Gut–liver–muscle axis -Front. Med. 2026

### The Gut–Liver–Muscle Axis: Overview and Key Insights

The "gut-liver-muscle axis" is an emerging concept that highlights the interconnected relationship between gut microbiota, liver metabolism, and skeletal muscle health. This axis provides a framework to understand how disruptions in one organ system (e.g., the gut) can lead to systemic effects on the liver and skeletal muscles, particularly in the context of chronic liver diseases. Below is a detailed breakdown of the concept:

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### 1. **What is the Gut–Liver–Muscle Axis?**

The gut-liver-muscle axis is a physiological network that connects the gut, liver, and skeletal muscle through metabolic, immunological, and hormonal pathways. It emphasizes the role of gut microbiota in modulating liver function and skeletal muscle homeostasis, thereby influencing energy metabolism, protein synthesis, and inflammation.

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### 2. **Role of Gut Microbiota in the Axis**

• **Gut Dysbiosis**: Imbalances in gut microbiota, such as reduced microbial diversity, decreased beneficial bacteria, and increased pathogenic bacteria, play a central role in disrupting the gut-liver-muscle axis.
• **Intestinal Barrier Dysfunction**: Gut barrier integrity is often weakened in chronic liver diseases, allowing bacterial products (e.g., lipopolysaccharides or LPS) to enter the portal circulation and trigger liver inflammation.
• **Microbial Metabolites**: Key products of gut bacteria, such as short-chain fatty acids (SCFAs), bile acids, and amino acid metabolites, influence both liver and muscle metabolism.

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### 3. **Liver's Role in the Axis**

• **Energy Metabolism**: The liver is a critical organ for energy storage and nutrient metabolism. In chronic liver disease, impaired liver function disrupts glucose, lipid, and protein metabolism, contributing to malnutrition and muscle wasting.
• **Inflammation**: Persistent liver inflammation due to gut-derived LPS and other microbial products exacerbates metabolic dysfunction and promotes muscle protein breakdown.
• **Amino Acid Imbalances**: Liver dysfunction leads to impaired branched-chain amino acid (BCAA) utilization and increased aromatic amino acids (AAAs), which negatively affect muscle protein synthesis.

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### 4. **Muscle's Role in the Axis**

• **Sarcopenia**: Sarcopenia, or the loss of skeletal muscle mass and strength, is a hallmark of malnutrition in chronic liver disease. It is influenced by systemic inflammation, hyperammonemia, and energy metabolic dysfunction.
• **Energy Deficits**: Reduced SCFA production and impaired nitrogen metabolism weaken muscle energy supply, contributing to muscle wasting.
• **Hyperammonemia**: Elevated blood ammonia levels (common in liver cirrhosis) impair muscle protein synthesis and energy metabolism.

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### 5. **Key Pathways in the Gut–Liver–Muscle Axis**

• **Inflammatory Signaling**: Gut-derived LPS activates liver Kupffer cells, inducing pro-inflammatory cytokines (e.g., TNF-α, IL-6) via NF-κB signaling. These cytokines promote muscle protein degradation and inhibit synthesis.
• **Nitrogen Metabolism**: Dysbiosis leads to increased ammonia-producing bacteria, exacerbating hyperammonemia and nitrogen imbalance, which impair muscle function.
• **SCFA Production**: SCFAs (e.g., butyrate, acetate, propionate) are crucial for energy metabolism. Reduced SCFA levels due to gut dysbiosis weaken muscle mitochondrial function and glycogen storage.
• **Bile Acid Signaling**: Gut microbiota modulate bile acid metabolism, which influences liver lipid metabolism and systemic energy regulation.

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### 6. **Chronic Liver Diseases and the Gut–Liver–Muscle Axis**

Several liver diseases are closely associated with disruptions in the gut-liver-muscle axis:

• **Non-Alcoholic Fatty Liver Disease (NAFLD)**: Gut dysbiosis contributes to insulin resistance, lipid metabolism disorders, and sarcopenic obesity in NAFLD.
• **Alcoholic Liver Disease (ALD)**: Chronic alcohol consumption disrupts gut microbiota, weakens the gut barrier, and promotes liver inflammation and muscle wasting.
• **Liver Cirrhosis**: Advanced cirrhosis is characterized by significant dysbiosis, hyperammonemia, and systemic inflammation, leading to severe sarcopenia.
• **Viral Hepatitis and Autoimmune Liver Diseases**: Persistent inflammation and immune dysregulation in these conditions are exacerbated by gut microbiota imbalances.

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### 7. **Therapeutic Implications of the Gut–Liver–Muscle Axis**

Understanding the gut-liver-muscle axis has opened new avenues for therapeutic interventions:

• **Probiotics/Prebiotics**: These can restore microbial balance, enhance SCFA production, and improve gut barrier function.
• **Faecal Microbiota Transplantation (FMT)**: FMT has shown promise in reducing gut-derived inflammation, improving ammonia metabolism, and restoring gut-liver axis function.
• **Nutritional Support**: Supplementing with branched-chain amino acids (BCAAs), dietary fiber, and polyunsaturated fatty acids (PUFAs) can improve muscle protein synthesis and energy metabolism.
• **Integrated Approaches**: Combining microbiome-based therapies with nutritional and pharmacological interventions may offer a comprehensive strategy for managing liver disease-related malnutrition and sarcopenia.

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### 8. **Future Directions**

• **Multi-Omics Research**: Advanced tools like metagenomics, metabolomics, and proteomics will help identify specific microbial and metabolic signatures associated with liver disease and sarcopenia.
• **Personalized Medicine**: Developing tailored microbiome interventions and nutritional therapies based on individual microbiota profiles.
• **Dynamic Modeling**: Using artificial intelligence and computational models to predict disease progression and optimize treatment strategies for the gut-liver-muscle axis.

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### Conclusion

The gut-liver-muscle axis is a critical and interconnected pathway that plays a significant role in the development of malnutrition and sarcopenia in chronic liver diseases. Gut dysbiosis, liver dysfunction, and muscle wasting are interlinked through complex metabolic and inflammatory pathways. By targeting the gut microbiota and its metabolites, novel therapeutic strategies can be developed to improve the nutritional outcomes, muscle health, and overall prognosis of patients with liver diseases.