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

Department of Psychology, University of Virginia, Charlottesville, VA 22904, United States.
Brain Behavior and Immunity (Impact Factor: 5.89). 08/2005; 19(4):334-44. DOI: 10.1016/j.bbi.2004.09.002
Source: PubMed


Abundant evidence now supports the idea that multiple pathways or mechanisms underlie communication from the immune system to the brain. The presence of a variety of mechanisms suggests that they may each contribute something different to immunosensory signaling. For instance, brain mediated immune signal transduction is dependent upon the presence of circulating mediators whereas peripheral sensory nerves are more likely to be important early on in an infection, prior to elevation of circulating cytokines, or in local infections within the terminal fields of these nerves. To test the hypothesis that local infection in the gut activates vagal sensory neurons, we assessed expression of the neuronal activation marker c-Fos in neurons in the vagal sensory ganglia and in the primary sensory relay nucleus for the vagus, the nucleus of the solitary tract (nTS) in mice treated orally either with saline or live Campylobacter jejuni (C. jejuni). Male CF1 mice were inoculated orally with either C. jejuni or saline, and c-Fos expression in the vagal sensory neurons and brain 4-12 h later was assessed via immunohistochemistry. Oral inoculation with C. jejuni led to a significant increase in c-Fos expression in neurons bilaterally in the vagal ganglia, in the absence of elevated levels of circulating pro-inflammatory cytokines. C. jejuni treatment activated neurons in the nTS, as well as in brain regions associated with primary viscerosensory pathways and the central autonomic network. These findings provide evidence that peripheral sensory neurons contribute an early signal to the brain regarding potential pathogens.

Download full-text


Available from: Lisa E Goehler, Feb 10, 2014
1 Follower
77 Reads
    • "While most of the current data for microbial modulation of neurotransmitter production and/or levels is available for the gut and periphery, local neurotransmitter regulation by gut bacteria may have long distance effects on the brain. Neurotransmitters or other molecules derived from gut microbes have the potential to modulate activity of the vagus nerve, the primary nerve connecting the ENS to the CNS, and subsequently influence brain function (Bravo et al., 2011; Goehler et al., 2005). It is also possible that microbially derived metabolites, which can act as precursors to neurotransmitter production (such as tryptophan) and may cross through the intestinal barrier and the BBB, could subsequently influence both systemic and CNS neurotransmitter concentrations. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Animals share an intimate and life-long partnership with a myriad of resident microbial species, collectively referred to as the microbiota. Symbiotic microbes have been shown to regulate nutrition and metabolism and are critical for the development and function of the immune system. More recently, studies have suggested that gut bacteria can impact neurological outcomes-altering behavior and potentially affecting the onset and/or severity of nervous system disorders. In this review, we highlight emerging evidence that the microbiome extends its influence to the brain via various pathways connecting the gut to the central nervous system. While understanding and appreciation of a gut microbial impact on neurological function is nascent, unraveling gut-microbiome-brain connections holds the promise of transforming the neurosciences and revealing potentially novel etiologies for psychiatric and neurodegenerative disorders. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell host & microbe 05/2015; 17(5):565-576. DOI:10.1016/j.chom.2015.04.011 · 12.33 Impact Factor
  • Source
    • "This pathogen to brain signalling, which appeared to be mediated by neurons within the vagus nerve, manifested itself in the mice as a display of significantly more anxiety-like behaviour. Colonisation of the gut by the pathogen Campylobacter jejuni also induced early (pre-infection symptom) anxiety in mice (Goehler et al. 2005, 2008). In humans, administration of bacterial lipopolysaccharide induces significant anxiety feelings soon after treatment (Reichenberg et al. 2001). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The human body is home to trillions of microorganisms which are increasingly being shown to have significant effects on a variety of disease states. Evidence exists that a bidirectional communication is taking place between us and our microbiome co-habitants, and that this dialogue is capable of influencing our health in a variety of ways. This review considers how host hormonal signals shape the microbiome, and what in return the microbiome residents may be signalling to their hosts.
    Journal of Endocrinology 03/2015; 225(2). DOI:10.1530/JOE-14-0615 · 3.72 Impact Factor
  • Source
    • "This concept of cytokine-induced fever was challenged by studies showing that neither LPS nor IL-1β administered peripherally crossed the blood-brain barrier and that LPS injected intravenously in animals induced febrile responses and PGE2 in VMPO before cytokines were elevated in the blood [2], [3]. Studies in mice genetically engineered to lack pyrogenic cytokines, the ability of PGE2 to cross blood-brain barrier, and observations of clinical fevers that frequently occur without increase of circulating cytokines suggested alternative routes for transmission of febrile signals [3]–[7]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Prostaglandin E2 (PGE2) is induced in vivo by bacterial products including TLR agonists. To determine whether PGE2 is induced directly or via IL-1β, human monocytes and macrophages were cultured with LPS or with Pam3CSK4 in presence of caspase-1 inhibitor, ZVAD, or IL-1R antagonist, Kineret. TLR agonists induced PGE2 in macrophages exclusively via IL-1β-independent mechanisms. In contrast, ZVAD and Kineret reduced PGE2 production in LPS-treated (but not in Pam3CSK4-treated) monocytes, by 30-60%. Recombinant human IL-1β augmented COX-2 and mPGES-1 mRNA and PGE2 production in LPS-pretreated monocytes but not in un-primed or Pam3CSK4-primed monocytes. This difference was explained by the finding that LPS but not Pam3CSK4 induced phosphorylation of IRF3 in monocytes suggesting activation of the TRIF signaling pathway. Knocking down TRIF, TRAM, or IRF3 genes by siRNA inhibited IL-1β-induced COX-2 and mPGES-1 mRNA. Blocking of TLR4 endocytosis during LPS priming prevented the increase in PGE2 production by exogenous IL-1β. Our data showed that TLR2 agonists induce PGE2 in monocytes independently from IL-1β. In the case of TLR4, IL-1β augments PGE2 production in LPS-primed monocytes (but not in macrophages) through a mechanism that requires TLR4 internalization and activation of the TRIF/IRF3 pathway. These findings suggest a key role for blood monocytes in the rapid onset of fever in animals and humans exposed to bacterial products and some novel adjuvants.
    PLoS ONE 05/2014; 9(5):e98517. DOI:10.1371/journal.pone.0098517 · 3.23 Impact Factor
Show more