Gastroenterology

Gastroenterology

Volume 139, Issue 6, December 2010, Pages 2102-2112.e1
Gastroenterology

Basic—Alimentary Tract
Chronic Gastrointestinal Inflammation Induces Anxiety-Like Behavior and Alters Central Nervous System Biochemistry in Mice

https://doi.org/10.1053/j.gastro.2010.06.063Get rights and content

Background & Aims

Clinical and preclinical studies have associated gastrointestinal inflammation and infection with altered behavior. We investigated whether chronic gut inflammation alters behavior and brain biochemistry and examined underlying mechanisms.

Methods

AKR mice were infected with the noninvasive parasite Trichuris muris and given etanercept, budesonide, or specific probiotics. Subdiaphragmatic vagotomy was performed in a subgroup of mice before infection. Gastrointestinal inflammation was assessed by histology and quantification of myeloperoxidase activity. Serum proteins were measured by proteomic analysis, circulating cytokines were measured by fluorescence activated cell sorting array, and serum tryptophan and kynurenine were measured by liquid chromatography. Behavior was assessed using light/dark preference and step-down tests. In situ hybridization was used to assess brain-derived neurotrophic factor (BDNF) expression in the brain.

Results

T muris caused mild to moderate colonic inflammation and anxiety-like behavior that was associated with decreased hippocampal BDNF messenger RNA (mRNA). Circulating tumor necrosis factor-α and interferon-γ, as well as the kynurenine and kynurenine/tryptophan ratio, were increased. Proteomic analysis showed altered levels of several proteins related to inflammation and neural function. Administration of etanercept, and to a lesser degree of budesonide, normalized behavior, reduced cytokine and kynurenine levels, but did not influence BDNF expression. The probiotic Bifidobacterium longum normalized behavior and BDNF mRNA but did not affect cytokine or kynurenine levels. Anxiety-like behavior was present in infected mice after vagotomy.

Conclusions

Chronic gastrointestinal inflammation induces anxiety-like behavior and alters central nervous system biochemistry, which can be normalized by inflammation-dependent and -independent mechanisms, neither of which requires the integrity of the vagus nerve.

Section snippets

Animals

Male BALB/c or AKR mice (Harlan, Mississauga, ON, Canada) were purchased at the age of 6–8 weeks and housed in a conventional specific pathogen-free unit at McMaster University Central Animal Facility. All experiments were conducted in accordance with the guidelines of the Canadian Council on Animal Care and received approval from the McMaster University Animal Research Ethics Board. A group of mice (n = 24) underwent subdiaphragmatic vagotomy, as described previously.31 Briefly, after

Assessment of Inflammation

T muris infection induced mild to moderate chronic colitis affecting mainly the cecum and the proximal colon. Macroscopically, the cecum appeared edematous with mild erythema, but no ulcers or erosions were noted. MPO values in infected mice treated with placebo were significantly higher compared with uninfected controls (Figure 1). The chronic inflammatory infiltrate was increased in infected mice compared with controls. Treatment with etanercept or budesonide tended to decrease MPO values and

Discussion

We show that chronic infection associated with mild gut inflammation caused by the noninvasive parasite T muris induces anxiety-like behavior in mice. Chronic inflammation was modest in severity and was not associated with macroscopic tissue damage such as ulceration. We show that abnormal behavior in T muris colitis was associated with decreased levels of hippocampal BDNF. Circulating proinflammatory cytokines and kynurenine were mildly, but significantly, increased and proteomic analysis

Acknowledgments

The authors are grateful to Mrs Jeannette Pearce for the technical support.

P.B. and E.F.V. contributed equally to this manuscript.

References (59)

  • L.E. Goehler et al.

    Activation in vagal afferents and central autonomic pathways: early responses to intestinal infection with Campylobacter jejuni

    Brain Behav Immun

    (2005)
  • J.E. Ghia et al.

    The vagus nerve: a tonic inhibitory influence associated with inflammatory bowel disease in a murine model

    Gastroenterology

    (2006)
  • E.F. Verdú et al.

    Lactobacillus paracasei normalizes muscle hypercontractility in a murine model of postinfective gut dysfunction

    Gastroenterology

    (2004)
  • M. Bourin et al.

    The mouse light/dark box test

    Eur J Pharmacol

    (2003)
  • P. Bercík et al.

    Immune-mediated neural dysfunction in a murine model of chronic Helicobacter pylori infection

    Gastroenterology

    (2002)
  • P. Bercík et al.

    Visceral hyperalgesia and intestinal dysmotility in a mouse model of postinfective gut dysfunction

    Gastroenterology

    (2004)
  • K. Kato et al.

    Serine proteinase inhibitor 3 and murinoglobulin I are potent inhibitors of neuropsin in adult mouse brain

    J Biol Chem

    (2001)
  • M. Maes et al.

    Lower serum vitamin E concentrations in major depressionAnother marker of lowered antioxidant defenses in that illness

    J Affect Disord

    (2000)
  • M.B. Heaton et al.

    Ethanol-induced reduction of neurotrophin secretion in neonatal rat cerebellar granule cells is mitigated by vitamin E

    Neurosci Lett

    (2004)
  • L. Desbonnet et al.

    The probiotic Bifidobacteria infantis: an assessment of potential antidepressant properties in the rat

    J Psychiatr Res

    (2008)
  • R.S. Duman et al.

    A neurotrophic model for stress-related mood disorders

    Biol Psychiatry

    (2006)
  • D.T. Balu et al.

    Differential regulation of central BDNF protein levels by antidepressant and non-antidepressant drug treatments

    Brain Res

    (2008)
  • S.M. Collins et al.

    The relationship between intestinal microbiota and the central nervous system in normal gastrointestinal function and disease

    Gastroenterology

    (2009)
  • A.C. Logan et al.

    Major depressive disorder: probiotics may be an adjuvant therapy

    Med Hypotheses

    (2005)
  • A.K. Varghese et al.

    Antidepressants attenuate increased susceptibility to colitis in a murine model of depression

    Gastroenterology

    (2006)
  • Y. Lecrubier et al.

    Panic and depression: a worldwide primary care perspective

    Int Clin Psychopharmacol

    (1998)
  • R.C. Kessler et al.

    Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication

    Arch Gen Psychiatry

    (2005)
  • N. Frasure-Smith et al.

    Depression and coronary artery disease

    Herz

    (2006)
  • T.O. Bruce

    Comorbid depression in rheumatoid arthritis: pathophysiology and clinical implications

    Curr Psychiatry Rep

    (2008)
  • Cited by (530)

    • Altering the Gut Microbiome for Cognitive Benefit

      2024, The Gut-Brain Axis, Second Edition
    View all citing articles on Scopus

    Conflicts of interest These authors disclose the following: Drs Corthesy-Theulaz, Cherbut, and Bergonzelli are employees of Nestle, Switzerland. The remaining authors disclose no conflicts.

    Funding This work was supported by grants from Canadian Institutes of Health Research (S.M.C., P.B.), Nestle (S.M.C., E.F.V.), Crohn's & Colitis Foundation of Canada (P.B., S.M.C.), and Advanced Foods and Materials Network (S.M.C., P.B., E.F.V.). E. F. Verdu is partially supported by grants from Canadian Association of Gastroenterology/CIHR. P. Bercik and E. F. Verdu hold Internal Career Awards by the Department of Internal Medicine, McMaster University.

    View full text