New Frontiers: The Gut-Joint And Gut-Muscle Axis In Injury Prevention

Tennis - WTA 1000 - Italy’s Jasmine Paolini in action during the final against Russia’s Anna Kalinskaya REUTERS/Rula Rouhana

More than 2000 years ago, Hippocrates said, “All disease begins in the gut.” Today, clinicians are close to understanding the importance of gut health. However, they struggle to apply genomics, proteomics, and metabolomics disciplines in daily clinical practice. As the center of health, the gut goes beyond its important physiological functions, such as food digestion, nutrient absorption, neurotransmitter release, and immune system regulation. The gastrointestinal (GI) tract has a complex ecosystem known as the gut microbiota. It includes bacteria, fungi, protozoa, and viruses, accounting for over 38 trillion microorganisms and 1000 species. The gut defends the delicate homeostasis balance between the microbiota and the host, and it is the largest immunity organ.

A balanced gut microbiota contributes to the host’s health by strengthening the intestinal barrier and ensuring a low inflammatory state. It works on the immune system and hormonal signaling and secretes several bioactive metabolites. Pathological conditions cause dysbiosis and result in an imbalanced microbiota, negatively affecting microbial species’ abundance and metabolite release. Moreover, multiple external factors cause dysbiosis, but the most relevant include an unhealthy diet, excessive physical activity, drug intake, environmental toxins, and psychological distress.

Researchers are close to unraveling the connections between the gut, muscles, and joints. Therefore, it opens up new avenues and treatment possibilities for injury prevention and management in athletes. The challenge is translating the research into clinical practice.

Acute and chronic sports injuries affect the musculoskeletal system. Training type and intensity, athlete gender and age, inadequate diet, bad sleeping habits, and insufficient recovery increase injury risk. For example, elite youth football has high injury rates, possibly due to the intense schedules without adequate nutrition and recovery. Furthermore, in professional football, injuries affect player availability, impacting team performance and the club economically (approximately €6 million per club per season). Muscle injuries usually account for 20-37% of all injuries in professional football players, followed by ligament–joint injuries. However, the economic loss for ligament–joint injuries is nearly six times higher than for muscle injuries due to the longer recovery time⁽¹⁾.

Studying the gut-joint and gut-muscle axis opens the possibility of redirecting communication between the musculoskeletal system and the intestine toward gut microbiota-based therapies. Physical activity and dietary habits significantly influence an athlete’s performance. Selecting functional foods and pre-probiotics optimizes brain, bone, muscle, and cardiovascular health. Improved overall health reduces GI discomfort and inflammation and lowers the risk of injury⁽²⁾.

The Gut-Muscle Axis

Gut microbiota releases active microbial metabolites that influence muscle physiology (see figure 1)⁽³⁾. Crossing the intestinal barrier, they impact muscle metabolism, eliciting different effects (positive and negative):

1. Lipopolysaccharides (LPS): Intestinal disorders and poor microbial diversity jeopardize the integrity of the gut barrier. This opens the way to harmful microbial products, such as LPS, that easily enter the circulation and elicit systemic inflammation. Therefore, during periods of intense training, systemic inflammation increases the risk of muscle damage and joint injuries. Moreover, LPS upregulate pro-inflammatory cytokines, negatively affecting skeletal muscle function⁽⁴⁾.
2. Short-chain fatty acids (SCFAs): Bacterial fermentation of carbohydrates and proteins produces SCFAs, bioactive molecules on human metabolism and immunity. For example, they stimulate hormone signals that regulate mitochondrial function and play an active role in lipid, protein, and carbohydrate metabolism in skeletal muscle. Short-chain fatty acids contribute to maintaining insulin sensitivity in skeletal muscle and promote aerobic metabolism by increasing mitochondrial fatty acids oxidation⁽³⁾. However, gut dysbiosis negatively affects their release, resulting in declining muscle metabolism and increasing injury risk. Researchers at the Department of Cellular and Structural Biology in Texas showed that butyrate supplementation in aging mice increases muscle fiber cross-sectional area and reduces fat deposition into the muscle. Moreover, glucose metabolism and mitochondrial biogenesis improved. The researchers showed that butyrate supplementation has positive effects on muscle mass. This provides clinicians with interventions for sarcopenia and age-related metabolic disease, with implications for older athletes⁽⁵⁾.
3. Secondary bile acids (BAs): Liver cells produce primary bile acids. On the contrary, microbial metabolism produces secondary bile acids. They exist in a free form or are conjugated to amino acids. Binding to specific receptors, they play different roles in physiology and metabolism. Exercise-induced expression of bile acid receptor TGR5 improves muscle function (as muscle cell differentiation and hypertrophy) and explains the beneficial effect of exercise on skeletal muscle activity⁽⁶⁾. 
4. Metabolites from amino acids digestion: Bacteria metabolize amino acids and peptides when they enter the large intestine. Some metabolites, such as p-cresol sulfate (PCS), imidazole propionate, and indoxyl sulfate (IS), may affect muscle physiology and pathology. Imidazole propionate is a histidine-derived metabolite that impairs insulin signals at the level of the receptor substrate, promoting insulin resistance. Its concentration is higher in T2D and non-type two diabetic patients, representing a biomarker of impaired glucose metabolism⁽⁷⁾. Indoxyl sulfate is a bacterial metabolite of tryptophan that increases risk factors associated with skeletal muscle catabolism, such as reactive oxygen species and inflammatory cytokines and promotes the expression of muscle atrophy-related genes⁽⁸⁾. P-cresol sulfate, a protein-bound uremic toxin, is a microbial metabolite derived from tyrosine. Animal studies on PCS supplementation for four weeks showed a significant increase in insulin resistance and altered insulin signaling in skeletal muscle, contributing to the development of chronic kidney disease-associated features⁽⁹⁾.