Protein network mechanisms by which gut microbial metabolites regulate neuroinflammation in Alzheimer’s disease: Recent advances in gut-brain axis research

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Protein network mechanisms by which gut microbial metabolites regulate neuroinflammation in Alzheimer's disease: Recent advances in gut-brain axis researchAlzheimer's disease (AD) is characterized by 𝛽-amyloid deposits, tau protein hyperphosphorylation, and neuronal loss.Neuroinflammation, particularly chronic inflammation mediated by microglia, is closely associated with AD. 1 The gut-brain axis, serving as a bidirectional communication channel between the gut microbiota and the central nervous system, is a critical pathway regulating neuroinflammation in AD.Gut microbial metabolites can cross the intestinal barrier, enter the bloodstream, and influence the brain's immune microenvironment, acting as key messengers in gut-brain axis signaling.2 These metabolites primarily exert their effects through host protein networks (membrane receptors, nuclear receptors, signaling molecules, and transcription factors).This review summarizes how major gut microbial metabolites act along the "metabolite-protein network-AD neuroinflammation " axis via specific protein network hubs, providing a new perspective for understanding the gut-derived mechanisms of AD and developing novel intervention strategies.Gut microbial metabolites serve as key messengers linking the gut and the brain, and their diversity in type and origin profoundly influences the neuroinflammatory process in AD.Those closely associated with AD neuroinflammation primarily include: shortchain fatty acids (SCFAs, such as acetic acid, propionic acid, and butyric acid); secondary bile acids (such as tauroursodeoxycholic acid); tryptophan metabolites (such as kynurenine, indole derivatives, and 5-HT precursors); and trimethylamine Noxide (TMAO).Correspondingly, in the progression of AD, the execution and regulation of neuroinflammation depend on multiple core protein signaling pathways, primarily including nuclear factor-𝜅B (NF-𝜅B), the NLRP3 inflammasome, signal transducer and activator of transcription 3 (STAT3), mitogen-activated protein kinase (MAPK) pathways, as well as the release networks of pro-inflammatory factors TNF-𝛼, IL-1 𝛽, and IL-6.