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One of the most transformative developments in neurogastroenterology is the realization that many functions normally attributed to enteric neurons involve interactions with enteric glial cells: a large population of peripheral neuroglia associated with enteric neurons throughout the gastrointestinal tract. The notion that glial cells function solely as passive support cells has been refuted by compelling evidence that demonstrates that enteric glia are important homeostatic cells of the intestine. Active signalling mechanisms between enteric glia and neurons modulate gastrointestinal reflexes and, in certain circumstances, function to drive neuroinflammatory processes that lead to long-term dysfunction. Bidirectional communication between enteric glia and immune cells contributes to gastrointestinal immune homeostasis, and crosstalk between enteric glia and cancer stem cells regulates tumorigenesis. These neuromodulatory and immunomodulatory roles place enteric glia in a unique position to regulate diverse gastrointestinal disease processes. In this Review, we discuss current concepts regarding enteric glial development, heterogeneity and functional roles in gastrointestinal pathophysiology and pathophysiology, with a focus on interactions with neurons and immune cells. We also present a working model to differentiate glial states based on normal function and disease-induced dysfunctions. Enteric glia regulate homeostasis in the enteric nervous system and influence gastrointestinal function. This Review provides an update on enteric glial biology and the underlying mechanisms by which enteric glia regulate gastrointestinal function and disease, with a focus on neuronal and immune interactions. Key points Enteric glia are a heterogeneous population of peripheral neuroglia that regulate homeostasis in the enteric nervous system. Bidirectional communication between enteric glia and neurons modulates intestinal reflexes. Enteric glia are central players in neuroinflammation and contribute to neuroplasticity through interactions with neurons and immune cells. Enteric glia regulate disease processes involved in tumorigenesis and extragastrointestinal diseases. Therapies targeting glial mechanisms, such as gliotransmitter release or signalling pathways that promote gliosis, could substantially advance the treatment of common gastrointestinal diseases.

Neurogastroenterology encompasses control of digestion through the enteric nervous system, the central nervous system and integrative centers in sympathetic ganglia. In this Review, John Furness provides a broad overview of the rapidly developing field of neurogastroenterology, with a focus on the roles of the enteric nervous system in the control of the musculature of the gastrointestinal tract and transmucosal fluid movement. Neurogastroenterology is defined as neurology of the gastrointestinal tract, liver, gallbladder and pancreas and encompasses control of digestion through the enteric nervous system (ENS), the central nervous system (CNS) and integrative centers in sympathetic ganglia. This Review provides a broad overview of the field of neurogastroenterology, with a focus on the roles of the ENS in the control of the musculature of the gastrointestinal tract and transmucosal fluid movement. Digestion is controlled through the integration of multiple signals from the ENS and CNS; neural signals also pass between distinct gut regions to coordinate digestive activity. Moreover, neural and endocrine control of digestion is closely coordinated. Interestingly, the extent to which the ENS or CNS controls digestion differs considerably along the digestive tract. The importance of the ENS is emphasized by the life-threatening effects of certain ENS neuropathies, including Hirschsprung disease and Chagas disease. Other ENS disorders, such as esophageal achalasia and gastroparesis, cause varying degrees of dysfunction. The neurons in enteric reflex pathways use a wide range of chemical messengers that signal through an even wider range of receptors. These receptors provide many actual and potential targets for modifying digestive function. Key Points The enteric nervous system (ENS) is an extensive reflex control system for digestive function that works with the central nervous system (CNS) and neural pathways that pass through sympathetic ganglia The ENS of the small intestine and colon has complete reflex pathways that control patterns of contractile activity, local blood flow and transmucosal movement of fluids The CNS has essential roles in control of esophageal, stomach and colorectal functions Control of transmucosal fluid movement by the ENS and CNS is closely integrated The ENS interacts with both the gut endocrine and immune systems and has roles in modifying nutrient absorption and maintaining the mucosal barrier Enteric neuropathies in which control of muscle contractile activity or neural control of transmucosal fluid movement fail are life-threatening

Gastrointestinal motility results from coordinated contractions of the smooth muscle tissues forming the tunica muscularis of the alimentary canal. Smooth muscle cells are organized into an electrical syncytium that also incorporates interstitial cells. Myogenic, neural and humoral factors provide integrated control of contractile activity. Kenton Sanders and colleagues provide an overview of the cells and mechanisms that generate and regulate smooth muscle contractile behaviour and gastrointestinal motility. Gastrointestinal motility results from coordinated contractions of the tunica muscularis , the muscular layers of the alimentary canal. Throughout most of the gastrointestinal tract, smooth muscles are organized into two layers of circularly or longitudinally oriented muscle bundles. Smooth muscle cells form electrical and mechanical junctions between cells that facilitate coordination of contractions. Excitation–contraction coupling occurs by Ca 2+ entry via ion channels in the plasma membrane, leading to a rise in intracellular Ca 2+ . Ca 2+ binding to calmodulin activates myosin light chain kinase; subsequent phosphorylation of myosin initiates cross-bridge cycling. Myosin phosphatase dephosphorylates myosin to relax muscles, and a process known as Ca 2+ sensitization regulates the activity of the phosphatase. Gastrointestinal smooth muscles are 'autonomous' and generate spontaneous electrical activity (slow waves) that does not depend upon input from nerves. Intrinsic pacemaker activity comes from interstitial cells of Cajal, which are electrically coupled to smooth muscle cells. Patterns of contractile activity in gastrointestinal muscles are determined by inputs from enteric motor neurons that innervate smooth muscle cells and interstitial cells. Here we provide an overview of the cells and mechanisms that generate smooth muscle contractile behaviour and gastrointestinal motility. Key Points Gastrointestinal motility occurs by the coordinated contractions of the tunica muscula ris , which forms the outer wall of the alimentary canal from the distal oesophagus to the external anal sphincter Excitation–contraction coupling results from Ca 2+ entry into smooth muscle cells, Ca 2+ release from the sarcoplasmic reticulum, activation of myosin light chain kinase and phosphorylation of the regulatory light chains of myosin Contractile force is tuned by Ca 2+ sensitization mechanisms that balance rates of myosin phosphorylation and dephosphorylation Interstitial cells of Cajal (ICC) provide spontaneous pacemaker activity in gastrointestinal muscles; ICC and PDGFRα + cells also contribute to mediation of inputs from enteric motor neurons Gastrointestinal motility patterns are highly integrated behaviours requiring coordination between smooth muscle cells and utilizing regulatory inputs from interstitial cells, neurons, and endocrine and immune cells Therapeutic regulation and tissue engineering of gastrointestinal motility is proving difficult

The gut is innervated by many types of extrinsic sensory neurons, and little consensus exists about the different classes that these afferents might belong to. In this Review, Simon Brookes and colleagues suggest that five different morphological types of endings can be distinguished by their structure, and that this scheme is compatible with physiologically based classifications. Visceral sensory neurons activate reflex pathways that control gut function and also give rise to important sensations, such as fullness, bloating, nausea, discomfort, urgency and pain. Sensory neurons are organised into three distinct anatomical pathways to the central nervous system (vagal, thoracolumbar and lumbosacral). Although remarkable progress has been made in characterizing the roles of many ion channels, receptors and second messengers in visceral sensory neurons, the basic aim of understanding how many classes there are, and how they differ, has proven difficult to achieve. We suggest that just five structurally distinct types of sensory endings are present in the gut wall that account for essentially all of the primary afferent neurons in the three pathways. Each of these five major structural types of endings seems to show distinctive combinations of physiological responses. These types are: 'intraganglionic laminar' endings in myenteric ganglia; 'mucosal' endings located in the subepithelial layer; 'muscular–mucosal' afferents, with mechanosensitive endings close to the muscularis mucosae; 'intramuscular' endings, with endings within the smooth muscle layers; and 'vascular' afferents, with sensitive endings primarily on blood vessels. 'Silent' afferents might be a subset of inexcitable 'vascular' afferents, which can be switched on by inflammatory mediators. Extrinsic sensory neurons comprise an attractive focus for targeted therapeutic intervention in a range of gastrointestinal disorders. Key Points The gut is innervated by several classes of extrinsic sensory neurons that have distinct combinations of properties making them sensitive to particular mechanical and chemical stimuli Progress has been made in identifying the morphology of sensory endings in the gut wall, possibly providing a more robust means to classify sensory innervation Five different morphological types of endings can be distinguished by their structure; these account for the great majority of sensory nerves to the gastrointestinal tract and seem to correspond to distinct major physiological classes The physiological properties of extrinsic afferent nerves innervating the gut are characterized by variability and by plasticity, which can make it difficult to reliably distinguish the classes of sensory neurons that underlie gut sensation

Enteric glia encompass a diverse range of glial cells that populate the gastrointestinal tract. In this Review, Gulbransen & Sharkey provide a timely update on the different types of enteric glia and their role in normal and abnormal gut function. In addition, key areas in which further knowledge is needed to fully appreciate the physiology of these cells are also highlighted. Enteric glia are a unique class of peripheral glial cells within the gastrointestinal tract. Major populations of enteric glia are found in enteric ganglia in the myenteric and submucosal plexuses of the enteric nervous system (ENS); these cells are also found outside of the ENS, within the circular muscle and in the lamina propria of the mucosa. These different populations of cells probably represent unique classes of glial cells with differing functions. In the past few years, enteric glia have been found to be involved in almost every gut function including motility, mucosal secretion and host defence. Subepithelial glia seem to have a trophic and supporting relationship with intestinal epithelial cells, but the necessity of these roles in the maintenance of normal epithelial functions remains to be shown. Likewise, glia within enteric ganglia are activated by synaptic stimulation, suggesting an active role in synaptic transmission, but the precise role of glial activation in normal enteric network activity is unclear. Excitingly, enteric glia can also give rise to new neurons, but seemingly only under limited circumstances. In this Review, we discuss the current body of evidence supporting functional roles of enteric glia and identify key gaps in our understanding of the physiology of these unique cells. Key Points Unique populations of glial cells reside at multiple levels through the gut wall along the length of the gastrointestinal tract At the level of the mucosa, enteric glia influence epithelial cells and, thus, epithelial barrier function Within enteric ganglia, enteric glia are similar to the astrocytes of the central nervous system, detecting and integrating neural activity Enteric glia have the potential to modulate enteric neurotransmission, but exactly how they influence enteric circuits is unknown Enteric glia have a neurogenic capacity in vitro that seems to be largely suppressed in vivo

The migrating motor complex (MMC) is a cyclic, recurring motility pattern that occurs in the stomach and small bowel during fasting. The physiological role of the MMC is incompletely understood, and the regulation of the MMC is complex, involving different gut hor-mones and activation of the parasympathetic and enteric nervous system. In this Review, the authors summarize current knowledge of the MMC, especially its role in health and disease. The migrating motor complex (MMC) is a cyclic, recurring motility pattern that occurs in the stomach and small bowel during fasting; it is interrupted by feeding. The MMC is present in the gastrointestinal tract of many species, including humans. The complex can be subdivided into four phases, of which phase III is the most active, with a burst of contractions originating from the antrum or duodenum and migrating distally. Control of the MMC is complex. Phase III of the MMC with an antral origin can be induced in humans through intravenous administration of motilin, erythromycin or ghrelin, whereas administration of serotonin or somatostatin induces phase III activity with duodenal origin. The role of the vagus nerve in control of the MMC seems to be restricted to the stomach, as vagotomy abolishes the motor activity in the stomach, but leaves the periodic activity in the small bowel intact. The physiological role of the MMC is incompletely understood, but its absence has been associated with gastroparesis, intestinal pseudo-obstruction and small intestinal bacterial overgrowth. Measuring the motility of the gastrointestinal tract can be important for the diagnosis of gastrointestinal disorders. In this Review we summarize current knowledge of the MMC, especially its role in health and disease. Key Points The migrating motor complex (MMC) is a cyclic motor pattern in the gastrointestinal tract that occurs during the interdigestive state in humans and other animals Levels of endogenous motilin fluctuate together with the different MMC phases, and exogenously administered motilin can induce phase III contractions Exogenously administered ghrelin induces phase III contractions; detailed studies of fluctuations of endogenous ghrelin levels with the MMC phases in humans are lacking Serotonin and somatostatin inhibit the occurrence of antral phase III contractions and redirect the origin of these contractions towards the duodenum Vagotomy abolishes the MMC pattern in the stomach, but has a minimal effect on the small bowel pattern The activity of the MMC is a clinical marker for the functionality of the gastrointestinal tract, and several disorders are linked to a disturbed MMC

Immature gastrointestinal motility impedes preterm infant survival. The enteric nervous system controls gastrointestinal motility, yet it is unknown when the human enteric nervous system matures enough to carry out vital functions. Here we demonstrate that the second trimester human fetal enteric nervous system takes on a striped organization akin to the embryonic mouse. Further, we perform ex vivo functional assays of human fetal tissue and find that human fetal gastrointestinal motility matures in a similar progression to embryonic mouse gastrointestinal motility. Together, this provides critical knowledge, which facilitates comparisons with common animal models to advance translational disease investigations and testing of pharmacological agents to enhance gastrointestinal motility in prematurity. Dershowitz and colleagues assess second trimester human fetal enteric nervous system development and function. They describe structural reorganization of the enteric nervous system that corresponds to gastrointestinal motility onset in ex vivo preparations.

The enteric nervous system (ENS) arises from neural crest-derived cells. Here, Heather Young and colleagues provide an overview of the progress made in the past five years in our understanding of ENS development and the potential involvement of defects in ENS development in paediatric motility disorders. The enteric nervous system (ENS) arises from neural crest-derived cells that migrate into and along the gut, leading to the formation of a complex network of neurons and glial cells that regulates motility, secretion and blood flow. This Review summarizes the progress made in the past 5 years in our understanding of ENS development, including the migratory pathways of neural crest-derived cells as they colonize the gut. The importance of interactions between neural crest-derived cells, between signalling pathways and between developmental processes (such as proliferation and migration) in ensuring the correct development of the ENS is also presented. The signalling pathways involved in ENS development that were determined using animal models are also described, as is the evidence for the involvement of the genes encoding these molecules in Hirschsprung disease—the best characterized paediatric enteric neuropathy. Finally, the aetiology and treatment of Hirschsprung disease in the clinic and the potential involvement of defects in ENS development in other paediatric motility disorders are outlined. Key Points Enteric neural crest-derived cells (ENCCs) mostly migrate within the gut mesenchyme; a subpopulation, however, migrates across the mesentery to the postcaecal hindgut, forming the colonic enteric nervous system (ENS) Precise spatiotemporal regulation of ENCC proliferation, differentiation and migration is essential for ENS development ENCC proliferation is influenced by their density, and studies of mice have shown that ENCCs have some ability to act collectively to adapt to prevailing conditions Enteric neurogenesis occurs over a protracted period of time during prenatal and postnatal development, but does not seem to occur in adults, except after injury or activation of 5-HT4 receptors Hirschsprung disease is the best characterized developmental disorder of the ENS and is caused by a failure of neural crest-derived cells to colonize the distal bowel Transplantation of ENS progenitors, activation of the neurogenic potential of glia and 5-HT4 receptor activation are potential ways of generating enteric neurons in patients with enteric neuropathies

The gastrointestinal tract is the only internal organ to have evolved with its own independent nervous system, known as the enteric nervous system (ENS). This Review provides an update on advances that have been made in our understanding of how neurons within the ENS coordinate sensory and motor functions. Understanding this function is critical for determining how deficits in neurogenic motor patterns arise. Knowledge of how distension or chemical stimulation of the bowel evokes sensory responses in the ENS and central nervous system have progressed, including critical elements that underlie the mechanotransduction of distension-evoked colonic peristalsis. Contrary to original thought, evidence suggests that mucosal serotonin is not required for peristalsis or colonic migrating motor complexes, although it can modulate their characteristics. Chemosensory stimuli applied to the lumen can release substances from enteroendocrine cells, which could subsequently modulate ENS activity. Advances have been made in optogenetic technologies, such that specific neurochemical classes of enteric neurons can be stimulated. A major focus of this Review will be the latest advances in our understanding of how intrinsic sensory neurons in the ENS detect and respond to sensory stimuli and how these mechanisms differ from extrinsic sensory nerve endings in the gut that underlie the gut–brain axis.The enteric nervous system (ENS) is essential for life and controls the function of the gastrointestinal tract. Here, an overview of sensory transduction and neural circuits in the ENS is provided, yielding insights into the generation of gastrointestinal motility.