Microbial diversity and fitness in the gut-brain axis: influences on developmental risk for Alzheimer's disease

Abstract

The gut-brain axis (GBA) denotes the dynamic and bidirectional communication system that connects the gastrointestinal tract and the central nervous system (CNS). This review explored this axis, focusing on the role of microbial diversity and fitness in maintaining gastrointestinal health and preventing neurodegeneration, particularly in Alzheimer's disease (AD). Gut dysbiosis, characterized by the imbalance in populations of beneficial and harmful bacteria, has been associated with increased systemic inflammation, neuroinflammation, and the progression of AD through pathogenic mechanisms involving amyloid deposition, tauopathy, and increased blood-brain barrier (BBB) permeability. Emerging evidence highlighted the therapeutic potential of probiotics, dietary interventions, and intermittent fasting in restoring microbial balance, reducing inflammation, and minimizing neurodegenerative risks. Probiotics and synbiotics are promising in helping improve cognitive function and metabolic health, while dietary patterns like the Mediterranean diet were linked to decreased neuroinflammation and enhanced gut-brain communication. Despite significant advancement, further research is needed to elucidate the specific microbial strains, metabolites, and mechanisms influencing brain health. Future studies employing longitudinal designs and advanced omics technologies are essential to developing targeted microbiome-based therapies for managing AD-related disorders.

Keywords: Alzheimer’s disease; gut dysbiosis; gut-brain axis; microbial diversity; microbiota-gut-brain axis; neurodegenerative diseases; neuroinflammation; neuromodulators; probiotics; quorum sensing.

Figure 1.

Overview of the gut–brain axis. Gut microbes release neurotransmitters and QSMs that travel through the vagus nerve and influence the CNS. In the event of gut dysbiosis, neurodegenerative disorders may arise as a result of the stress response, immunological response, and neuroinflammation. Created with BioRender.com.

Figure 2.

Cross-kingdom signaling in the GBA. The gut microbiota releases several neuromodulators, such as neurotransmitters, oligopeptides, and other metabolites, interacting with epithelial and immune cells. Specialized cells lining the intestinal epithelium maintain intestinal homeostasis, form a mucus barrier, and facilitate the passage of material through the intestines. neurons also recognize neurotransmitters, which travel through the vagus nerve to the brain. Gut dysbiosis resulting from imbalanced gut microbial populations leads to immunological effects and neuroinflammation, possibly resulting in neurodegenerative and psychiatric disorders. Created with BioRender.com.

Figure 3.

Dynamic alterations in the GBM. Shifts in different microbiota populations resulting from gut dysbiosis can enhance present risk factors that increase the likelihood of developing MCI/AD pathology. Created with BioRender.com.

Figure 4.

Neurological impact of different diets. Western diets (left) were primarily composed of processed carbohydrates and saturated fats that may impair the BBB and increase the likelihood of neuroinflammation and gut dysbiosis, leading to worsening of neurodegeneration. In contrast, the Mediterranean diet (right) primarily consists of essential fibers, nutrients, and minerals that help maintain the integrity of the BBB and restore gut dysbiosis, thereby preventing neuroinflammation that leads to neurological impairment—created with BioRender.com.