Principles and clinical implications of the brain-gut-enteric microbiota axis

Abstract

While bidirectional brain-gut interactions are well known mechanisms for the regulation of gut function in both healthy and diseased states, a role of the enteric flora--including both commensal and pathogenic organisms--in these interactions has only been recognized in the past few years. The brain can influence commensal organisms (enteric microbiota) indirectly, via changes in gastrointestinal motility and secretion, and intestinal permeability, or directly, via signaling molecules released into the gut lumen from cells in the lamina propria (enterochromaffin cells, neurons, immune cells). Communication from enteric microbiota to the host can occur via multiple mechanisms, including epithelial-cell, receptor-mediated signaling and, when intestinal permeability is increased, through direct stimulation of host cells in the lamina propria. Enterochromaffin cells are important bidirectional transducers that regulate communication between the gut lumen and the nervous system. Vagal, afferent innervation of enterochromaffin cells provides a direct pathway for enterochromaffin-cell signaling to neuronal circuits, which may have an important role in pain and immune-response modulation, control of background emotions and other homeostatic functions. Disruption of the bidirectional interactions between the enteric microbiota and the nervous system may be involved in the pathophysiology of acute and chronic gastrointestinal disease states, including functional and inflammatory bowel disorders.

Figures

Figure 1

Schematic representation of the pattern of bidirectional brain–gut–microbe interactions. The brain can modulate various functions of the gut, as well as the perception of gut stimuli, via a set of parallel outflow systems that are referred to as the EMS, which include the sympathetic and parasympathetic branches of the ANS, the HPA axis, and endogenous pain-modulation systems. Activation of the EMS can occur via interoceptive and exteroceptive stressors. The enteric microbiota are likely to interact with gut-based effector systems and with visceral afferent pathways, which establish a bidirectional brain–gut–enteric microbiota axis. Abbreviations: ANS, autonomic nervous system; CNS, central nervous system; EMS, emotional motor system; GI, gastrointestinal; HPA, hypothalamus–pituitary–adrenal.

Figure 2

Interface between the enteric microbiota, immune cells in the lamina propria and the ANS. The vagal and sympathetic branches of the ANS (as well as the HPA) can modulate the activity of Mφ, and the SNS can modulate the activity of MCs by regulating their numbers, prompting release of individual cells from MC clusters (degranulation), and upregulating or downregulating MC activity. MC products, such as CRF, can increase epithelial permeability to bacteria, which facilitates their access to immune cells in the lamina propria. The ANS might also directly modify the behavior of the luminal, commensal flora through the ECC-mediated secretion of signaling molecules, such as serotonin, in the intestinal lumen. The SNS can effect changes in the bulk and quality of the intestinal mucus layer, which modifies the environment in which the microbial biofilm thrives. Abbreviations: ANS, autonomic nervous system; CRF, corticotropin-releasing factor; DC, dendric cell; ECC, enterochromaffin cell; MC, mast cell; Mφ, macrophage; SNS, sympathetic nervous system; 5-HT, serotonin. Permission obtained from Wiley-Blackwell © Iweala, O. I. & Nagler, C. R. Immune privilege in the gut: the establishment and maintenance of nonresponsiveness to dietary antigens and commensal flora. Immunol. Rev. 213, 82–100 (2006).

Figure 3

Schematic representation of the interkingdom, adrenergic signaling between host and enteric microbiota. NE released into the gut lumen (as spillover from noradrenergic nerve terminals or from capillaries within the gut wall) can activate adrenergic-like QseC receptors on the surface of bacteria in the gut lumen and alter the virulence of micro-organism, AI-3-mediated signaling. Similarly, NE-like signaling molecules, such as AI-3, which is released by bacteria into the intestinal lumen, can activate adrenergic receptors expressed on the luminal side of the gut epithelium, like α2AR. Activation of α2AR on epithelial cells reduces their fluid secretion. Abbreviations: α2AR, α2 adrenergic receptor; AI-3, autoinducer 3; NE, norepinephrine; SNS, sympathetic nervous system. Permission obtained from Elsevier © Furness, J. B. & Clerc, N. Responses of afferent neurons to the contents of the digestive tract, and their relation to endocrine and immune responses. Prog. Brain Res. 122, 159–172 (2000).

Figure 4

Schematic representation of endocrine cell-mediated signaling from enteric microbiota to host. Presence of bacteria or their secretory products in the gut lumen might influence endocrine cells in the epithelium (e.g. enterochromaffin cells). Hormones released by the bacteria-stimulated enterochromaffin cells can influence host function by entering circulation and by direct endocrine communication with immunocytes (blue), which would affect immune response and terminals of visceral afferent nerves (red). Abbreviations: CNS, central nervous system; ECC, enterochromaffin cell. Permission obtained from Elsevier © Furness, J. B. & Clerc, N. Responses of afferent neurons to the contents of the digestive tract, and their relation to endocrine and immune responses. Prog. Brain Res. 122, 159–172 (2000).

Figure 5

Enterochromaffin cells as bidirectional signal transducers between host and enteric microbiota. ECCs, which are interspersed among epithelial cells throughout the intestinal epithelium, can secrete 5-HT on either side of the intestinal epithelium (basolateral or luminal side). Other signaling molecules, such as CRF, SST and dynorphin, might also be similarly processed by ECCs. Secretion of signaling molecules can be triggered by luminal stimuli, as well as by neural signals from autonomic nerve terminals (pink) and/or from terminals of primary afferent neurons (purple). Although this mechanism has not yet been proven, 5-HT and other signaling molecules might be released into the gut lumen via neural activation of ECCs and thus alter the behavior of enteric microbiota. As a consequence, the pattern of enteric microbiota–epithelium interactions may be altered. Furthermore, the enteric microbiota could also release various signaling molecules that might interact with receptors on epithelial cells. Abbreviations: CRF, corticotropin-releasing factor; ECC, enterochromaffin cell; SNS, sympathetic nervous system; SST, somatostatin; 5-HT, serotonin. Permission obtained from Elsevier © Furness, J. B. & Clerc, N. Responses of afferent neurons to the contents of the digestive tract, and their relation to endocrine and immune responses. Prog. Brain Res. 122, 159–172 (2000).