Mapping the human brain metabolome and influences of gut microbiome

Abstract

AbstractBackgroundThere is compelling evidence implying critical role of gut‐brain axis in neuropsychiatric diseases including Alzheimer’s disease (AD). Consequently, microbially‐derived metabolites, e.g., secondary bile acids, have been shown to be altered in blood, faecal and brain tissues of AD patients. The presence of these microbially‐derived products in brain suggests that gut metabolites can cross the blood brain barrier and modify brain function. Yet it remains challenging to disentangle human and microbial contributions to the brain metabolome and to link microbial metabolites back to species of origin.MethodBased on a literature review effort, a database of over 500 metabolites was manually curated, including microbial metabolites of endogenous and exogenous compounds, as well as their human‐biotransformed products, and health‐reporting compounds which are related to CNS diseases. Human brains (n=514; dorsolateral prefrontal cortex) from the ROSMAP cohort were profiled on the Metabolon TD4 non‐targeted metabolomics platform which measured 1,055 metabolites. Here, by combining the curated database and the metabolic profiling data from the ROSMAP brains, we built a new database of metabolites found in the human brain. In addition, metabolites from both efforts were mapped to the global human reconstruction, Recon3D, and to a resource of 7,206 human microbial reconstructions, AGORA2.Result667 (63.2%) metabolites were retained after filtering out metabolites for high missing values. Of these metabolites, 254 were mapped onto genome‐scale metabolic reconstructions (Recon3D and AGORA2) with 67 being found only in human, 13 only in microbes, and 174 in both human and microbes. 12 additional metabolites were of microbial or mainly microbial origin according to our in‐house database. Many of these (13+12) metabolites were associated (adjusted p‐value <0.05) with AD clinical phenotypes including clinical diagnosis at time of death, AD pathology, and cognitive decline.ConclusionWe developed a database of the human brain metabolome with comprehensive annotations of human and microbial metabolic networks, ranked in order of importance. The human brain database will be a valuable tool for researchers to define metabolic aberrances in Alzheimer’s disease and the contribution of the gut microbiome, genome, and life style influences on brain metabolic states in health and disease.