Epigenetic modulation of the gut-muscle axis in pompe disease: Microbiota fingerprints to cellular and molecular pathomechanisms

: Inter-organ cross-talk is increasingly recognised as a fundamental determinant in the pathogenesis of neurodegenerative and neuromuscular disorders, modulating neuroinflammation, protein misfolding, and cellular dysfunction through systemic mediators such as cytokines, adipokines, and growth factors. In neuromuscular diseases, particularly Pompe disease, muscle degeneration is tightly linked to impaired autophagy and chronic inflammation. Recent evidence highlights the gut microbiota as a key regulator of innate and adaptive immune responses, exerting direct effects on skeletal muscle and supporting the existence of a gut-muscle axis. Dysbiosis has been proposed to influence myopathy progression, suggesting that modulation of the intestinal ecosystem may hold therapeutic relevance. Consequently, interventions employing probiotics, prebiotics, and targeted nutritional compounds have emerged as promising strategies to modulate immune activity, attenuate inflammation, and enhance autophagic efficiency, thereby contributing to the restoration of intestinal eubiosis and complementing enzyme replacement therapy. In parallel, epigenetic mechanisms are gaining prominence as additional modulators of pathogenic pathways, with the potential to influence microbiome composition and function. Collectively, these insights position the gut-muscle axis as a central regulatory node in Pompe disease and a compelling target for personalised nutritional and nutraceutical approaches. This review aims to provide a comprehensive examination of the gut-muscle axis and its implications in Pompe disease. Understanding how nutrient-induced changes in microbial gene expression may be harnessed to develop novel, synergistic therapeutic strategies could ultimately improve clinical outcomes and enhance the quality of life of affected individuals.