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

Journal Article · · Scientific Reports
; ; ; ; ; ;

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.

Research Organization:
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Sponsoring Organization:
National Cancer Institute (NCI); National Institute of Environmental Health Sciences (NIEHS); National Institutes of Health (NIH); National Natural Science Foundation of China (NSFC); USDOE; USDOE Laboratory Directed Research and Development (LDRD) Program; USDOE Office of Science (SC), Biological and Environmental Research (BER)
Grant/Contract Number:
AC02-05CH11231
OSTI ID:
1756482
Journal Information:
Scientific Reports, Journal Name: Scientific Reports Journal Issue: 1 Vol. 11; ISSN 2045-2322
Publisher:
Nature Publishing GroupCopyright Statement
Country of Publication:
United Kingdom
Language:
English

References (59)

Genetic Variants Associated With Anxiety and Stress-Related Disorders: A Genome-Wide Association Study and Mouse-Model Study journal September 2019
Therapist-supported Internet cognitive behavioural therapy for anxiety disorders in adults journal March 2016
Measures of anxiety: State-Trait Anxiety Inventory (STAI), Beck Anxiety Inventory (BAI), and Hospital Anxiety and Depression Scale-Anxiety (HADS-A) journal November 2011
A systematic review of reviews on the prevalence of anxiety disorders in adult populations journal June 2016
Allele variants in functional MicroRNA target sites of the neurotrophin-3 receptor gene ( NTRK3 ) as susceptibility factors for anxiety disorders journal July 2009
The polymorphism architecture of mouse genetic resources elucidated using genome-wide resequencing data: implications for QTL discovery and systems genetics journal August 2007
Status and access to the Collaborative Cross population journal July 2012
Global Burden of Disease and the Impact of Mental and Addictive Disorders journal February 2019
Intestinal infection associated with future onset of an anxiety disorder: Results of a nationally representative study journal October 2016
Antibiotic-induced microbiota perturbation causes gut endocannabinoidome changes, hippocampal neuroglial reorganization and depression in mice journal January 2018
Features of emotional and social behavioral phenotypes of calsyntenin2 knockout mice journal August 2017
Targeting the Microbiota-Gut-Brain Axis: Prebiotics Have Anxiolytic and Antidepressant-like Effects and Reverse the Impact of Chronic Stress in Mice journal October 2017
Dorsal Amygdala Neurotrophin-3 Decreases Anxious Temperament in Primates journal December 2019
Association of Alterations in Intestinal Microbiota With Impaired Psychological Function in Patients With Inflammatory Bowel Diseases in Remission journal August 2020
The size and burden of mental disorders and other disorders of the brain in Europe 2010 journal September 2011
Association between fecal microbiota and generalized anxiety disorder: Severity and early treatment response journal December 2019
Association between gender, estrogen receptors genes and anxiety levels in patients undergoing orthognathic surgery journal August 2019
Corticosteroid-induced dendrite loss and behavioral deficiencies can be blocked by activation of Abl2/Arg kinase journal December 2017
Disturbance of the gut microbiota in early-life selectively affects visceral pain in adulthood without impacting cognitive or anxiety-related behaviors in male rats journal September 2014
Induction of anxiety-like behavior in mice during the initial stages of infection with the agent of murine colonic hyperplasia Citrobacter rodentium journal October 2006
Assessment of mouse anxiety-like behavior in the light–dark box and open-field arena: Role of equipment and procedure journal June 2014
The mouse light/dark box test journal February 2003
Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017 journal November 2018
Behavioral alterations in mice deficient for the extracellular matrix glycoprotein tenascin-R journal October 2003
An Outbreak of Acute Bacterial Gastroenteritis Is Associated With an Increased Incidence of Irritable Bowel Syndrome in Children journal January 2010
Gut microbiome remodeling induces depressive-like behaviors through a pathway mediated by the host’s metabolism journal April 2016
The Collaborative Cross, a community resource for the genetic analysis of complex traits journal January 2004
Influence of early life exposure, host genetics and diet on the mouse gut microbiome and metabolome journal November 2016
Anxiety disorders journal May 2017
Nucleus accumbens shell small conductance potassium channels underlie adolescent ethanol exposure-induced anxiety journal May 2019
Dlgap1 knockout mice exhibit alterations of the postsynaptic density and selective reductions in sociability journal February 2018
Identification of genetic factors that modify motor performance and body weight using Collaborative Cross mice journal November 2015
Genetic association of cyclic AMP signaling genes with bipolar disorder journal October 2012
A gene regulatory network in mouse embryonic stem cells journal October 2007
Normal gut microbiota modulates brain development and behavior journal January 2011
Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve journal August 2011
Central amygdala nucleus (Ce) gene expression linked to increased trait-like Ce metabolism and anxious temperament in young primates journal October 2012
The Collaborative Cross: A Recombinant Inbred Mouse Population for the Systems Genetic Era journal January 2011
The PDE4B gene confers sex-specific protection against schizophrenia journal January 2007
The Intestinal Microbiota in Acute Anorexia Nervosa and During Renourishment: Relationship to Depression, Anxiety, and Eating Disorder Psychopathology journal January 2015
Reduced anxiety-like behavior and central neurochemical change in germ-free mice: Behavior in germ-free mice journal November 2010
The anxiolytic effect of Bifidobacterium longum NCC3001 involves vagal pathways for gut-brain communication journal October 2011
Commensal microbiota modulate murine behaviors in a strictly contamination-free environment confirmed by culture-based methods journal March 2013
Improved Bacterial 16S rRNA Gene (V4 and V4-5) and Fungal Internal Transcribed Spacer Marker Gene Primers for Microbial Community Surveys journal December 2015
Exploring the genetics of irritable bowel syndrome: a GWA study in the general population and replication in multinational case-control cohorts journal September 2014
Diverse tumour susceptibility in Collaborative Cross mice: identification of a new mouse model for human gastric tumourigenesis journal March 2019
The Microbiota-Gut-Brain Axis journal October 2019
Diet and exercise orthogonally alter the gut microbiome and reveal independent associations with anxiety and cognition journal January 2014
Comprehensive behavioral analysis of mice deficient in Rapgef2 and Rapgef6, a subfamily of guanine nucleotide exchange factors for Rap small GTPases possessing the Ras/Rap-associating domain journal May 2018
Host genetic variation in mucosal immunity pathways influences the upper airway microbiome journal February 2017
Viruses in the Built Environment (VIBE) meeting report journal January 2020
Genetic and metabolic links between the murine microbiome and memory journal April 2020
SCA-12: Tremor with cerebellar and cortical atrophy is associated with a CAG repeat expansion journal February 2001
Modeling Host Genetic Regulation of Influenza Pathogenesis in the Collaborative Cross journal February 2013
Dual role of T-type calcium channels in anxiety-related behavior journal October 2019
Csmd2 Is a Synaptic Transmembrane Protein that Interacts with PSD-95 and Is Required for Neuronal Maturation journal March 2019
The LIM-Homeobox Gene Islet-1 Is Required for the Development of Restricted Forebrain Cholinergic Neurons journal March 2008
A cross-species genetic analysis identifies candidate genes for mouse anxiety and human bipolar disorder journal July 2015
Gut-Brain Psychology: Rethinking Psychology From the Microbiota–Gut–Brain Axis journal September 2018

Similar Records

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
Behavioural genetics
Microbiome