Gut Microbiota Dysbiosis Drives Alzheimer's Pathology via Gut-Brain Axis, Suggesting Therapeutic Modulation

Alzheimer's disease (AD) is a chronic, progressive neurodegenerative condition characterized by memory loss, cognitive decline, and neuropathological features like amyloid plaque accumulation and neurofibrillary tangles. Current treatments primarily manage symptoms, failing to halt disease progression. Emerging research highlights the critical role of the gut-brain axis, a bidirectional communication system, in AD pathogenesis. Understanding how gut microbes influence brain health provides a novel perspective on disease mechanisms and potential therapeutic targets beyond traditional amyloid and tau pathways.

This comprehensive review synthesized current literature on the bidirectional gut-brain axis and its intricate role in Alzheimer's disease (AD) pathogenesis. Researchers analyzed studies exploring how microbial dysbiosis, intestinal barrier integrity, and microbial metabolites influence neuroinflammation, amyloid-beta deposition, and neurotransmitter balance within the central nervous system. The review focused on identifying mechanistic insights and evaluating potential therapeutic strategies involving microbiota modulation, including probiotics, prebiotics, postbiotics, synbiotics, and antibiotics.

The review established a strong association between intestinal microbes and Alzheimer's disease pathogenesis. Gut microbial dysbiosis, often triggered by diet or environmental factors, was linked to weakened intestinal barrier function and systemic inflammation. This inflammation, in turn, contributes to defective regulation of the amyloid precursor protein (APP), leading to increased deposition of amyloidogenic peptides (Aβ). The enteric nervous system, which expresses APP, was identified as a potential initial site of Aβ deposition, impacting gastrointestinal motility and inflammatory susceptibility. Furthermore, gut microbiota produce crucial neurotransmitters like serotonin, dopamine, acetylcholine, histamine, and gamma-aminobutyric acid (GABA), which influence the CNS via neural, immune, and endocrine pathways. An imbalance in these neuroactive molecules can disrupt synaptic signaling and contribute to AD-related cognitive dysfunction. > The interplay between gut microbiota and the brain's inflammatory and amyloidogenic pathways represents a critical, modifiable factor in Alzheimer's disease progression.