Abstract
Research on gut microbiota in Alzheimer’s disease (AD) has progressed from observational correlation studies toward investigation of causal relationships in preclinical models. Human observational studies have reported associations between alterations in gut microbiota and 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 currently derives from germ-free or antibiotic-treated animal models, fecal microbiota transplantation (FMT) between healthy controls and AD patients, and colonization by specific bacterial strains or metabolites—interventions that have been shown to modulate Aβ load, tau phosphorylation, microglial activation, synaptic pruning, and cognitive behavior in animal models. Mechanistically, the gut–brain axis in AD has been proposed to integrate four interconnected pathways, with the strength of evidence and the extent of human validation varying considerably across them: (1) reduced production of SCFA-producing 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 metabolites, and LPS), has been proposed to collectively regulate Aβ homeostasis, tau pathology, microglial activation, and blood–brain barrier (BBB) integrity. Clinically, the evidence base remains uneven: probiotics have been associated with some improvements in some inflammatory markers and cognitive measures in small randomized controlled trials (RCTs); FMT has been reported in case studies in human AD; modified ketogenic diets have been associated with cerebrospinal fluid (CSF) biomarkers; and molecules such as GV-971 (Sodium Oligomannate) provide proof-of-concept for microbiota-targeted strategies, though independent validation is needed. Overall, gut microbiota research in AD has advanced considerably, with animal and human studies suggesting that dysbiosis may contribute to AD pathology through immune, metabolic, and barrier-related pathways, although clinical intervention evidence remains preliminary and requires further validation.