Deciphering the role of microbially-derived metabolites on the microbiota-gut-brain axis

Abstract

The trillions of microbial organisms residing in the gut, microbiota, are now recognized as major modulators of physiology and health, quickly becoming one of the most exciting emerging areas in neuroscience. Preclinical and clinical research alike suggests that the metabolites produced by these gut microbes modulate brain, behavior and disease. Short-chain fatty acids, tryptophan metabolites and bile acids are promising targets for new microbiome-based therapies. But, little is known about their mechanisms. To this end, the second chapter of the thesis collates 278 studies relating to the human microbiota-gut-brain axis, identifying trends and technical/bioinformatics limitations. These studies across different disorders of the brain as well as healthy human behavioral functions. Then a 35 of these studies was reanalyzed with an up-to-date bioinformatics pipeline. New tools, mainly the gut-brain modules provide a predictive framework for identifying whether these gut microbial metabolic pathways are dysregulated in brain diseases and disorders. We uncovered evidence of disease-related alterations in microbial metabolic pathways in Alzheimer’s Disease, schizophrenia, anxiety and depression. Previous human studies suggest that astrocyte immunity and metabolism is affected by short-chain fatty acids. Thus we grew primary male and female mouse astrocyte cultures, treating them with acetate, butyrate and propionate. Butyrate treatment (0 – 25μM) increased gene expression of Bdnf and Pgc1-α expression, implicating histone-deacetylase inhibitor pathways only in female cells. Acetate (0 – 1500 μM) positively correlated with Ahr and Gfap expression in males, suggesting an immune modulatory role. These findings show a novel sex-dependent impact of acetate and butyrate, but not propionate on astrocyte gene expression. These studies increase understanding of microbial metabolites and how they might impact the brain. It also provides guidance to improve and direct future investigations aimed at identifying the mechanisms of other metabolites.