Fig. 1

The potential association between gut microbiota and their metabolites with lipid dysregulation in AD. Throughout the progression of Alzheimer’s disease (AD), there is a reduction in phosphatidylcholine (PC) and phosphatidylethanolamine (PE). PC exhibits a negative correlation with the severity of AD pathology, while PE serves as a prognostic indicator for patients with mild cognitive impairment. Plasmalogens (PlsEtns) mitigate tau phosphorylation and experience downregulation in AD. Cholesterol, a pivotal lipid in AD, notably increases in the brain, accompanied by a significant elevation in cholesterol esters (CE). Cholesterol and CE play pivotal roles in AD, contributing to Aβ pathology, tau hyperphosphorylation, and neuroinflammation. Gut microbiota metabolites such as BAs, SCFAs, and LPS interact with cholesterol, thereby modulating AD pathology. Ceramide (Cer) levels escalate in AD, stabilizing BACE1 and fostering Aβ production, whereas sphingosine-1-phosphate (S1P) exhibits neuroprotective effects, and its decrease facilitates neurodegeneration. Tryptophan metabolites (TRYCATs) are intricately associated with sphingolipids through the AhR receptor. Fatty acids like docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) decrease in AD, playing a role in inhibiting Aβ generation. Arachidonic acid (AA) is a prominent participant in neuroinflammation, instigating neuronal degeneration. Palmitic acid (PA), a representative saturated fatty acid, fosters AD through heightened β-secretase activity and tau hyperphosphorylation. Trimethylamine N-oxide (TMAO) exacerbates AD progression by promoting fatty acid oxidation and oxidative stress