Role of microbes in the pathogenesis of neuropsychiatric disorders

Highlights

• The human microbiome in the context of psychiatric disorders is an emerging field of study.

• The gut-brain axis has been associated with several neuropsychiatric disorders.

• Oral and skin microbiome could affect mental health via inflammatory pathways.

• Large samples and appropriate designs are needed to verify the microbiome-brain association.

Abstract

Microbes inhabit different anatomical sites of the human body including oral cavity, gut, and skin. A growing literature highlights how microbiome variation is associated with human health and disease. There is strong evidence of bidirectional communication between gut and brain mediated by neurotransmitters and microbial metabolites. Here, we review the potential involvement of microbes residing in the gut and in other body sites in the pathogenesis of eight neuropsychiatric disorders, discussing findings from animal and human studies. The data reported provide a comprehensive overview of the current state of the microbiome research in neuropsychiatry, including hypotheses about the mechanisms underlying the associations reported and the translational potential of probiotics and prebiotics.

Introduction

Microbes reside in the human body and not all of them are necessarily harmful. Their presence/absence and balance/imbalance are associated with health and disease. Some microbes are beneficial and their diversity across human body sites contributes to the overall health status of an individual (Lloyd-Price et al., 2016, Gevers et al., 2012). Fluctuations in the relative diversity and composition of the microbiome across the human body are hypothesized to affect the risk of several diseases, including inflammatory bowel disease (IBD) (Glassner et al., 2020), cancer (Bhatt et al., 2017), and immunological disorders (Belkaid and Hand, 2014).

There is considerable literature supporting the association between human microbiome variation and mental health, also including several review articles focused on specific disorders or specific mental health domains, such as depression (Marx et al., 2021, Bastiaanssen et al., 2020, Cruz-Pereira et al., 2020), mood disorders (Margolis et al., 2021, Cruz-Pereira and Cryan, 2020), neurodegenerative disorders (Cryan et al., 2020), and neurodevelopment (Cowan et al., 2020). However, to our knowledge, a review presenting the current state of microbiome research across multiple neuropsychiatric disorders and different body sites is missing. The current article aims to provide a compendium of the current state of human microbiome research across the neuropsychiatric spectrum to help investigators with different expertise to understand the evidence available to date. We include an initial overview of three microbiome domains (gut, mouth, and skin; Fig. 1) and then review findings specifically related to eight neuropsychiatric disorders (Alzheimer’s disease, attention deficit hyperactivity disorder, anorexia nervosa, autism spectrum disorder, bipolar disorder, major depressive disorder, schizophrenia, and substance use disorders; Table 1). Due to size constraints, we decided to focus on those psychiatric disorders that were investigated by numerous studies or that were not reviewed previously.

The studies reviewed were conducted using a wide range of different methods and designs. For example, diversity metrics include several measures of alpha diversity (e.g., the Shannon index assumes the observed abundances reflect random sampling of the microbiome and thus is maximized when abundances increase evenly across all taxonomic units; the Simpson index gives more weight to highly abundant taxanomic groups and is less influenced by very low abundance organisms; the Chao1 index uses a Poisson distribution to estimates the number of taxa in a sample by extrapolating the number of rare organisms that may have been missed due to under-sampling; rarefaction assesses species richness through construction of rarefaction curves). Beta diversity reflects a comparison of abundances between two microbiome samples (e.g., Jaccard distance is measures similarity in the presence or absence of taxonomic groups without regard to abundance; Bray–Curtis dissimilarity measures the differences in abundances of each taxonomic units; Unweighted UniFrac is the distance between two samples by calculating the fraction of the branch length in a phylogenetic tree that leads to descendants) (Ashton et al., 2016). Because analytic variability undermines comparison between studies and contributes to the lack of reproducibility among microbiome studies, investigators have highlighted the need for establishing standards for microbiome analysis and interpretation (Morton et al., 2019, Sczyrba et al., 2017). Due to the difficulty of comparing results that used different statistics, we decide to compare the finding of the studies reviewed relying on the interpretation made by the authors.