Age-related microbiome metabolites alter RNA splicing and chromatin accessibility in the brain

The gut microbiome generates diverse metabolites that can enter the bloodstream and alter host biology, including brain function. Hundreds of physiologically relevant, gut-brain signaling molecules likely exist; however, there has been no systematic, high-throughput effort to identify and validate them. Here, we integrate computational, in vitro, and in vivo approaches to pinpoint microbiome-derived metabolites whose blood levels change during aging, and that induce corresponding changes in the mouse brain. First, we mine large-scale metabolomics datasets from human cohorts (each n [≥] 1200) to identify 30 microbiome-associated metabolites whose blood levels change with age. We then screen this panel in an in vitro transcriptomic assay to identify metabolites that perturb genes linked to age-related neurodegeneration. We then test four metabolites in an acute-exposure mouse model, and use multi-omic approaches to evaluate their impact on cellular functions in the brain. We confirm the known neurodegeneration-promoting effects of trimethylamine N-oxide (TMAO), including mitochondrial dysfunction, and further discover its disruptive impact on the pathways of glycolysis, GABAergic signaling, and RNA splicing. Additionally, we identify glycodeoxycholic acid (GDCA), a microbiome-derived secondary bile acid, as a potent regulator of chromatin accessibility and suppressor of genes that protect the brain from age-related, neurodegeneration-promoting insults. GDCA also acutely reduces mobility. In summary, we present a scalable framework for linking microbiome metabolites to host pathologies, and apply it to identify microbial metabolites that induce molecular changes related to neurodegeneration.