Fig. 2

The connection mechanisms between gut microbiota and pathology of Alzheimer’s disease. The dysregulation of gut microbiota compromises the integrity of the intestinal and blood-brain barriers, allowing gut microbiota metabolites to enter the central nervous system and participate in the pathological processes of Alzheimer’s disease (AD). Astrocytes within the central nervous system synthesize lipids through key genes such as SREBP, APOE, ABCA1, CLU, ABCA7, TREM2, transferring them to neurons and microglial cells. Microbial metabolites can interact with these genes, influencing lipid homeostasis. Furthermore, gut microbiota metabolites primarily contribute to AD pathology through involvement in Aβ pathology, tau pathology, neuroinflammation, oxidative stress, mitochondrial dysfunction, and epigenetic regulation. SCFAs binding to GPR41, dependent on CD14 expression, inhibits NRF2 signaling, reducing oxidative stress in endothelial cells, maintaining the blood-brain barrier. In contrast, LPS binding to TLR4 promotes Myd88 expression, activating NF-κB transcription, releasing pro-inflammatory cytokines, damaging the blood-brain barrier. For Aβ Pathology: LPS reduces α-secretase activity, promoting APP production, while both LPS and TMAO upregulate BACE-1 and γ-secretase activities, enhancing Aβ production. SCFAs and TUDCA promote α-secretase activity and inhibit Aβ generation. Tau Pathology: SCFAs and TUDCA inhibit GSK-3β activity by promoting AKT phosphorylation, thereby suppressing tau phosphorylation, and reducing NFTs formation. Neuroinflammation: SCFAs upregulate GPR41 expression, inhibit the ERK/JNK/NF-κB pathway, reducing COX2 and IL-1β levels, alleviating neuroinflammation. TUDCA binds to the TGR5 receptor in microglial cells, increases cAMP levels, inhibits the NF-κB pathway, induces an anti-inflammatory phenotype, and mitigates inflammation. Indole reduces NLRP3 inflammasome expression through the AhR/NF-κB pathway, decreasing the release of inflammatory factors TNF-α, IL-6, IL-1β, and IL-18, inhibiting microglia-induced neuroinflammation. TREM2 activates the PI3K/AKT/Foxo3a pathway, suppressing the inflammatory response. Conversely, downregulation of TREM2 expression by LPS leads to an increased inflammatory response. LPS also activates TLR4 and NF-κB transcription, leading to the release of pro-inflammatory cytokines TNFα, IL-6, and IL-1β. Oxidative Stress and Mitochondrial Function: SCFAs binding to GPR109A blocks NF-κB signaling, reducing neuronal oxidative stress levels. SCFAs binding to sodium-coupled monocarboxylate transporter 1 (SMCT1) or activating GPR41 promotes NRF2, leading to increased SOD1 production and inhibition of NOX2, preventing excessive accumulation of neuronal ROS. Indole binds to respiratory chain complex enzymes, reducing mitochondrial electron leakage, neutralizing hydroxyl radicals, and inhibiting ROS production. Epigenetic Regulation: SCFAs inhibit HDAC activity, promoting excessive acetylation of histone H3K18, improving cognition. Alternatively, SCFAs promote histone acetylation, restoring synaptic plasticity and cognitive function in an ACSS2-dependent manner