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Gut Microbiome–Sphingolipid Metabolism–Brain Axis Interactions: Neuroprotective Effects of Amitriptyline as Functional Inhibitor of Acid Sphingomyelinase in a Mouse Model of Tauopathy
Mennatallah Ibrahim, Asmaa M. Khalil, Heba Attia, Saleh Alseekh, Ahmed F. Mohamed, Mohammed F. El-Yamany. Journal of Neuroimmune Pharmacology, 2026-01-03
Topic: Brain proteins, microglia and lab models
Tauopathies are neurodegenerative diseases characterized by accumulation of hyperphosphorylated tau protein (P-tau). 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 A and neurogenesis were assessed along with cognitive behavior. AMI treatment significantly reduced colonic ASM, ceramide levels, increased abundance of Harryflintia, Dubosiella, and Parasutterella and decreased abundance of Lactobacillus, Lachnoclostridium, Oscillibacter, Oscillospiracea UCG-003, Colidextribacter, Roseburia, Butyricicoccus, 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 Ruminococcaceae. 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.
Key findings
- AMI treatment significantly reduced colonic ASM, ceramide levels, increased abundance of Harryflintia, Dubosiella, and Parasutterella and decreased abundance of Lactobacillus, Lachnoclostridium, Oscillibacter, Oscillospiracea UCG-003, Colidextribacter, Roseburia, Butyricicoccus, 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 Ruminococcaceae.
- 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.
Why it matters
In P301S tau mice, amitriptyline reduced colonic acid sphingomyelinase and ceramide levels and changed the gut microbiome profile. This is an animal study, so it does not yet show that amitriptyline treats tauopathy in humans.
Study details
- Evidence strengthLow
How this study scored 37/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Journal of Neuroimmune Pharmacology) |
| Journal's citation record | 1 / 4 | Journal of Neuroimmune Pharmacology: journal h-index 108 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 5 / 5 | 2026 — within 1 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Laboratory or animal study (title names “mouse”) — scores zero |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 1 / 7 | Cited 2 times (OpenAlex, 2026-10-10) |
| Citations per year | 1 / 5 | 1.0 citations a year over 2 year(s) since 2026 |
| Impact for its field and year | 4 / 6 | Cited 8.3× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 0 / 6 | No other study in this library cites it |
| Still being cited | 0 / 4 | Cited 2 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 1 / 4 | Last-listed author Mohammed F. El-Yamany: h-index 15 (OpenAlex, whole career) |
| Institution's track record | 0 / 3 | Cairo University: institution h-index 575 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 4 institution(s) in 2 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 41484454) |
| Free to read | 2 / 2 | Free to read |
| Total | 37 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
- DOI: 10.1007/s11481-025-10270-x
- PubMed: 41484454
- Original source →
- Free full text: Journal of Neuroimmune Pharmacology →
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. Check the citation against the original before you use it.
APA 7th
Ibrahim, M., Khalil, A. M., Attia, H., Alseekh, S., Mohamed, A. F., & El-Yamany, M. F. (2026). Gut Microbiome–Sphingolipid Metabolism–Brain Axis Interactions: Neuroprotective Effects of Amitriptyline as Functional Inhibitor of Acid Sphingomyelinase in a Mouse Model of Tauopathy. Journal of Neuroimmune Pharmacology. https://doi.org/10.1007/s11481-025-10270-x
Vancouver
Ibrahim M, Khalil AM, Attia H, Alseekh S, Mohamed AF, El-Yamany MF. Gut Microbiome–Sphingolipid Metabolism–Brain Axis Interactions: Neuroprotective Effects of Amitriptyline as Functional Inhibitor of Acid Sphingomyelinase in a Mouse Model of Tauopathy. Journal of Neuroimmune Pharmacology. 2026. doi:10.1007/s11481-025-10270-x. PMID: 41484454.
BibTeX
@article{ibrahim2026-41484454,
author = {Ibrahim, Mennatallah and Khalil, Asmaa M. and Attia, Heba and Alseekh, Saleh and Mohamed, Ahmed F. and El-Yamany, Mohammed F.},
title = {{Gut Microbiome–Sphingolipid Metabolism–Brain Axis Interactions: Neuroprotective Effects of Amitriptyline as Functional Inhibitor of Acid Sphingomyelinase in a Mouse Model of Tauopathy}},
journal = {Journal of Neuroimmune Pharmacology},
year = {2026},
doi = {10.1007/s11481-025-10270-x},
pmid = {41484454},
url = {https://doi.org/10.1007/s11481-025-10270-x}
}
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