Mining microbes for mental health: Determining the role of microbial metabolic pathways in human brain health and disease

SimonSpichak^a,b,1,Thomaz F.S.Bastiaanssen^a,b,1, Kirsten Berding^a,b,1, Klara Vlckova^a,b,1, Gerard Clarke^b,c,1, Timothy G.Dinan^b,c,1, John F.Cryan^a,b,1

Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland.

Abstract

There is increasing knowledge regarding the role of the microbiome in modulating the brain and behaviour. Indeed, the actions of microbial metabolites are key for appropriate gut-brain communication in humans. Among these metabolites, short-chain fatty acids, tryptophan, and bile acid metabolites/pathways show strong preclinical evidence for involvement in various aspects of brain function and behaviour. With the identification of neuroactive gut-brain modules, new predictive tools can be applied to existing datasets. We identified 278 studies relating to the human microbiota-gut-brain axis which included sequencing data. This spanned across psychiatric and neurological disorders with a small number also focused on normal behavioural development. With a consistent bioinformatics pipeline, thirty-five of these datasets were reanalysed from publicly available raw sequencing files and the remainder summarised and collated. Among the reanalysed studies, we uncovered evidence of disease-related alterations in microbial metabolic pathways in Alzheimer’s Disease, schizophrenia, anxiety and depression. Amongst studies that could not be reanalysed, many sequencing and technical limitations hindered the discovery of specific biomarkers of microbes or metabolites conserved across studies. Future studies are warranted to confirm our findings. We also propose guidelines for future human microbiome analysis to increase reproducibility and consistency within the field.

Keywords: Microbiota, Brain, Enteric-nervous system, Short-chain fatty acids, Bile acid, Tryptophan, Indole, Psychiatry, Neurodegenerative disease, Diet.