteurised yogurt enhanced leucine concentrations in 33 young adults, including 16 lactose-intolerant individuals(Reference Parra and Martínez70). Although, those with lactose intolerance demonstrated reduced leucine assimilation rates, live probiotics improved short-term (3-hour) amino acid uptake. Moreover, Tarik et al. (2022)(Reference Tarik, Ramakrishnan and Bhatia71) investigated a 60-day intervention where resistance-trained males consumed 20 g/d of whey protein with 2 × 109 colony-forming units (CFU) of Bacillus coagulans Unique IS-2 vs. placebo. The probiotic group exhibited a 16.1 % increase in plasma-free amino acids, including elevated BCAA, while showing significant improvements in leg press and vertical jump power. Similarly, in a 28-day trial, Bacillus subtilis DE111 supplementation (109 CFU) with whey protein increased peak plasma BCAA concentrations and reduced time-to-peak in active adults(Reference Townsend, Vantrease and Jones72). Finally, a multi-strain probiotic (5 × 109 CFU L. paracasei LP-DG (CNCM I-1572) with 5 × 109 CFU L. paracasei LPC-S01 (DSM 26760)) increased plasma BCAA absorption from pea protein in a randomised 2-week crossover trial(Reference Jäger, Zaragoza and Purpura73). Higher peak BCAA concentrations and total amino acid suggest enhanced plant protein digestion, potentially benefiting muscle health in sarcopenia via improved amino acid bioavailability. Collectively, these findings highlight the potential of probiotic interventions to modulate gut microbiota and enhance BCAA bioavailability, offering promising therapeutic strategies for improving muscle health and function in older age, although further human studies are needed to elucidate underlying mechanisms and optimise clinical applications. Importantly, overall, translating these findings to humans remains challenging due to interindividual microbial variability, ethical considerations, costs and more complex physiological interactions compared to animal models.
Conclusions
The role of the gut microbiome in sarcopenia presents a promising avenue for therapeutic interventions, with probiotics demonstrating potential in enhancing muscle health through modulation of microbial composition and related metabolites such as SCFAs. Animal studies have established robust links between gut microbiota and muscle health outcomes; however, research in humans is currently scarce. Some challenges persisting include inconsistent microbial assessments, lack of dietary control and interindividual variability driven by diet, age, genetics, comorbidities, and medication use. These factors could reduce microbial signatures and therapeutic efficacy, necessitating standardised protocols to ensure more robust and reproducible findings. Delivery methods such as capsules, fermented foods, or fortified products may also influence outcomes, while probiotic stability and dietary restrictions in older adults could complicate implementation. Although preclinical models highlight mechanisms such as BCAA biosynthesis and inflammatory profile modulation, translating these to humans requires rigorous clinical trials to address ethical, costing, and physiological barriers. Future research should integrate multi-omics approaches and control for confounders to optimise gut microbiome-based interventions, paving the way for personalised strategies to combat, in part, sarcopenia and improve quality of life in ageing populations.
Acknowledgments
I would like to thank The Nutrition Society for this invitation.
Financial support
This manuscript received no financial support.
Competing interests
The author declares no conflicts of interest.
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