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PMID: 21876150 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve.

Bravo JA, Forsythe P, Chew MV, Escaravage E, Savignac HM, Dinan TG, Bienenstock J, Cryan JF

Abstract

There is increasing, but largely indirect, evidence pointing to an effect of commensal gut microbiota on the central nervous system (CNS). However, it is unknown whether lactic acid bacteria such as Lactobacillus rhamnosus could have a direct effect on neurotransmitter receptors in the CNS in normal, healthy animals. GABA is the main CNS inhibitory neurotransmitter and is significantly involved in regulating many physiological and psychological processes. Alterations in central GABA receptor expression are implicated in the pathogenesis of anxiety and depression, which are highly comorbid with functional bowel disorders. In this work, we show that chronic treatment with L. rhamnosus (JB-1) induced region-dependent alterations in GABA(B1b) mRNA in the brain with increases in cortical regions (cingulate and prelimbic) and concomitant reductions in expression in the hippocampus, amygdala, and locus coeruleus, in comparison with control-fed mice. In addition, L. rhamnosus (JB-1) reduced GABA(Aα2) mRNA expression in the prefrontal cortex and amygdala, but increased GABA(Aα2) in the hippocampus. Importantly, L. rhamnosus (JB-1) reduced stress-induced corticosterone and anxiety- and depression-related behavior. Moreover, the neurochemical and behavioral effects were not found in vagotomized mice, identifying the vagus as a major modulatory constitutive communication pathway between the bacteria exposed to the gut and the brain. Together, these findings highlight the important role of bacteria in the bidirectional communication of the gut-brain axis and suggest that certain organisms may prove to be useful therapeutic adjuncts in stress-related disorders such as anxiety and depression.

MeSH Terms
Amplified Fragment Length Polymorphism Analysis Animals Anxiety/physiopathology Brain/metabolism,physiopathology Corticosterone/blood DNA, Bacterial/genetics Depression/physiopathology Emotions/physiology Fever/blood,microbiology,physiopathology Gene Expression Host-Pathogen Interactions In Situ Hybridization Lactobacillus/genetics,physiology Male Maze Learning/physiology Mice Mice, Inbred BALB C Motor Activity/physiology RNA, Messenger/genetics,metabolism Receptors, GABA/genetics Receptors, GABA-A/genetics Receptors, GABA-B/genetics Species Specificity Vagotomy Vagus Nerve/physiology,surgery
Chemicals
DNA, Bacterial GABA type B receptor, subunit 1 RNA, Messenger Receptors, GABA Receptors, GABA-A Receptors, GABA-B Corticosterone
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Bravo Javier A
Laboratory of NeuroGastroenterology, Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland.
Forsythe Paul
Chew Marianne V
Escaravage Emily
Savignac Hélène M
Dinan Timothy G
Bienenstock John
Cryan John F
References (47)
47 references, click to expand
  1. Inhibitory effects of Lactobacillus reuteri on visceral pain induced by colorectal distension in Sprague-Dawley rats.
    Gut. 2006 Feb;55(2):191-6 PMID: 16361309
  2. The significance of glucocorticoid pulsatility.
    Eur J Pharmacol. 2008 Apr 7;583(2-3):255-62 PMID: 18339373
  3. Analysis of GABAA receptor function and dissection of the pharmacology of benzodiazepines and general anesthetics through mouse genetics.
    Annu Rev Pharmacol Toxicol. 2004;44:475-98 PMID: 14744255
  4. Chronic gastrointestinal inflammation induces anxiety-like behavior and alters central nervous system biochemistry in mice.
    Gastroenterology. 2010 Dec;139(6):2102-2112.e1 PMID: 20600016
  5. Lactobacillus acidophilus modulates intestinal pain and induces opioid and cannabinoid receptors.
    Nat Med. 2007 Jan;13(1):35-7 PMID: 17159985
  6. Evidence for a role of GABAA receptor in the acute restraint stress-induced enhancement of spatial memory.
    Brain Res. 2007 Nov 21;1181:61-73 PMID: 17916335
  7. Mood and gut feelings.
    Brain Behav Immun. 2010 Jan;24(1):9-16 PMID: 19481599
  8. Efficacy of vagus nerve stimulation in the treatment of depression.
    Expert Rev Neurother. 2010 Jan;10(1):87-92 PMID: 20021323
  9. Activation in vagal afferents and central autonomic pathways: early responses to intestinal infection with Campylobacter jejuni.
    Brain Behav Immun. 2005 Jul;19(4):334-44 PMID: 15944073
  10. Decreased GABAA-receptor clustering results in enhanced anxiety and a bias for threat cues.
    Nat Neurosci. 1999 Sep;2(9):833-9 PMID: 10461223
  11. Don't worry 'B' happy!: a role for GABA(B) receptors in anxiety and depression.
    Trends Pharmacol Sci. 2005 Jan;26(1):36-43 PMID: 15629203
  12. Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning.
    Behav Neurosci. 1992 Apr;106(2):274-85 PMID: 1590953
  13. Assessment of psychotropic-like properties of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in rats and human subjects.
    Br J Nutr. 2011 Mar;105(5):755-64 PMID: 20974015
  14. Bacterial infection causes stress-induced memory dysfunction in mice.
    Gut. 2011 Mar;60(3):307-17 PMID: 20966022
  15. Alterations in the central CRF system of two different rat models of comorbid depression and functional gastrointestinal disorders.
    Int J Neuropsychopharmacol. 2011 Jun;14(5):666-83 PMID: 20860876
  16. Vagus nerve stimulation potentiates hippocampal LTP in freely-moving rats.
    Physiol Behav. 2007 Mar 16;90(4):583-9 PMID: 17207505
  17. Validation of open:closed arm entries in an elevated plus-maze as a measure of anxiety in the rat.
    J Neurosci Methods. 1985 Aug;14(3):149-67 PMID: 2864480
  18. Induction of anxiety-like behavior in mice during the initial stages of infection with the agent of murine colonic hyperplasia Citrobacter rodentium.
    Physiol Behav. 2006 Oct 30;89(3):350-7 PMID: 16887154
  19. VNS therapy in treatment-resistant depression: clinical evidence and putative neurobiological mechanisms.
    Neuropsychopharmacology. 2006 Jul;31(7):1345-55 PMID: 16641939
  20. Lactobacillus reuteri-induced regulatory T cells protect against an allergic airway response in mice.
    Am J Respir Crit Care Med. 2009 Feb 1;179(3):186-93 PMID: 19029003
  21. Specific roles of GABA(B(1)) receptor isoforms in cognition.
    Behav Brain Res. 2007 Jul 19;181(1):158-62 PMID: 17498817
  22. Luminal administration ex vivo of a live Lactobacillus species moderates mouse jejunal motility within minutes.
    FASEB J. 2010 Oct;24(10):4078-88 PMID: 20519636
  23. The alpha1 subunit of the GABA(A) receptor modulates fear learning and plasticity in the lateral amygdala.
    Front Behav Neurosci. 2009 Oct 20;3:37 PMID: 19876409
  24. Lactobacillus reuteri ingestion prevents hyperexcitability of colonic DRG neurons induced by noxious stimuli.
    Am J Physiol Gastrointest Liver Physiol. 2009 Apr;296(4):G868-75 PMID: 19179624
  25. GABA(B(1)) receptor isoforms differentially mediate the acquisition and extinction of aversive taste memories.
    J Neurosci. 2006 Aug 23;26(34):8800-3 PMID: 16928868
  26. GABAB receptor antagonist SGS742 improves spatial memory and reduces protein binding to the cAMP response element (CRE) in the hippocampus.
    Neuropharmacology. 2005 Jun;48(7):956-64 PMID: 15857622
  27. Frequency and severity of the symptoms of irritable bowel syndrome across the anxiety disorders and depression.
    J Anxiety Disord. 2009 Mar;23(2):290-6 PMID: 18819774
  28. Genetics of mouse behavior: interactions with laboratory environment.
    Science. 1999 Jun 4;284(5420):1670-2 PMID: 10356397
  29. cAMP response element-binding protein is essential for the upregulation of brain-derived neurotrophic factor transcription, but not the behavioral or endocrine responses to antidepressant drugs.
    J Neurosci. 2002 Apr 15;22(8):3262-8 PMID: 11943827
  30. Live Lactobacillus rhamnosus [corrected] is essential for the inhibitory effect on tumor necrosis factor alpha-induced interleukin-8 expression.
    Infect Immun. 2004 Sep;72(9):5308-14 PMID: 15322027
  31. Juvenile stress-induced alteration of maturation of the GABAA receptor alpha subunit in the rat.
    Int J Neuropsychopharmacol. 2008 Nov;11(7):891-903 PMID: 18364065
  32. Probiotics and the gut microbiota in intestinal health and disease.
    Nat Rev Gastroenterol Hepatol. 2010 Sep;7(9):503-14 PMID: 20664519
  33. Protective effects of Lactobacillus rhamnosus [corrected] and Bifidobacterium infantis in murine models for colitis do not involve the vagus nerve.
    Am J Physiol Regul Integr Comp Physiol. 2008 Oct;295(4):R1131-7 PMID: 18667710
  34. The microbiome-gut-brain axis: from bowel to behavior.
    Neurogastroenterol Motil. 2011 Mar;23(3):187-92 PMID: 21303428
  35. Sustained conditioned responses in prelimbic prefrontal neurons are correlated with fear expression and extinction failure.
    J Neurosci. 2009 Jul 1;29(26):8474-82 PMID: 19571138
  36. Probiotic treatment of rat pups normalises corticosterone release and ameliorates colonic dysfunction induced by maternal separation.
    Gut. 2007 Nov;56(11):1522-8 PMID: 17339238
  37. Corticosterone facilitates extinction of fear memory in BALB/c mice but strengthens cue related fear in C57BL/6 mice.
    Exp Neurol. 2009 Apr;216(2):375-82 PMID: 19162011
  38. Principles and clinical implications of the brain-gut-enteric microbiota axis.
    Nat Rev Gastroenterol Hepatol. 2009 May;6(5):306-14 PMID: 19404271
  39. Reduced anxiety-like behavior and central neurochemical change in germ-free mice.
    Neurogastroenterol Motil. 2011 Mar;23(3):255-64, e119 PMID: 21054680
  40. Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice.
    J Physiol. 2004 Jul 1;558(Pt 1):263-75 PMID: 15133062
  41. Lactobacillus and bifidobacterium in irritable bowel syndrome: symptom responses and relationship to cytokine profiles.
    Gastroenterology. 2005 Mar;128(3):541-51 PMID: 15765388
  42. A randomized, double-blind, placebo-controlled pilot study of a probiotic in emotional symptoms of chronic fatigue syndrome.
    Gut Pathog. 2009 Mar 19;1(1):6 PMID: 19338686
  43. Behavioral evaluation of mice deficient in GABA(B(1)) receptor isoforms in tests of unconditioned anxiety.
    Psychopharmacology (Berl). 2007 Mar;190(4):541-53 PMID: 17171558
  44. GABAB receptor antagonist-mediated antidepressant-like behavior is serotonin-dependent.
    J Pharmacol Exp Ther. 2005 Jan;312(1):290-6 PMID: 15333677
  45. Early life stress alters behavior, immunity, and microbiota in rats: implications for irritable bowel syndrome and psychiatric illnesses.
    Biol Psychiatry. 2009 Feb 1;65(3):263-7 PMID: 18723164
  46. Normal gut microbiota modulates brain development and behavior.
    Proc Natl Acad Sci U S A. 2011 Feb 15;108(7):3047-52 PMID: 21282636
  47. Clinical trial: the effects of a trans-galactooligosaccharide prebiotic on faecal microbiota and symptoms in irritable bowel syndrome.
    Aliment Pharmacol Ther. 2009 Mar 1;29(5):508-18 PMID: 19053980
Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
1091-6490
Published
2011-09-20
Epub
2011-00-29
Pages
16050-5
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC3179073
Subset
IM
Corrections
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