Gut-microbiota-microglia-brain interactions in Alzheimer's disease: knowledge-based, multi-dimensional...

Area of Science:

• Neuroscience
• Microbiology
• Genetics

Background:

• The gut microbiota, microglia, and aging are implicated in Alzheimer's disease (AD) pathogenesis.
• The precise mechanisms linking these factors in AD remain largely unknown.

Purpose of the Study:

• To elucidate the complex interactions among microbial metabolites, microglia, and AD.
• To develop a systems biology approach for identifying mechanistic links in AD.

Main Methods:

• Developed an integrated, knowledge-driven pipeline to construct a microbial metabolite-gene-pathway-phenotype network (MGPPN).
• Utilized publicly available datasets and a network-based ranking algorithm to identify AD-associated interactions.
• Analyzed genetic and phenotypic data to evaluate the association between microglia function and AD pathology.

Main Results:

• The network comprised 34,509 nodes and 1,032,942 edges, revealing significant associations between AD risk genes/phenotypes and microglia function.
• Identified 8094 interactions involving microglia, microbial metabolites, genes, pathways, and phenotypes relevant to AD.
• Short-chain fatty acids (SCFAs) emerged as top-ranked microbial metabolites associated with AD, demonstrating their role in microglia-mediated gut-microbiota-brain interactions.

Conclusions:

• The study presents a novel framework for understanding the mechanistic links between gut microbial metabolites, microglia, and AD.
• Findings facilitate disease mechanism comprehension, therapeutic target identification, and guide future experimental studies in AD.