{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T15:32:10Z","timestamp":1786375930670,"version":"build-2736575974"},"reference-count":102,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T00:00:00Z","timestamp":1786320000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pathophysiology"],"abstract":"<jats:p>Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder in which systemic pathophysiological alterations significantly contribute to disease progression and non-motor manifestations, such as depression and anxiety. The microbiota\u2013gut\u2013brain axis represents a critical bidirectional pathway in which intestinal dysbiosis and epithelial barrier disruption catalyze central neuroinflammation. This scoping review synthesizes evidence from 43 empirical and analytical studies across 28 countries and maps the findings under the WHO International Classification of Functioning (ICF) framework. Pathophysiological data reveal a profound taxonomic shift in patients with ALS, characterized by severe depletion of neuroprotective, butyrate-producing genera (Akkermansia and Prevotella) and enrichment of pro-inflammatory Enterobacteriaceae. This dysbiotic state leads to structural damage to the intestinal mucosa, alteration of Paneth cells, and downregulation of tight junction proteins (zonulin), triggering a \u201cleaky gut\u201d phenomenon. 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) has demonstrated significant efficacy in restoring epithelial integrity, mitigating mitochondrial hypermetabolism, and reducing emotional distress. This review identifies a critical research gap in the microstructural characterization of the enteric nervous system in ALS. Incorporating microbiome-targeted biomarkers into clinical protocols is crucial for implementing a stratified, multi-systemic therapeutic strategy aimed at enhancing patient prognosis and psychological well-being.<\/jats:p>","DOI":"10.3390\/pathophysiology33030059","type":"journal-article","created":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T15:10:24Z","timestamp":1786374624000},"page":"59","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Microbiota\u2013Gut\u2013Brain Axis and Nutritional Interventions in Amyotrophic Lateral Sclerosis: Pathophysiological Mechanisms, Neuroinflammation, and Non-Motor Manifestations\u2014Scoping Review"],"prefix":"10.3390","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-5606-0899","authenticated-orcid":false,"given":"Elena","family":"Sanchis-Sanchis","sequence":"first","affiliation":[{"name":"Doctoral School, Catholic University of Valencia San Vicente M\u00e1rtir, 46001 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6808-9505","authenticated-orcid":false,"given":"Jos\u00e9 Enrique","family":"de la Rubia Ort\u00ed","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and Health Sciences, Catholic University of Valencia San Vicente M\u00e1rtir, 46007 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4911-5058","authenticated-orcid":false,"given":"David","family":"Sancho-Cantus","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and Health Sciences, Catholic University of Valencia San Vicente M\u00e1rtir, 46007 Valencia, Spain"},{"name":"Nursing and Mental Health Research Group, Department of Nursing, Catholic University of Valencia, 46007 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Cunha-P\u00e9rez","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and Health Sciences, Catholic University of Valencia San Vicente M\u00e1rtir, 46007 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9647-5980","authenticated-orcid":false,"given":"Jorge","family":"Casa\u00f1a-Mohedo","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and Health Sciences, Catholic University of Valencia San Vicente M\u00e1rtir, 46007 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1038\/nrneurol.2013.203","article-title":"The epidemiology of ALS: A conspiracy of genes, environment and time","volume":"9","author":"Hardiman","year":"2013","journal-title":"Nat. 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