The authors searched PubMed, Web of Science, Embase, CNKI, Wanfang Data, and VIP through April 2026, compiling human studies that examined gut microbial composition, microbial metabolites, or microbiota-related pathways in relation to sarcopenia or related muscle phenotypes. The review deliberately distinguishes human observational and intervention evidence from animal and cell experiments, a distinction the authors emphasize is critical for clarifying the limits of causal interpretation and clinical translation. The human studies were organized into three categories: sarcopenia in general older populations, sarcopenia in disease-specific populations such as chronic kidney disease, liver cirrhosis, heart failure, and maintenance hemodialysis, and explicitly defined isolated muscle phenotypes such as low muscle mass or low handgrip strength.

The central finding of the synthesis is one of striking heterogeneity. Human studies have reported differences in gut microbial composition between individuals with and without sarcopenia, but the patterns vary across populations and methods, and their contribution to muscle impairment remains uncertain. For example, some studies reported lower abundance of the butyrate-producing bacterium Faecalibacterium prausnitzii in people with sarcopenia, while others found this species elevated. Findings for genera such as Lactobacillus and Bifidobacterium were similarly inconsistent. The review cautions that sarcopenia-associated microbial alterations should be examined at the level of individual taxa and their metabolic functions, rather than interpreted as a uniform reduction in all taxa commonly regarded as beneficial.

Diversity findings were equally mixed. In the population-based Xiangya Sarcopenia Study, shotgun metagenomics of 1,417 participants identified differences in microbial community composition between participants with and without sarcopenia, yet Shannon alpha-diversity was not associated with the condition. A Japanese outpatient study found that men with sarcopenia had lower alpha-diversity and distinct beta-diversity profiles, whereas corresponding differences were not observed in women. The authors stress that compositional differences can occur without any detectable reduction in richness or diversity, and that the available cross-sectional evidence does not establish which microbial measures, if any, predict subsequent muscle decline.

Beyond taxonomy, the review examines six candidate mechanisms through which gut microbes might communicate with skeletal muscle. The first involves short-chain fatty acids, principally acetate, propionate, and butyrate, produced through microbial fermentation of dietary carbohydrates. A human multi-omics study of 482 healthy, community-dwelling postmenopausal Chinese women found that a selected microbial functional measure related to butyrate synthesis was positively associated with serum butyrate and skeletal muscle index. One-sample Mendelian randomization supported a potential causal relationship between this functional measure and appendicular lean mass, though the two-sample analysis did not reach conventional statistical significance. Animal work adds mechanistic depth: germ-free mice show reduced muscle mass and strength, with partial reversal after microbial colonization, and butyrate supplementation improved muscle strength in some models. However, in a study where female mice received 5% sodium butyrate in the diet from 16 months of age, treated mice at 26 months exhibited less muscle loss and intramuscular fat accumulation, yet the age-related decline in grip strength was not improved.

A second mechanism centers on microbial nicotinic acid metabolism and muscle NAD+ homeostasis. One study integrating human metagenomics, metabolomics, and experimental validation found that individuals with sarcopenia had lower abundance of Bifidobacterium adolescentis, associated with poorer measures of muscle health. Nicotinic acid produced by this bacterium was identified as a candidate effector. In aged mice, supplementation with either the bacterium or nicotinic acid improved muscle mass and function, restored muscle NAD+ levels, suppressed atrophy-related signaling, and enhanced mitochondrial abundance and ATP content. The authors note, however, that human evidence remains observational, while intervention effects have been demonstrated only in preclinical models.

Branched-chain amino acid metabolism offers a third route. In a multiethnic cross-sectional study of 283 participants, individuals with sarcopenia had lower abundance of Prevotella copri and lower fecal levels of selected BCAAs and their derivatives. In a subsequent eight-week intervention in 20-month-old mice, oral gavage with live P. copri increased circulating BCAA levels and muscle weights and improved grip strength, hanging, and rotarod performance. Yet the picture is complicated by context: in other work, P. copri increased circulating BCAAs but also worsened glucose intolerance and insulin resistance, indicating that increases in bacterial abundance or circulating BCAAs must be interpreted in relation to diet, strain identity, and host metabolic status. The review also highlights that whether higher circulating BCAA levels translate into greater amino acid uptake and incorporation into skeletal muscle protein remains a critical unresolved link.

The remaining mechanisms involve bile acid transformation, inflammatory exposure to microbial products, and trimethylamine N-oxide co-metabolism. Antibiotic-induced microbiota depletion in mice disrupted microbial bile acid transformation, suppressed ileal FXR-FGF15 signaling, and reduced muscle protein synthesis, with supplementation of FGF19 partially restoring these responses. TGR5-deficient mice exhibited reduced muscle mass and strength, while muscle-specific TGR5 overexpression induced hypertrophy in both young and aged mice. On the inflammation front, LPS exposure activated TLR4-mediated inflammatory responses in muscle cells and induced atrophy in mice, with a TLR4 inhibitor attenuating these abnormalities. A randomized controlled trial of a multicomponent supplement containing HMB, carnosine, magnesium, butyrate, and lactoferrin reported improvements in muscle mass and physical function alongside reductions in C-reactive protein, TNF-alpha, and zonulin levels, though the formulation contained several active ingredients with potential direct effects on muscle, preventing attribution specifically to microbiota pathways. TMAO findings were notably context-dependent: it exerted cytoprotective effects under oxidative stress in cell models, yet aggravated sarcopenic obesity in aged rats fed a high-fat diet.

On interventions, the review strikes a deliberately cautious tone. A randomized, double-blind trial of Lactobacillus plantarum TWK10 in frail older adults reported improvements in selected muscle-related outcomes, though some findings reflected within-group changes rather than significant differences from placebo, and frailty is not interchangeable with a confirmed diagnosis of sarcopenia. Other bacterial interventions, including Bifidobacterium longum OLP-01 and Lactobacillus casei Shirota, were evaluated only in mice. A retrospective study comparing 85 patients receiving fecal microbiota transplantation plus resistance training with 87 receiving resistance training alone over 24 weeks reported improvements in muscle-related and inflammatory outcomes with the combined intervention, but the nonrandomized design limits causal interpretation. The authors conclude that probiotics, prebiotics, FMT, and microbiota-guided approaches remain investigational for this indication.

The review is candid about its own limitations: evidence selection was not exhaustive, no formal risk-of-bias assessment was performed, and possible overlap between human research reports was not resolved. The synthesis is therefore qualitative and hypothesis-generating rather than a quantitative estimate of the total evidence. Three challenges limit clinical translation: most human studies are cross-sectional and cannot determine whether microbial alterations precede or follow muscle decline; microbial signatures vary across populations and methods, and reproducible biomarkers have not been validated; and intervention studies have not established effective regimens, suitable target populations, or long-term safety. The authors call for longitudinal cohorts integrating metagenomics, metabolomics, dietary assessment, and repeated muscle measurements, alongside adequately powered randomized controlled trials evaluating strain- or metabolite-specific interventions using standardized sarcopenia definitions and clinically meaningful outcomes such as muscle strength and physical performance.

Subject of Research: The gut-muscle axis: how gut microbiota and microbial metabolites relate to sarcopenia

Article Title: The interaction mechanisms between sarcopenia and gut microbiota based on the gut-muscle axis

Article References: Ma, Y., Sui, Y., Xia, X., Zhou, L., Yue, J., Dong, B., Ge, N., & Liu, X. (2026). The interaction mechanisms between sarcopenia and gut microbiota based on the gut-muscle axis. Frontiers in Medicine, 13, Article 1892866. https://doi.org/10.3389/fmed.2026.1892866

Image Credits: AI Generated

DOI: 10.3389/fmed.2026.1892866

Keywords: sarcopenia, gut microbiota, gut-muscle axis, short-chain fatty acids, nicotinic acid, branched-chain amino acids, bile acids, TMAO, probiotics, fecal microbiota transplantation, aging, muscle mass