The Gut–Brain Axis Mechanism in Alzheimer’s Disease: From Animal Models to Clinical Translation and Emerging Treatment Strategies

Research on gut microbiota in Alzheimer’s disease (AD) has progressed from observational correlations to the validation of causal relationships. Human studies consistently demonstrate that alterations in gut microbiota span the entire spectrum of AD, from the preclinical stage to dementia, and are associated with Amyloid-beta (Aβ) deposition, phosphorylated Tau (p-tau) positivity, dysregulation of bile acid and short-chain fatty acid (SCFA) metabolism, as well as impaired intestinal barrier function. The strongest causal evidence comes from germ-free/antibiotic-treated animal models, fecal microbiota transplantation (FMT) between healthy controls and AD patients, and colonization by specific pathogenic bacteria or metabolites—interventions that directly modulate Aβ load, tau phosphorylation, microglial activation, synaptic pruning, and cognitive behavior. Mechanistically, the gut-brain axis in AD integrates four interconnected pathways: (1) reduced production of SCFA-producing acidogenic bacteria accompanied by upregulation of pro-inflammatory pathways; (2) disruption of intestinal epithelial tight junctions, allowing lipopolysaccharide (LPS) and bacterial toxins to enter the systemic circulation; (3) reprogramming of peripheral and central innate immune systems, leading to hyperactivation of microglia and complement-mediated synaptic clearance; and (4) global rearrangement of microbial metabolite networks (including SCFAs, bile acids, tryptophan-ketouric acid derivatives, and LPS), collectively regulating Aβ homeostasis, tau pathology, microglial activation, and blood-brain barrier (BBB) integrity. Clinically, evidence levels remain uneven: probiotics/bifidobiotics have demonstrated improvements in inflammation and certain cognitive domains in small randomized controlled trials (RCTs); FMT has only been supported by case reports in human AD; modified ketogenic diets have shown correlations with cerebrospinal fluid (CSF) biomarkers; molecules such as GV-971 provide proof-of-concept for microbiota-targeted strategies but require broader independent validation. Overall, gut microbiota research in AD has entered a new phase, with animal and human studies indicating that dysbiosis can drive AD pathology through multiple pathways including immune, metabolic, and barrier dysfunction, though clinical intervention evidence remains inconsistent and requires further validation.