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The gut microbiota (GM) is symbiotic with the host and altered in neurodegenerative diseases. Amitriptyline (AMI) is a functional inhibitor of acid sphingomyelinase (ASM) which is abnormally highly expressed in brains of Alzheimer patients. Little data is known about the role of colonic ASM in management of tauopathy. Therefore, the aim of this study was to investigate the role of AMI on reversing gut dysbiosis, ceramide levels, colonic inflammation and intestinal barrier disruption in tauopathy through the bidirectional gut-brain axis. P301S transgenic mice were administered AMI for 35 days. Colonic ASM, ceramides, inflammation and membrane integrity were assessed besides fecal microbiome analysis and serum lipopolysaccharides to assess intestinal membrane disruption. Levels of hippocampal P-tau, protein phosphatase 2\u00a0A and neurogenesis were assessed along with cognitive behavior. AMI treatment significantly reduced colonic ASM, ceramide levels, increased abundance of\n Harryflintia<\/jats:italic>\n ,\n Dubosiella<\/jats:italic>\n , and\n Parasutterella<\/jats:italic>\n and decreased abundance of\n Lactobacillus<\/jats:italic>\n ,\n Lachnoclostridium<\/jats:italic>\n ,\n Oscillibacter<\/jats:italic>\n ,\n Oscillospiracea UCG-003<\/jats:italic>\n ,\n Colidextribacter<\/jats:italic>\n ,\n Roseburia<\/jats:italic>\n ,\n Butyricicoccus<\/jats:italic>\n , and Sphingomondales. In contrast, P301S mice displayed an altered GM profile with enriched Firmicutes and Clostridia, and low proportions of Bacteroidota- a phylum associated with intestinal barrier protection-, and\n Ruminococcaceae<\/jats:italic>\n . Also, AMI treatment decreased inflammation and restored colonic membrane integrity with subsequent decrease in serum lipopolysaccharides, P-tau in hippocampus and improvement in cognitive behaviour and neurogenesis. The current results indicate that AMI has neuroprotective effects against tauopathy through modulation of ASM activity, associated ceramide levels, GM composition, colonic inflammation and membrane integrity through bidirectional gut-brain axis.\n <\/jats:p>\n \n Graphical Abstract<\/jats:bold>\n <\/jats:p>","DOI":"10.1007\/s11481-025-10270-x","type":"journal-article","created":{"date-parts":[[2026,1,4]],"date-time":"2026-01-04T01:54:19Z","timestamp":1767491659000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Gut Microbiome\u2013Sphingolipid Metabolism\u2013Brain Axis Interactions: Neuroprotective Effects of Amitriptyline as Functional Inhibitor of Acid Sphingomyelinase in a Mouse Model of Tauopathy"],"prefix":"10.1007","volume":"21","author":[{"given":"Mennatallah","family":"Ibrahim","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asmaa M.","family":"Khalil","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heba","family":"Attia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saleh","family":"Alseekh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7678-0643","authenticated-orcid":false,"given":"Ahmed F.","family":"Mohamed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed F.","family":"EL-Yamany","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,1,3]]},"reference":[{"key":"10270_CR1","doi-asserted-by":"publisher","first-page":"222","DOI":"10.1038\/s41575-023-00890-0","volume":"21","author":"MR Aburto","year":"2024","unstructured":"Aburto MR, Cryan JF (2024) Gastrointestinal and brain barriers: unlocking gates of communication across the microbiota\u2013gut\u2013brain axis. 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