Brain-Gut Interactions in Inflammatory Bowel Disease

Psycho-neuro-endocrine-immune modulation through the brain-gut axis likely has a key role in the pathogenesis of inflammatory bowel disease (IBD). The brain-gut axis involves interactions among the neural components, including (1) the autonomic nervous system, (2) the central nervous system, (3) the stress system (hypothalamic-pituitary-adrenal axis), (4) the (gastrointestinal) corticotropin-releasing factor system, and (5) the intestinal response (including the intestinal barrier, the luminal microbiota, and the intestinal immune response). Animal models suggest that the cholinergic anti-inflammatory pathway through an anti–tumor necrosis factor effect of the efferent vagus nerve could be a therapeutic target in IBD through a pharmacologic, nutritional, or neurostimulation approach. In addition, the psychophysiological vulnerability of patients with IBD, secondary to the potential presence of any mood disorders, distress, increased perceived stress, or maladaptive coping strategies, underscores the psychological needs of patients with IBD. Clinicians need to address these issues with patients because there is emerging evidence that stress or other negative psychological attributes may have an effect on the disease course. Future research may include exploration of markers of brain-gut interactions, including serum/salivary cortisol (as a marker of the hypothalamic-pituitary-adrenal axis), heart rate variability (as a marker of the sympathovagal balance), or brain imaging studies. The widespread use and potential impact of complementary and alternative medicine and the positive response to placebo (in clinical trials) is further evidence that exploring other psycho-interventions may be important therapeutic adjuncts to the conventional therapeutic approach in IBD. Psycho-neuro-endocrine-immune modulation through the brain-gut axis likely has a key role in the pathogenesis of inflammatory bowel disease (IBD). The brain-gut axis involves interactions among the neural components, including (1) the autonomic nervous system, (2) the central nervous system, (3) the stress system (hypothalamic-pituitary-adrenal axis), (4) the (gastrointestinal) corticotropin-releasing factor system, and (5) the intestinal response (including the intestinal barrier, the luminal microbiota, and the intestinal immune response). Animal models suggest that the cholinergic anti-inflammatory pathway through an anti–tumor necrosis factor effect of the efferent vagus nerve could be a therapeutic target in IBD through a pharmacologic, nutritional, or neurostimulation approach. In addition, the psychophysiological vulnerability of patients with IBD, secondary to the potential presence of any mood disorders, distress, increased perceived stress, or maladaptive coping strategies, underscores the psychological needs of patients with IBD. Clinicians need to address these issues with patients because there is emerging evidence that stress or other negative psychological attributes may have an effect on the disease course. Future research may include exploration of markers of brain-gut interactions, including serum/salivary cortisol (as a marker of the hypothalamic-pituitary-adrenal axis), heart rate variability (as a marker of the sympathovagal balance), or brain imaging studies. The widespread use and potential impact of complementary and alternative medicine and the positive response to placebo (in clinical trials) is further evidence that exploring other psycho-interventions may be important therapeutic adjuncts to the conventional therapeutic approach in IBD. Over the past decade, analyses of the pathobiology of irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) have intersected across several domains despite having very distinct etiologies. In recent years, there has been heightened interest in exploring the role of inflammation and the gut microbiome in IBS1Lee K.J. Tack J. Altered intestinal microbiota in irritable bowel syndrome.Neurogastroenterol Motil. 2010; 22: 493-498Crossref PubMed Scopus (29) Google Scholar; the former is a critical underpinning of IBD, and the latter is a potentially important driver of the aberrant immune response in IBD.2Shanahan F. 99th Dahlem conference on infection, inflammation and chronic inflammatory disorders: host-microbe interactions in the gut: target for drug therapy, opportunity for drug discovery.Clin Exp Immunol. 2010; 160: 92-97Crossref PubMed Scopus (0) Google Scholar Although alterations in the brain-gut axis have been considered a pillar of the modern view of the pathobiology of IBS,3Mayer E.A. Tillisch K. The brain-gut axis in abdominal pain syndromes.Annu Rev Med. 2011; 62: 381-396Crossref PubMed Scopus (297) Google Scholar there has been increasing interest in the brain-gut axis as it pertains to IBD. Why should the brain-gut axis be solely in the domain of IBS? These are conditions that share many similar symptoms. For the practicing gastroenterologist, a common diagnostic dilemma is discerning whether a patient's symptoms are from IBS or IBD or whether a patient harbors both conditions.4Burgmann T. Clara I. Graff L.A. et al.The Manitoba IBD Cohort study: prolonged symptoms before diagnosis-how much is IBS?.Clin Gastroenterol Hepatol. 2006; 4: 614-620Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar In understanding the pathogenesis of IBD, it is important to not only explore the peripheral mediators of inflammation (the cellular elements and their by-products) but also the drivers of the immunoinflammatory response. Recently, in IBD, the gut microbiome has garnered increasing attention as an integral player in this process.2Shanahan F. 99th Dahlem conference on infection, inflammation and chronic inflammatory disorders: host-microbe interactions in the gut: target for drug therapy, opportunity for drug discovery.Clin Exp Immunol. 2010; 160: 92-97Crossref PubMed Scopus (0) Google Scholar However, psychoneuroimmune modulation may be the platform that serves to interface the human experience, the state of mind, the gut microbiome, and the immune response that ultimately drives the phenotypic expression of IBD, which to date has been the focus of IBD therapy. A biopsychosocial understanding of illness describes clinical outcome and disease exacerbation as influencing and strongly influenced by both biological and psychosocial factors.5Lix L.M. Graff L.A. 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Shaffer J. et al.Psychological disorder and severity of inflammatory bowel disease predict health-related quality of life in ulcerative colitis and Crohn's disease.Am J Gastroenterol. 2002; 97: 1994-1999Crossref PubMed Google Scholar In this review, we explore the supporting evidence in animal models for the importance of the psychoneurological basis of intestinal inflammation, the clinical evidence that these mechanisms have an effect on disease course, and where they could potentially be harnessed therapeutically. The brain and the gut communicate through the autonomic nervous system (ANS) and the circumventricular organs8Mulak A. Bonaz B. Irritable bowel syndrome: a model of the brain-gut interactions.Med Sci Monit. 2004; 10: RA55-RA62PubMed Google Scholar both in physiological and pathological conditions. The ANS, represented by the parasympathetic and sympathetic nervous systems (SNS), includes the vagus nerves (VNs), the sacral parasympathetic pelvic nerves, and the splanchnic nerves. These are mixed nerves containing afferent fibers (90% for VNs and 50% for sympathetic nerves) and efferent fibers facilitating neurotransmission between the gut and the central nervous system (CNS; brain and spinal cord). The VNs typically transmit information to the CNS regarding luminal osmolarity, carbohydrate levels, mechanical distortion of the mucosa, and the presence of cytostatic drugs and bacterial products, whereas sympathetic afferents classically transmit visceral pain. Visceral information transmitted through ANS afferents reaches the CNS at 2 different levels: (1) the nucleus tractus solitarius (NTS), located in the medulla oblongata, receiving VN afferents, and (2) the thoracolumbar and sacral spinal cord, receiving splanchnic and pelvic nerve afferents, respectively. In addition, the circumventricular organs, located outside the blood-brain barrier, are sensitive to the vascular content (eg, circulating interleukins [ILs]) and modulate the activity of neighboring neurons that in turn stimulate the hypothalamic-pituitary-adrenal (HPA) axis, thereby suppressing mucosal inflammation via glucocorticoids (Figure 1). After reaching the CNS, visceral information is integrated in the central ANS, composed of brain regions involved in the autonomic, endocrine, motor, and behavioral responses essential for survival.9Benarroch E.E. The central autonomic network: functional organization, dysfunction, and perspective.Mayo Clin Proc. 1993; 68: 988-1001Abstract Full Text Full Text PDF PubMed Google Scholar Output of the central ANS is directly linked through many positive and negative feedback loops governing both sympathetic and parasympathetic outputs on peripheral organs, including the immune system. Many of these reflex loops are unconscious or become conscious in pathological conditions. Stress is the response of the organism to a solicitation of the environment.10Selye H. A Syndrome produced by diverse nocuous agents.Nature. 1936; 138: 32Crossref Google Scholar The reaction of stress is physiologic but may become pathologic in the case of an imbalance between the capacities of adaptation and the requirement of the environment, leading to functional, metabolic, and even lesional disorders.11Chrousos G.P. Stress and disorders of the stress system.Nat Rev Endocrinol. 2009; 5: 374-381Crossref PubMed Scopus (1517) Google Scholar The HPA axis is the classic pathway through which stress induces an adaptation. Corticotropin-releasing factor (CRF), the principal neuromediator of stress, directly administered into the brain reproduces the overall endocrine, behavioral, autonomic, and visceral changes induced by stress in experimental animals.11Chrousos G.P. 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The molecular mechanisms underlying the regulation of the biological activity of corticotropin-releasing hormone receptors: implications for physiology and pathophysiology.Endocr Rev. 2006; 27: 260-286Crossref PubMed Scopus (274) Google Scholar Stress induces modifications of motility, secretion, visceral sensitivity, intestinal permeability, and local inflammatory responses in the gastrointestinal (GI) tract.15Taché Y. Perdue M.H. Role of peripheral CRF signalling pathways in stress-related alterations of gut motility and mucosal function.Neurogastroenterol Motil. 2004; 16: 137-142Crossref PubMed Scopus (244) Google Scholar, 16Taché Y. Bonaz B. Corticotropin-releasing factor receptors and stress-related alterations of gut motor function.J Clin Invest. 2007; 117: 33-40Crossref PubMed Scopus (270) Google Scholar Stress is involved in the initiation and relapse of experimental colitis.17Gué M. Bonbonne C. Fioramonti J. et al.Stress-induced enhancement of colitis in rats: CRF and arginine vasopressin are not involved.Am J Physiol. 1997; 272: G84-G91Crossref PubMed Google Scholar, 18Qiu B.S. Vallance B.A. Blennerhassett P.A. et al.The role of CD4+ lymphocytes in the susceptibility of mice to stress-induced reactivation of experimental colitis.Nat Med. 1999; 5: 1178-1182Crossref PubMed Scopus (23) Google Scholar Stress may play a deleterious role in IBD through 8 main pathways (Figure 2). 1. Activation of mast cells and the SNS. Mast cells of the intestinal mucosa serve as end effectors of the brain-gut axis and release several mediators, cytokines, and chemokines that can profoundly affect GI physiology under stress conditions by inducing intestinal hyperpermeability and activation of mucosal immune function.15Taché Y. Perdue M.H. 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Zhang M. et al.Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin.Nature. 2000; 405: 458-462Crossref PubMed Scopus (2621) Google Scholar Acetylcholine (ACh), released at the distal end of VN efferents, decreases the production of proinflammatory cytokines such as TNF by human macrophages through α7 nicotinic acetylcholine receptor (α7nAChR) expressed by macrophages26Pavlov V.A. Wang H. Czura C.J. et al.The cholinergic anti-inflammatory pathway: a missing link in neuroimmunomodulation.Mol Med. 2003; 9: 125-134Crossref PubMed Google Scholar (Figure 3). Vagus nerve stimulation (VNS) attenuates the systemic inflammatory response to endotoxin25Borovikova L.V. Ivanova S. Zhang M. et al.Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin.Nature. 2000; 405: 458-462Crossref PubMed Scopus (2621) Google Scholar and intestinal inflammation.27de Jonge W.J. van der Zanden E.P. 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This dichotomous effect results from the up-regulation and down-regulation of anti-inflammatory α7nAChR on colonic CD4 T cells induced by cytokines characteristic of the inflammatory milieu.30Galitovskiy V. Qian J. Chernyavsky A.I. et al.Cytokine-induced alterations of α7 nicotinic receptor in colonic CD4 T cells mediate dichotomous response to nicotine in murine models of Th1/Th17- versus Th2-mediated colitis.J Immunol. 2011; 187: 2677-2687Crossref PubMed Scopus (69) Google Scholar Stress decreases VN efferent outflow16Taché Y. Bonaz B. Corticotropin-releasing factor receptors and stress-related alterations of gut motor function.J Clin Invest. 2007; 117: 33-40Crossref PubMed Scopus (270) Google Scholar, 31Wood S.K. Woods J.H. 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The activity level of the sympathovagal balance and the HPA axis, represented by peripheral measures such as heart rate variability (HRV) and cortisol, are associated with the activity of the prefrontal cortex (PFC) and amygdala, respectively.33Thayer J.F. Sternberg E. Beyond heart rate variability: vagal regulation of allostatic systems.Ann N Y Acad Sci. 2006; 1088: 361-372Crossref PubMed Scopus (277) Google Scholar The PFC contributes to negative feedback control of the HPA axis.34Czéh B. Perez-Cruz C. Fuchs E. et al.Chronic stress-induced cellular changes in the medial prefrontal cortex and their potential clinical implications: does hemisphere location matter?.Behav Brain Res. 2008; 190: 1-13Crossref PubMed Scopus (86) Google Scholar The amygdala (ie, central nucleus) is a target region for the control of the HPA axis and receives large inputs from the VN35Ricardo J.A. Koh E.T. Anatomical evidence of direct projections from the nucleus of the solitary tract to the hypothalamus, amygdala, and other forebrain structures in the rat.Brain Res. 1978; 153: 1-26Crossref PubMed Scopus (1129) Google Scholar that trigger the negative feedback on the HPA axis. An inverse relationship between the plasma level of cortisol and the amplitude of HRV reflects the inhibitory influence of the PFC on the amygdala.33Thayer J.F. Sternberg E. Beyond heart rate variability: vagal regulation of allostatic systems.Ann N Y Acad Sci. 2006; 1088: 361-372Crossref PubMed Scopus (277) Google Scholar The hypoactivity of the PFC and the enhancement of amygdala activity are strongly influenced by stress.34Czéh B. Perez-Cruz C. Fuchs E. et al.Chronic stress-induced cellular changes in the medial prefrontal cortex and their potential clinical implications: does hemisphere location matter?.Behav Brain Res. 2008; 190: 1-13Crossref PubMed Scopus (86) Google Scholar The PFC regulates peripheral immune cells through the autonomic and neuroendocrine pathways.36Tracey K.J. The inflammatory reflex.Nature. 2002; 420: 853-859Crossref PubMed Scopus (2294) Google Scholar The PFC also controls the parasympathetic tone by modulating the VN efferent outflow. A dysregulation of this balance between the amygdala and the PFC induces an imbalance between the HPA axis and the ANS, as observed in IBD,37Straub R.H. Herfarth H. Falk W. et al.Uncoupling of the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis in inflammatory bowel disease?.J Neuroimmunol. 2002; 126: 116-1125Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar and consequently a proinflammatory condition. Increased inflammatory markers (eg, C-reactive protein [CRP]) and IL-6) are associated with decreased parasympathetic activity (decreased HRV), indicating that the cholinergic anti-inflammatory pathway counter-regulates inflammation.38Sloan R.P. McCreath H. Tracey K.J. et al.RR interval variability is inversely related to inflammatory markers: the CARDIA study.Mol Med. 2007; 13: 178-184Crossref PubMed Scopus (184) Google Scholar 4. Down-regulation of the hypothalamic CRFergic system. An adaptation of the hypothalamic CRFergic system is observed in chronic stress.39Bonaz B. Rivest S. 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CRF1 and CRF2 agonists exert a biphasic effect on macrophages with a suppressive effect of TNF release at the early phase and TNF production at the later stage of the inflammatory response.52Tsatsanis C. Androulidaki A. Dermitzaki E. et al.Corticotropin releasing factor receptor 1 (CRF1) and CRF2 agonists exert an anti-inflammatory effect during the early phase of inflammation suppressing LPS-induced TNF-alpha release from macrophages via induction of COX-2 and PGE2.J Cell Physiol. 2007; 210: 774-783Crossref PubMed Scopus (0) Google Scholar CRF peptides induce Toll-like receptor (TLR)4 expression through CRF2.53Tsatsanis C. Androulidaki A. 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Lombardo G. et al.Divergent effects of corticotropin releasing hormone on endothelial cell nitric oxide synthase are associated with different expression of CRH type 1 and 2 receptors.Br J Pharmacol. 2001; 134: 837-844Crossref PubMed Google Scholar CRF1 promotes intestinal inflammation and endogenous and inflammatory angiogenesis, whereas CRF2 inhibits these activities.56lm E. Rhee S.H. Park Y.S. et al.Corticotropin-releasing hormone family of peptides regulates intestinal angiogenesis.Gastroenterology. 2010; 138: 2457-2467Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar The peripheral CRFergic system forms an interacting and balanced system, and the differences observed among studies depend on the model of inflammation and the receptors activated and the ligands; an imbalance of this sys