Chakraborty, M.; Shi, S. M.; Porter, I. E.; Richard, D. J.; Marinov, G. K.; Moore, A. A.; Blum, J. L. E.; Natarajan, A.; Jahng, J. W.; Wu, J. C.; Lu, S. X.; Davidson, S. M.; Greenleaf, W. J.; Saw, N. L.; Shamloo, M.; Brunet, A.; Wyss-Coray, T.; Bhatt, A. S.

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. Taken together, this work identifies microbiome-derived signals relevant to age-related neurodegeneration, and defines a scalable framework for linking microbiome metabolites to host pathologies.