Modulation of the Brain-Gut Axis as a Therapeutic Approach in Gastrointestinal Disease

E. A. Mayer; K. Tillisch; S. Bradesi

Disclosures

Aliment Pharmacol Ther. 2006;24(6):919-933. 

In This Article

Summary and Introduction

Background: The importance of bi-directional brain-gut interactions in gastrointestinal illness is increasingly being recognized, most prominently in the area of functional gastrointestinal disorders. Numerous current and emerging therapies aimed at normalizing brain-gut interactions are a focus of interest, particularly for irritable bowel syndrome and functional dyspepsia.
Methods: A literature search was completed for preclinical and clinical studies related to central modulation of gastrointestinal functions and published in English between 1980 and 2006.
Results: Existing data, while sparse, support the use of different classes of antidepressant drugs, including tricyclics, and selective and non-selective serotonin reuptake inhibitors in irritable bowel syndrome. Serotonin receptor agonists and antagonists with peripheral and possibly central effects are effective in treating specific subtypes of irritable bowel syndrome. Based largely on theoretical and preclinical evidence, several novel compounds that selectively target receptors at multiple levels within the brain-gut axis such as neurokinin, somatostatin and corticotropin-releasing factor receptor antagonists are promising.
Conclusions: This review discusses the rationale for modulation of the brain-gut axis in the treatment of functional gastrointestinal disorders and highlights the most promising current and future therapeutic strategies.

Bi-directional brain-gut interactions play an important role in the regulation of many vital functions in health and disease. In health, brain-gut interactions play a crucial role in the regulation of digestive processes (including appetite and food intake), in the modulation of the gut-associated immune system, and in the co-ordination of the overall physical and emotional state of the organism with activity in the gastrointestinal (GI) tract. In disease, altered brain-gut interactions are likely to underlie the symptom generation in functional GI disorders (FGIDs),[1] and may be involved in the modulation of immune activity in irritable bowel syndrome (IBS),[2] and in the pathophysiology of various eating disorders.[3] In this current review article, we will focus on evolving pharmacological strategies aimed at various targets within the brain-gut axis, which may yield novel therapies for IBS and related FGIDs. Even though the gut itself is one component of the brain-gut axis, the review will not deal with targets restricted to peripheral mechanisms in the gut and the reader is referred to other recent reviews.[4,5]

While research over the past few years has provided significant advances in the understanding of IBS pathophysiology, the precise mechanisms underlying the symptom generation remains incompletely understood. However, the various aspects of IBS symptomatology can best be viewed as a dysregulation in the complex interplay between events occurring in the gut lumen, the mucosa, the enteric nervous system (ENS) and the central nervous system (CNS) leading to alterations in sensation, motility and immune function.[6] A schematic of the afferent component of the brain-gut axis is shown in Figure 1.

Brain-gut axis: visceral afferent pathways and their modulation. Shown are principal ascending (afferent) and descending (modulatory) pathways involved in visceral perception. + denotes pain facilitatory; - denotes pain inhibitory pathways. A6 = locus coeruleus; RVM = rostra ventral medulla; NTS = nucleus tractus solitarius. For details, see text.

Rationale for Modulation of Brain-gut Interactions. Over the past decade, a remarkable convergence of research strategies pursued by different specialties (in particular pain, psychiatry, psychology and stress neurobiology) in understanding the interface among the stress, pain and emotion has occurred. Rather than viewing each of these areas as mutually exclusive targets of research, the overlap of CNS circuits and neurotransmitter systems involved in the regulation and modulation of these processes is fundamentally changing the perspective of national funding agencies and of the pharmaceutical industry. The fact that drugs acting at the brain-gut axis make up an important aspect of every recent review published on the pharmacologic treatment of IBS indicates the firm support of the field for this treatment approach.[4,5,8,9,10,11,12,13,14]

Afferent signals arising from the lumen of the gut are transmitted via various visceral afferent pathways (enteric, spinal and vagal) to the CNS.[15,16,17] Homeostatic reflexes, which generate appropriate gut responses to physiological as well as pathological visceral stimuli, occur at the level of the ENS, the spinal cord and the pontomedullary nuclei and limbic regions.[16] Vagal visceral afferent inputs may also play an important role in such diverse functions as modulation of emotion, pain, satiety and immune response.[18,19] Whereas the reflex circuits within the ENS, in principle, can regulate and synchronize all basic GI functions (motility, secretion and blood flow), co-ordination of gut functions with the overall homeostatic state of the organism requires continuous communication between the CNS and the GI tract.[20] As shown in Fig. 1 descending cortico-limbic influences can set the gain and responsiveness of these reflexes or impose distinct patterns of motor responses on lower circuits. These descending influences can be triggered by cognitive or emotional influences or in response to environmental demands and can override local reflex function during sleep, in the context of environmental stressors, or during strong emotions such as fear and anger.[7,21,22,23]

While the great majority of homeostatic afferent inputs from the gut (as well as other viscera) to the CNS is not consciously perceived,[24] there are both peripheral and central adaptive mechanisms that can result in the enhanced perception of visceral stimuli.[25] For example, acute tissue irritation and injury are typically associated with the sensitization of peripheral afferents, spinal circuits and spino-bulbo-spinal circuits,[26] which may result in a transient or prolonged up-regulation of afferent sensitivity, as demonstrated in preclinical models.[27] Similarly, various stressors have been shown to regulate the visceral pain responses in animal models,[28,29] and chronic life stressors have been associated with symptom severity in FGIDs.[30] There are multiple mechanisms within the brain-gut axis, which can tonically or phasically up- or down-regulate the sensitivity within visceral afferent pathways[31] and the responsiveness of homeostatic reflexes.[16] It is important to realize that only some of these mechanisms have a direct effect on the conscious perception of visceral pain and discomfort in humans.

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