Enteric nervous system: sensory transduction, neural circuits and gastrointestinal motility

Abstract

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.

Fig. 1:. Key developments in the enteric nervous system.

The figure shows the timeline of the major advances made in our understanding of the enteric nervous system (ENS) and the identification of motility reflexes. The first evidence of a reflex response in an isolated segment of the gut was provided in 1755 by Von Haller. It was not until 1995 that the first unequivocal evidence that the ENS contained its own population of sensory neurons was presented. For Cannon, Legros & Onimus and Langley see refs^,,

Fig. 2:. The major extrinsic neural pathways between the ENS and spinal cord and brain.

The major extrinsic motor pathways between the enteric nervous system (ENS) and spinal cord and brain are shown in blue. These motor pathways constitute the parasympathetic (vagal motor) and sympathetic nervous systems (arising from the thoracolumbar spinal cord and synapsing on the coeliac, superior mesenteric ganglia and inferior mesenteric ganglia). In the gut, the sympathetic nerves are inhibitory, whereas the parasympathetic nerves are excitatory. In the upper gut (oesophagus and stomach), the major extrinsic sensory nerves arise from the vagus nerve, whereas in the lower gut (colon), the influence of the vagus is reduced and the major extrinsic sensory nerves to the colon arise from spinal afferent nerves, whose cell bodies lie in dorsal root ganglia (DRG).

Fig. 3:. Different types of intrinsic sensory neurons and extrinsic sensory nerve endings in the enteric nervous system.

A range of intrinsic sensory neurons and extrinsic sensory nerve endings are known to exist in the enteric nervous system (ENS). (1) Dogiel type I neurons represents a class of myenteric interneuron in the colon that have been identified as being largely length sensitive and tension insensitive. (2) At least two classes of cholinergic and nitrergic myenteric neurons in the myenteric plexus have been demonstrated to be rapidly adapting myenteric excitatory neurons. (3) Extrinsic vagal afferent nerve endings innervate largely the upper gut and behave predominantly as slowly adapting tension receptors. (4) Spinal afferent nerve endings provide a very rich sensory innervation to the lower gut (distal colon) and are potently activated by stretch and increases in muscle tension. (5) Dogiel type II neurons in the myenteric plexus are both chemosensory and mechanosensitive and receive fast and slow synaptic inputs from other enteric neurons. (6) Intestinofugal neurons are usually thought of as second-order neurons but have been shown to be directly mechanosensitive and respond to direct mechanical compression stimuli.

Fig. 4:. Possible mechanisms underlying the activation of two major classes of intrinsic sensory neuron in the ENS.

Dogiel type I neurons are mechanosensory and have been functionally identified as interneurons. These neurons also have fine nerve projections into the circular muscle, which could facilitate stretch sensitivity and connectivity with the circular muscle layer. Dogiel type II neurons have projections into the mucosa. They also have been shown to have fine varicose projections into the circular muscle layers. The functional role of enterochromaffin (EC) cells in the physiological activation of the nerve endings of these intrinsic sensory neurons is unknown but serotonin (5-hydroxytryptamine; 5-HT) could have a role.

Fig. 5:. Major intrinsic neuronal circuits in the large intestine active during neurogenic motor patterns.

A fundamental pathway involves the synaptic convergence of ascending and descending interneurons, such that increased activation of ascending pathways leads to a corresponding increased activation of descending inhibitory pathways. Furthermore, common ascending interneurons simultaneously activate independent populations of excitatory motor neurons to the longitudinal muscle and circular muscle orally; at the same time, common descending interneurons simultaneously activate separate populations of inhibitory motor neurons to both the longitudinal muscle and circular muscle aborally. Thus, temporally coordinated firing of ascending and descending interneurons simultaneously activates cholinergic excitatory motor neurons and nitrergic inhibitory motor neurons. These pathways underlie major neurogenic motility patterns in the large intestine. In the colon, calbindin-immunoreactive Dogiel type II neurons project to the mucosa and receive nicotinic inputs from some populations of myenteric interneurons. The Dogiel type II neurons (in the colon) preferentially provide synaptic outputs to local cholinergic excitatory motor neurons and cholinergic ascending interneurons, and rarely or never to nitrergic neurons.