Gut microbiome‐related metabolites in plasma are associated with general cognition

Abstract

AbstractBackgroundIncreasing evidence suggests a role for gut microbiome in pathogenesis of neurological disorders including Alzheimer’s disease. Gut bacteria produce a large number of metabolites that become part of the human blood metabolome. We hypothesized that the effect of gut microbiome on Alzheimer’s disease is through certain metabolites derived or influenced by the gut microbiota. Identifying metabolites associated with gut microbiota as well as with general cognition may help to discover new targets for drugs and prevention.MethodWe profiled plasma samples of 1146 participants of the Rotterdam study for 1387 metabolites using a non‐targeted metabolomics platform. After preprocessing and quality control, plasma levels of 964 metabolites were available for analysis of 1040 participants. Gut microbiome information was available for participants based on 16sRNA sequencing (microbial taxa = 190). We evaluated the gut‐microbial association with metabolite levels in plasma using linear regression adjusting for age, sex, body mass index, medication use, and technical covariates. We further assessed these gut microbiota associated metabolites for association of metabolites with general cognition (G‐factor) using linear regression. Multiple testing correction was performed based on the false discovery rate (FDR) by Benjamini Hochberg (FDR<0.05).ResultWe found significant association of 400 metabolites (Grouped into xenobiotics, lipids, amino acids, peptides, co‐factor and vitamins, carbohydrates, energy and partially characterized molecules) with various gut microbial taxa. Among the gut‐microbiota‐associated metabolites, eleven also showed significant associations with general cognition after multiple testing. Among these associations, higher ergothioneine (xenobiotic) levels showed the most significant association with better cognition (β = 0.012, P = 6.40x10‐7). Ergothioneine showed significant association with genus RuminococcaceaeUCG003 (id 11361) (β = 0.064, P = 5.94x10‐5) and genus Romboutsia (id 11347) (β = 0.042, P = 1.98x10‐4), suggesting an implication of these genera in cognitive function mediated by ergothioneine.ConclusionOur study provides evidence for the association between gut microbiota and plasma metabolites of diverse biochemical groups, which also associates with cognition in a population‐based cohort. Further, studies are warranted to elucidate the complex relationship of gut microbiota, diet, genome, human metabolome, and cognition.