Gut microbiome partially mediates and coordinates the effects of genetics on anxiety-like behavior in Collaborative Cross mice

X Jin,Y Xia,A M Snijders,Y Zhang,J.-H Mao,H Chang,S E Celniker

doi:10.1038/s41598-020-79538-x

Abstract

Growing evidence suggests that the gut microbiome (GM) plays a critical role in health and disease. However, the contribution of GM to psychiatric disorders, especially anxiety, remains unclear. We used the Collaborative Cross (CC) mouse population-based model to identify anxiety associated host genetic and GM factors. Anxiety-like behavior of 445 mice across 30 CC strains was measured using the light/dark box assay and documented by video. A custom tracking system was developed to quantify seven anxiety-related phenotypes based on video. Mice were assigned to a low or high anxiety group by consensus clustering using seven anxiety-related phenotypes. Genome-wide association analysis (GWAS) identified 141 genes (264 SNPs) significantly enriched for anxiety and depression related functions. In the same CC cohort, we measured GM composition and identified five families that differ between high and low anxiety mice. Anxiety level was predicted with 79% accuracy and an AUC of 0.81. Mediation analyses revealed that the genetic contribution to anxiety was partially mediated by the GM. Our findings indicate that GM partially mediates and coordinates the effects of genetics on anxiety.

Highlights

Growing evidence suggests that the gut microbiome (GM) plays a critical role in health and disease
Seven anxiety-related phenotypes were extracted from each video file: number of full and partial transitions between light and dark, speed, distance traveled and total time spent in the light compartment, average time spent in light for each transition and latency to first transition into the dark compartment (Table 1)
Correlation analysis between anxiety related phenotypes revealed several positive correlations including for example between total time spent in the light compartment and distance traveled in the light compartment (R=0.86; FDR

Summary

Introduction

Growing evidence suggests that the gut microbiome (GM) plays a critical role in health and disease. A recent large-scale GWAS among 12,655 individuals with various anxiety and stress-related diagnoses and 19,225 controls identified variants of the gene Phosphodiesterase 4B (PDE4B) encoding a protein that plays a role in signal transduction by regulating the cellular concentrations of cyclic n ucleotides[8] Altered activity of this protein has been associated with schizophrenia and bipolar affective disorder and with anxiety and stress-related disorder[9,10,11]. The fecal microbiome from patients with major depressive disorder could induce depression-like behaviors after transplantation in germ-free m ice[19] These studies indicate that the gut microbiome plays an important role in anxiety and depression-like disorders and highlight that this effect appears to be dependent on host genetics and environment[20,21]. The mechanisms behind the regulation and interventions of gut-brain communication and function remains largely unexplored

Methods

Results

Conclusion