Anatomical and Molecular Foundations of the Gut–Brain Axis in Alzheimer’s Disease: From Molecular Mechanisms to Therapeutic Translation
6 affiliations
- 1Department of Anatomy, College of Medicine and Health Sciences, Arabian Gulf University, Manama P.O. Box 26671, Bahrain
- 2School of Medicine, IMU University, 126, Jln Jalil Perkasa 19, Bukit Jalil, Kuala Lumpur 57000, Federal Territory of Kuala Lumpur, Malaysia
- 3Physiology Discipline, Human Biology Department, IMU University, 126, Jln Jalil Perkasa 19, Bukit Jalil, Kuala Lumpur 57000, Federal Territory of Kuala Lumpur, Malaysia
- 4Department of Pre-clinical Sciences, M. Kandiah Faculty of Medicine and Health Sciences, University Tunku Abdul Rahman, Kajang 43000, Selangor, Malaysia
- 5Department of Medical Sciences, Faculty of Medicine and Health Sciences, Universiti Sains Islam Malaysia, Bandar Baru Nilai 71800, Malaysia
- 6Anatomy Discipline, Human Biology Department, IMU University, 126, Jln Jalil Perkasa 19, Bukit Jalil, Kuala Lumpur 57000, Federal Territory of Kuala Lumpur, Malaysia
Abstract
Alzheimer’s disease (AD) is a complex disease that involves systemic, vascular, and metabolic components affecting the brain, in addition to amyloid-beta (Aβ) and tau pathology. The microbiota–gut–brain axis, a bidirectional communication network between the gastrointestinal tract and the central nervous system, involving neural, immune, endocrine, and metabolic pathways, has arisen as a mechanistically plausible and clinically relevant contributor to AD pathogenesis among these systemic contributors. This review integrates information from human observational research, preclinical transgenic and germ-free models, and clinical trials to assess how gut dysbiosis, intestinal barrier dysfunction, and microbial metabolites converge on amyloidogenic and tau-associated pathways. In preclinical models, disruption of intestinal barrier integrity is proposed to allow translocation of lipopolysaccharide and bacterial amyloids into the systemic circulation, activating Toll-like receptor and NLRP3 inflammasome signaling that may prime microglia and astrocytes towards a chronic neuroinflammatory state. Further, dysbiosis-mediated changes in short-chain fatty acid, tryptophan–kynurenine, and bile acid metabolism may influence amyloid precursor protein processing, microglial clearance capability, and tau phosphorylation. Preclinical germ-free and fecal-transfer investigations provide fundamental evidence for these pathways in rodent models, while human case–control and Mendelian randomization data indicate converging yet diverse associations that have not yet established underlying directionality in human disease. Therapeutic modulation of the axis has shown promising early phase and observational signals using probiotics, synbiotics, dietary pattern interventions, fecal microbiota transplantation and pharmacological targeting of the GLP-1 pathway; however, the phase 3 EVOKE and EVOKE+ trials of oral semaglutide did not meet their primary cognitive endpoint, and heterogeneity of trials, short follow-up, and inconsistent reporting of biomarkers currently preclude definitive conclusions. We conclude that the microbiota-gut–brain axis is a biologically plausible and therapeutically tractable component of AD pathophysiology, but translation from mechanistic plausibility to clinical utility will depend upon longitudinal, biomarker-anchored and adequately powered interventional trials in genetically and microbiologically diverse populations. Because diet is among the most readily modifiable determinants of gut microbiome composition and function, this review prioritizes dietary patterns, prebiotic fibers, and probiotic or synbiotic supplementation as practical strategies for investigating the microbiota–gut–brain axis in AD. Their disease-modifying efficacy remains unproven; therefore, mechanistic and pharmacological approaches are discussed as complementary avenues for informing future research
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BibTeX
@article{potu2026anatomical,
title = {{Anatomical and Molecular Foundations of the Gut–Brain Axis in Alzheimer’s Disease: From Molecular Mechanisms to Therapeutic Translation}},
author = {Bhagath Kumar Potu and Abirami Arulkandan and Prarthana Kalerammana Gopalakrishna and Amardev Singh Thanu and Noor Azzizah Omar and Wael Amin Nasr El-Din and Thirupathirao Vishnumukkala},
journal = {Nutrients},
year = {2026},
month = oct,
doi = {10.3390/nu18213591},
url = {https://www.mdpi.com/2072-6643/18/21/3591},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Anatomical and Molecular Foundations of the Gut–Brain Axis in Alzheimer’s Disease: From Molecular Mechanisms to Therapeutic Translation
AU - Bhagath Kumar Potu
AU - Abirami Arulkandan
AU - Prarthana Kalerammana Gopalakrishna
AU - Amardev Singh Thanu
AU - Noor Azzizah Omar
AU - Wael Amin Nasr El-Din
AU - Thirupathirao Vishnumukkala
PY - 2026
DA - 2026/10/29
JO - Nutrients
DO - 10.3390/nu18213591
UR - https://www.mdpi.com/2072-6643/18/21/3591
AB - Alzheimer’s disease (AD) is a complex disease that involves systemic, vascular, and metabolic components affecting the brain, in addition to amyloid-beta (Aβ) and tau pathology. The microbiota–gut–brain axis, a bidirectional communication network between the gastrointestinal tract and the central nervous system, involving neural, immune, endocrine, and metabolic pathways, has arisen as a mechanistically plausible and clinically relevant contributor to AD pathogenesis among these systemic contributors. This review integrates information from human observational research, preclinical transgenic and germ-free models, and clinical trials to assess how gut dysbiosis, intestinal barrier dysfunction, and microbial metabolites converge on amyloidogenic and tau-associated pathways. In preclinical models, disruption of intestinal barrier integrity is proposed to allow translocation of lipopolysaccharide and bacterial amyloids into the systemic circulation, activating Toll-like receptor and NLRP3 inflammasome signaling that may prime microglia and astrocytes towards a chronic neuroinflammatory state. Further, dysbiosis-mediated changes in short-chain fatty acid, tryptophan–kynurenine, and bile acid metabolism may influence amyloid precursor protein processing, microglial clearance capability, and tau phosphorylation. Preclinical germ-free and fecal-transfer investigations provide fundamental evidence for these pathways in rodent models, while human case–control and Mendelian randomization data indicate converging yet diverse associations that have not yet established underlying directionality in human disease. Therapeutic modulation of the axis has shown promising early phase and observational signals using probiotics, synbiotics, dietary pattern interventions, fecal microbiota transplantation and pharmacological targeting of the GLP-1 pathway; however, the phase 3 EVOKE and EVOKE+ trials of oral semaglutide did not meet their primary cognitive endpoint, and heterogeneity of trials, short follow-up, and inconsistent reporting of biomarkers currently preclude definitive conclusions. We conclude that the microbiota-gut–brain axis is a biologically plausible and therapeutically tractable component of AD pathophysiology, but translation from mechanistic plausibility to clinical utility will depend upon longitudinal, biomarker-anchored and adequately powered interventional trials in genetically and microbiologically diverse populations. Because diet is among the most readily modifiable determinants of gut microbiome composition and function, this review prioritizes dietary patterns, prebiotic fibers, and probiotic or synbiotic supplementation as practical strategies for investigating the microbiota–gut–brain axis in AD. Their disease-modifying efficacy remains unproven; therefore, mechanistic and pharmacological approaches are discussed as complementary avenues for informing future research
SN - 2072-6643
ER -