Vivek Philip1, Dwight F Newton2, Hyunjung Oh3, Stephen M Collins4, Premysl Bercik4, Etienne Sibille5. 1. Campbell Family Mental Health Research Institute, The Centre for Addiction and Mental Health, Toronto, Canada; Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada. 2. Campbell Family Mental Health Research Institute, The Centre for Addiction and Mental Health, Toronto, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada. 3. Campbell Family Mental Health Research Institute, The Centre for Addiction and Mental Health, Toronto, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada. 4. Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada. 5. Campbell Family Mental Health Research Institute, The Centre for Addiction and Mental Health, Toronto, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada. Electronic address: Etienne.sibille@camh.ca.
Abstract
BACKGROUND: Studies of germ-free (GF) mice demonstrate that gut microbiota can influence behaviour by modulating neurochemical pathways in the brain, and that bacterial colonization normalizes behavioural deficits in GF-mice. Since disrupted GABAergic and glutamatergic signaling are reported in mood disorders, this study investigated the effect of gut microbiota manipulations on EIB-relevant gene expression in the brain. METHODS: GF Swiss-Webster mice were colonized with E. coli JM83, complex microbiota (specific-pathogen-free; SPF), or no microbiota, and compared with controls (n = 6/group). 21 synaptic genes representing GABAergic, glutamatergic, BDNF, and astrocytic functions were measured in the hippocampus, amygdala, and prefrontal cortex using quantitative PCR. Gene co-expression analysis was used to identify gene modules related to colonization status, and compared by permutation analysis. Gene expression profiles were compared to existing post-mortem cohorts of depressed subjects (n = 28 cases vs 28 controls). RESULTS: Region-specific alterations in gene expression were observed in GF-mice compared to controls. 58% of all genes (14/24) altered in GF-mice were normalized following SPF-colonization. GF-mice displayed disorganization of gene co-expression networks in all three brain regions (hippocampus, p = 0.0003; amygdala, p = 0.0012; mPFC, p = 0.0069), which was restored by SPF colonization in hippocampus (p v.s. GF = 0.0003, p v.s. control = 0.60). The hippocampal gene expression profile in GF-mice was significantly correlated with that in human depression (ρ = 0.51, p = 0.027), and this correlation was not observed after colonization. CONCLUSION: Together, we show that the absence of gut microbiota disrupts the expression of EIB-relevant genes in mice, and colonization restores EIB-relevant expression, in ways that are relevant to human depression.
BACKGROUND: Studies of germ-free (GF) mice demonstrate that gut microbiota can influence behaviour by modulating neurochemical pathways in the brain, and that bacterial colonization normalizes behavioural deficits in GF-mice. Since disrupted GABAergic and glutamatergic signaling are reported in mood disorders, this study investigated the effect of gut microbiota manipulations on EIB-relevant gene expression in the brain. METHODS: GF Swiss-Webster mice were colonized with E. coli JM83, complex microbiota (specific-pathogen-free; SPF), or no microbiota, and compared with controls (n = 6/group). 21 synaptic genes representing GABAergic, glutamatergic, BDNF, and astrocytic functions were measured in the hippocampus, amygdala, and prefrontal cortex using quantitative PCR. Gene co-expression analysis was used to identify gene modules related to colonization status, and compared by permutation analysis. Gene expression profiles were compared to existing post-mortem cohorts of depressed subjects (n = 28 cases vs 28 controls). RESULTS: Region-specific alterations in gene expression were observed in GF-mice compared to controls. 58% of all genes (14/24) altered in GF-mice were normalized following SPF-colonization. GF-mice displayed disorganization of gene co-expression networks in all three brain regions (hippocampus, p = 0.0003; amygdala, p = 0.0012; mPFC, p = 0.0069), which was restored by SPF colonization in hippocampus (p v.s. GF = 0.0003, p v.s. control = 0.60). The hippocampal gene expression profile in GF-mice was significantly correlated with that in human depression (ρ = 0.51, p = 0.027), and this correlation was not observed after colonization. CONCLUSION: Together, we show that the absence of gut microbiota disrupts the expression of EIB-relevant genes in mice, and colonization restores EIB-relevant expression, in ways that are relevant to human depression.
Authors: Daniel Erny; Anna Lena Hrabě de Angelis; Diego Jaitin; Peter Wieghofer; Ori Staszewski; Eyal David; Hadas Keren-Shaul; Tanel Mahlakoiv; Kristin Jakobshagen; Thorsten Buch; Vera Schwierzeck; Olaf Utermöhlen; Eunyoung Chun; Wendy S Garrett; Kathy D McCoy; Andreas Diefenbach; Peter Staeheli; Bärbel Stecher; Ido Amit; Marco Prinz Journal: Nat Neurosci Date: 2015-06-01 Impact factor: 24.884
Authors: Coco Chu; Mitchell H Murdock; Deqiang Jing; Tae Hyung Won; Hattie Chung; Adam M Kressel; Tea Tsaava; Meghan E Addorisio; Gregory G Putzel; Lei Zhou; Nicholas J Bessman; Ruirong Yang; Saya Moriyama; Christopher N Parkhurst; Anfei Li; Heidi C Meyer; Fei Teng; Sangeeta S Chavan; Kevin J Tracey; Aviv Regev; Frank C Schroeder; Francis S Lee; Conor Liston; David Artis Journal: Nature Date: 2019-10-23 Impact factor: 49.962