The Metabolomic Mind: Microbial Metabolite Programming of Microglia.

The gut microbiota is increasingly recognized as a critical regulator of brain function, influencing neurodevelopment, adult brain physiology, and disease vulnerability in part through its interactions with microglia, the resident immune cells of the central nervous system. Emerging evidence demonstrates that microbial metabolites, beginning prenatally and persisting throughout the lifespan, regulate fundamental aspects of microglial biology including maturation, metabolic function, and activation. Microglia from germ-free mice exhibit persistent immaturity, altered energy metabolism, and blunted inflammatory responses, which are partially reversible by restoring microbial communities or supplementing key microbial metabolites. Short-chain fatty acids, tryptophan-derived indoles, and other bacterial metabolites derived from the gut microbiota shape microglial function to modulate neurons and synaptic architecture, and influence neuroinflammatory processes. These findings reveal distinct metabolite-driven pathways linking microbial composition to microglial phenotypes, positioning the microbiome as a potential key influencer of neurodevelopmental trajectories and the pathophysiology of psychiatric and neurological disorders. Despite recent advances, major knowledge gaps persist in understanding the precise molecular intermediaries and mechanisms through which metabolite signaling to microglia shape neural function to influence susceptibility or resilience to brain-based disorders. Understanding both the bacterial metabolomic landscape and its collective impact on microglial programming holds substantial therapeutic promise, offering avenues to target microbial metabolite production or administer them directly to modulate brain health.