Molecular neurobiologySep 20, 2026

How Gut Imbalance and Its Chemicals May Affect the Brain's Protective Barrier in Alzheimer's Disease

Gut-Brain Axis Weekly Brief ↗PubMed ↗DOI ↗

Updated Sep 22, 2026

Abstract

Alzheimer's disease may be influenced by imbalances in gut microbiota and metabolite disturbances.

Patients with Alzheimer's disease often show reduced gut microbiota diversity and decreased populations of beneficial bacteria that produce short-chain fatty acids.
Altered bile acid profiles and increased levels of trimethylamine N-oxide and kynurenine pathway activity are commonly observed in Alzheimer's patients.
These gut microbiota changes may impair blood-brain barrier integrity and increase neuroinflammation through effects on various receptors and transporters.
Key pathological changes, including short-chain fatty acid deficiency and lipopolysaccharide leakage, may act together in a metabolic network associated with Alzheimer's disease.
Strategies targeting gut microbiota, such as dietary changes, probiotics, and fecal microbiota transplantation, could improve metabolite profiles and blood-brain barrier function.

Simplified

Alzheimer's disease (AD) is not merely a central nervous system disorder; rather, it is a systemic condition profoundly influenced by the peripheral internal environment. Recent research has revealed that imbalances in the gut microbiota (GM) and metabolite disturbances contribute to AD onset and progression. Clinical and animal studies have indicated that AD patients commonly exhibit reduced GM diversity, decreased populations of short-chain fatty acid (SCFA)-producing and indole-producing bacteria, disrupted bile acid (BA) profiles, and elevated levels of trimethylamine N-oxide (TMAO) and kynurenine pathway (KP) activity. These alterations not only reflect gut dysbiosis, but also impair blood-brain barrier (BBB) integrity and amplify neuroinflammation by modulating tight junction proteins and inflammatory signaling through their effects on receptors and transporters such as G protein-coupled receptors(GPR41/43), aryl hydrocarbon receptor(AhR), Farnesoid X receptor(FXR)/ Takeda G protein-coupled receptor 5(TGR5), L-type amino acid transporter 1(LAT1), and Major Facilitator Superfamily Domain containing 2A(MFSD2A). From an integrative perspective, these changes -including short-Chain Fatty Acids (SCFAs) deficiency, elevated TMAO and toxic BA levels, overactivation of the KP, and Lipopolysaccharides (LPS) leakage-often act synergistically, collectively forming key pathological nodes in the "metabolic network-BBB-AD" axis. GM-targeted strategies such as dietary interventions, probiotics and fecal microbiota transplantation (FMT) have demonstrated potential in improving metabolite profiles and BBB homeostasis. Future research should utilize induced pluripotent stem cell-derived organoids and multi-omics integration approaches to elucidate the spatiotemporal dynamics of metabolites within the gut-brain axis (GBA), thereby laying the foundation for precise microbiome-based interventions in AD.

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How Gut Imbalance and Its Chemicals May Affect the Brain's Protective Barrier in Alzheimer's Disease

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