Synthetic microbial communities: a novel emerging models for dissecting gut microbiota-host interactions in neurodegenerative diseases

The gut-brain axis (GBA) has emerged as a critical regulatory pathway underlying the pathogenesis of neurodegenerative diseases (NDs) such as Alzheimer’s disease and Parkinson’s disease. However, the high complexity and individual variability of native gut microbiotas hinder the precise elucidation of causal relationships between specific microbial taxa, their metabolites, and host neuroinflammatory or neurodegenerative processes. Synthetic microbial communities (SynComs), consisting of defined and reproducible bacterial strains, have recently emerged as powerful experimental models to overcome these limitations. This review summarizes the applications of SynComs in dissecting GBA crosstalk in NDs, highlighting their utility in validating key microbial mediators, deciphering molecular signaling pathways (e.g., microbial metabolite-brain barrier interactions, immune cell activation), and evaluating therapeutic strategies targeting the gut microbiota. By reducing community complexity while retaining core functional traits, SynComs enable controlled in vitro and in vivo studies that bridge the gap between observational microbiome profiling and mechanistic insights. Furthermore, the customization of SynComs allows for mimicking disease-specific microbial dysbiosis, facilitating the identification of novel therapeutic targets for NDs. Collectively, SynComs represent an innovative and standardized tool to advance our understanding of gut microbiota-host interactions in neurodegeneration and accelerate the development of microbiome-based interventions.