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Nervous modulation of gut immunity
Abstracts / Brain, Behavior, and Immunity 24 (2010) S1–S71
key nutrients, and to identify regulatory signaling pathways. Along with glycolysis, T cells induce the pentose phosphate pathway, but target little glucose into the Krebs cycle. However, they upregulate the expression and activity of enzymes that allow the use of glutamine as a Krebs cycle substrate. This suggests a model of metabolism for proliferating cells, with glutamine replacing glucose as the major Krebs cycle nutrient, freeing glucose to be used for anabolic pathways, such as amino acid and nucleotide synthesis. We have also found that signaling via the ERK/MAPK pathway is required for the coordinate induction of the ‘‘activated” metabolic phenotype, implicating ERK as an important regulator of cellular metabolism downstream of TCR stimulation. doi:10.1016/j.bbi.2010.07.161
Abstract # 417 Nervous modulation of gut immunity W. de Jonge Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, NH 1105AZ, USA In the healthy mucosa intestinal macrophages and dendritic cells have adopted a remarkably tolerant – or tolerance-inducing – phenotype, probably resulting from factors derived from the local tissue microenvironment. In IBD mucosa, mucosal macrophages may be predisposed to differentiate into phagocytes that have lost their tolerant state. Within this research program we have a special interest in the role of neural networks in mediating this process. The role of the enteric nervous system in mucosal immunity is particularly illustrated by the – only recently revealed – immune-modulatory potency of the parasympathetic vagus nerve. I would like to highlight the elegant mechanism by which this so-called ‘‘cholinergic anti-inflammatory pathway” regulates intestinal disease progression, and how it could be harnessed to treat intestinal disease. We and others have shown that the vagus nerve is an important negative regulator of intestinal innate immune cell reactivity via its release of its neurotransmitter acetylcholine (ACh) at the gut wall. We demonstrated that intestinal macrophages and dendritic cells express receptors for ACh, and that ACh attenuates the production of proinflammatory cytokines and inhibits inflammatory activation in these cells, whilst enhancing the macrophage capacity to take up and kill bacterial microbes. In conjunction with this, in animal models of intestinal inflammation, stimulation of the vagal nerve ameliorates disease activity. We delineated the molecular mechanism that underlie the ACh effects and interestingly, found that ACh ‘‘highjack’s” anti-inflammatory signaling pathways such as IL-10 and TGF-beta to induce a tolerant-anti-inflammatory phenotype as is required in intestinal mucosa. However, alternative – post-ganglionic – neuronal factors such as neuropeptides released by vagal afferents are likely to relay vagal anti-inflammatory effects. doi:10.1016/j.bbi.2010.07.162
Abstract # 418 From bowel to behaviour: Immune regulation of the brain–gut axis J. Cryan University College Cork, Cork, Ireland
S49
The central nervous system (CNS) and the gastrointestinal tract (GIT) are in constant reciprocal communication, orchestrating appropriate homeostatic function. The disorganization of this brain–gut axis is thought to be critically involved in the physiopathology of stressrelated GIT disorders most notably irritable bowel syndrome (IBS). Recent advances have shown that this bidirectional communication between the brain and GIT is strongly modulated by the immune system, facilitating the adaptation of gut physiology to local and systemic immune challenges. However, a growing corpus of data has revealed that an inappropriate signalling at the neuro-immune interface may also participate in the manifestation of IBS. The biological substrates underlying the links between bowel dysfunction and mood disturbances are not fully understood and appropriate animal models are central to unravelling the specific alterations. Our laboratory uses the maternally separated (MS) and Wistar-Kyoto (WKY) rat as models of brain–gut axis dysfunction. These show increased depression and anxiety-related behaviour, increased visceral hypersensitivity, increases in pro-inflammatory cytokines and differences in the intestinal microbiota when compared to control animals. In this presentation we will focus on our recent data showing specific alterations in some key mediators in these models, ranging from CRF, glutamate transporters and inflammatory mediators. These models are poised to dissect the relationships between affective and functional bowel disorders and to conceive new therapeutic strategies that are urgently needed. doi:10.1016/j.bbi.2010.07.163
Abstract # 419 ‘‘Gut feelings”: Pathways for influence of gut microbes on mood and behavior L.E. Goehler University of Virginia School of Nursing, Center for the Study of Complementary and Alternative Therapies, 202 Jeanette Lancaster Way, P.O. Box 800782, Charlottesville, VA 22908-0782, USA One of the critical functions of the brain is to coordinate responses to behavioral and physiological challenges, which are often referred to as ‘‘stressors”. Stressors can include physiological or ‘‘bottom up” challenges to our internal bodily function, or psychological ‘‘top-down” threats from the environment. Sensory signals regarding bodily conditions (viscerosensory) that signal well-being or danger influence ongoing mood and behavior. For example, viscerosensory threats, such as ‘‘subclinical” gastrointestinal (GI) infections in mice can lead to increases in anxiety-like behavior. The infected animals engage more ‘‘risk assessment” behaviors, and spend more time in ‘‘safe” areas of the behavior testing apparati. In mice challenged with per-oral live bacteria, these stimuli seem to use a vagal pathway to signal the brain, based on the lack of circulating cytokines and the expression in vagal sensory neurons of the activation marker protein c-Fos. In the brain, the activation pattern was consistent with viscerosensory challenge, and included activation in brain regions involved in behavioral defense. In particular the bacterial challenge seemed to enhance responses in limbic and hypothalamic brain regions involved in stress and coping responses. These findings provide strong evidence that viscerosensory pathways, especially those via the vagus, contribute to changes in mood, by influencing brain regions that coordinate defensive behavior and responses to stress. In this way, ‘‘gut feelings” can interface with, and potentially exacerbate, psychological stressors. doi:10.1016/j.bbi.2010.07.164
key nutrients, and to identify regulatory signaling pathways. Along with glycolysis, T cells induce the pentose phosphate pathway, but target little glucose into the Krebs cycle. However, they upregulate the expression and activity of enzymes that allow the use of glutamine as a Krebs cycle substrate. This suggests a model of metabolism for proliferating cells, with glutamine replacing glucose as the major Krebs cycle nutrient, freeing glucose to be used for anabolic pathways, such as amino acid and nucleotide synthesis. We have also found that signaling via the ERK/MAPK pathway is required for the coordinate induction of the ‘‘activated” metabolic phenotype, implicating ERK as an important regulator of cellular metabolism downstream of TCR stimulation. doi:10.1016/j.bbi.2010.07.161
Abstract # 417 Nervous modulation of gut immunity W. de Jonge Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, NH 1105AZ, USA In the healthy mucosa intestinal macrophages and dendritic cells have adopted a remarkably tolerant – or tolerance-inducing – phenotype, probably resulting from factors derived from the local tissue microenvironment. In IBD mucosa, mucosal macrophages may be predisposed to differentiate into phagocytes that have lost their tolerant state. Within this research program we have a special interest in the role of neural networks in mediating this process. The role of the enteric nervous system in mucosal immunity is particularly illustrated by the – only recently revealed – immune-modulatory potency of the parasympathetic vagus nerve. I would like to highlight the elegant mechanism by which this so-called ‘‘cholinergic anti-inflammatory pathway” regulates intestinal disease progression, and how it could be harnessed to treat intestinal disease. We and others have shown that the vagus nerve is an important negative regulator of intestinal innate immune cell reactivity via its release of its neurotransmitter acetylcholine (ACh) at the gut wall. We demonstrated that intestinal macrophages and dendritic cells express receptors for ACh, and that ACh attenuates the production of proinflammatory cytokines and inhibits inflammatory activation in these cells, whilst enhancing the macrophage capacity to take up and kill bacterial microbes. In conjunction with this, in animal models of intestinal inflammation, stimulation of the vagal nerve ameliorates disease activity. We delineated the molecular mechanism that underlie the ACh effects and interestingly, found that ACh ‘‘highjack’s” anti-inflammatory signaling pathways such as IL-10 and TGF-beta to induce a tolerant-anti-inflammatory phenotype as is required in intestinal mucosa. However, alternative – post-ganglionic – neuronal factors such as neuropeptides released by vagal afferents are likely to relay vagal anti-inflammatory effects. doi:10.1016/j.bbi.2010.07.162
Abstract # 418 From bowel to behaviour: Immune regulation of the brain–gut axis J. Cryan University College Cork, Cork, Ireland
S49
The central nervous system (CNS) and the gastrointestinal tract (GIT) are in constant reciprocal communication, orchestrating appropriate homeostatic function. The disorganization of this brain–gut axis is thought to be critically involved in the physiopathology of stressrelated GIT disorders most notably irritable bowel syndrome (IBS). Recent advances have shown that this bidirectional communication between the brain and GIT is strongly modulated by the immune system, facilitating the adaptation of gut physiology to local and systemic immune challenges. However, a growing corpus of data has revealed that an inappropriate signalling at the neuro-immune interface may also participate in the manifestation of IBS. The biological substrates underlying the links between bowel dysfunction and mood disturbances are not fully understood and appropriate animal models are central to unravelling the specific alterations. Our laboratory uses the maternally separated (MS) and Wistar-Kyoto (WKY) rat as models of brain–gut axis dysfunction. These show increased depression and anxiety-related behaviour, increased visceral hypersensitivity, increases in pro-inflammatory cytokines and differences in the intestinal microbiota when compared to control animals. In this presentation we will focus on our recent data showing specific alterations in some key mediators in these models, ranging from CRF, glutamate transporters and inflammatory mediators. These models are poised to dissect the relationships between affective and functional bowel disorders and to conceive new therapeutic strategies that are urgently needed. doi:10.1016/j.bbi.2010.07.163
Abstract # 419 ‘‘Gut feelings”: Pathways for influence of gut microbes on mood and behavior L.E. Goehler University of Virginia School of Nursing, Center for the Study of Complementary and Alternative Therapies, 202 Jeanette Lancaster Way, P.O. Box 800782, Charlottesville, VA 22908-0782, USA One of the critical functions of the brain is to coordinate responses to behavioral and physiological challenges, which are often referred to as ‘‘stressors”. Stressors can include physiological or ‘‘bottom up” challenges to our internal bodily function, or psychological ‘‘top-down” threats from the environment. Sensory signals regarding bodily conditions (viscerosensory) that signal well-being or danger influence ongoing mood and behavior. For example, viscerosensory threats, such as ‘‘subclinical” gastrointestinal (GI) infections in mice can lead to increases in anxiety-like behavior. The infected animals engage more ‘‘risk assessment” behaviors, and spend more time in ‘‘safe” areas of the behavior testing apparati. In mice challenged with per-oral live bacteria, these stimuli seem to use a vagal pathway to signal the brain, based on the lack of circulating cytokines and the expression in vagal sensory neurons of the activation marker protein c-Fos. In the brain, the activation pattern was consistent with viscerosensory challenge, and included activation in brain regions involved in behavioral defense. In particular the bacterial challenge seemed to enhance responses in limbic and hypothalamic brain regions involved in stress and coping responses. These findings provide strong evidence that viscerosensory pathways, especially those via the vagus, contribute to changes in mood, by influencing brain regions that coordinate defensive behavior and responses to stress. In this way, ‘‘gut feelings” can interface with, and potentially exacerbate, psychological stressors. doi:10.1016/j.bbi.2010.07.164