Pathophysiological Mechanisms of the Microbiota-Gut-Brain Axis in Amyotrophic Lateral Sclerosis: Intestinal Permeability, Neuroinflammation, and Therapeutic Horizons for Non-Motor Symptoms

Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder where systemic pathophysiological alterations significantly contribute to disease progression and non-motor manifestations, such as depression and anxiety. The microbiota-gut-brain axis represents a critical bidirectional pathway where intestinal dysbiosis and epithelial barrier disruption catalyze central neuroinflammation. This scoping review synthesizes evidence from 43 empirical and analytical studies across 28 countries, mapping the findings under the WHO International Classification of Functioning (ICF) framework. Pathophysiological data reveal a profound taxonomic shift in ALS patients, characterized by a severe depletion of neuroprotective, butyrate-producing genera (Akkermansia and Prevotella) and an enrichment of pro-inflammatory Enterobacteriaceae. This dysbiotic state leads to structural damage of the intestinal mucosa, alteration of Paneth cells, and down-regulation of tight junction proteins (zonulin), triggering a "leaky gut" phenomenon. The subsequent systemic translocation of lipopolysaccharides (LPS) induces TLR4-mediated endotoxemia, microglial hyperactivation, and accelerated motor neuron apoptosis. Conversely, therapeutic modulation via Fecal Microbiota Transplantation (FMT), psychobiotics, and metabolic interventions (ketogenic or Mediterranean diets) demonstrates significant efficacy in restoring epithelial integrity, mitigating mitochondrial hypermetabolism, and reducing emotional distress scales. This review identifies a critical research gap in the microstructural characterization of the enteric nervous system in ALS. Integrating microbiome-targeted biomarkers into clinical protocols is essential for a stratified, multi-systemic therapeutic approach to improve patient prognosis and psychological well-being.