Ji-Hong Chen

The origin of segmentation motor activity in the intestine

The segmentation motor activity of the gut that facilitates absorption of nutrients, was first described in the late 19th century but the fundamental mechanisms underlying it remain poorly understood. The dominant theory suggests alternate excitation and inhibition from the enteric nervous system. Here we demonstrate that typical segmentation can occur after total nerve blockade. The segmentation motor pattern emerges when the amplitude of the dominant pacemaker, the slow wave generated by ICC associated with the myenteric plexus (ICC-MP), is modulated by the phase of induced lower frequency rhythmic transient depolarizations, generated by ICC associated with the deep muscular plexus (ICC-DMP), resulting in a waxing and waning of the amplitude of the slow wave and a rhythmic checkered pattern of segmentation motor activity. Phase amplitude modulation of the slow waves points to an underlying system of coupled nonlinear oscillators originating in ICC.

Interstitial Cells of Cajal: Update on Basic and Clinical Science

The basic science and clinical interest in the networks of interstitial cells of Cajal (ICC) keep growing, and here, research from 2010 to mid-2013 is highlighted. High-resolution gastrointestinal manometry and spatiotemporal mapping are bringing exciting new insights into motor patterns, their function and their myogenic and neurogenic origins, as well as the role of ICC. Critically important knowledge is emerging on the partaking of PDGFRα+ cells in ICC pacemaker networks. Evidence is emerging that ICC and PDGFRα+ cells have unique direct roles in muscle innervation. Chronic constipation is associated with loss and injury to ICC, which is stimulating extensive research into maintenance and repair of ICC after injury. In gastroparesis, high-resolution electrical and mechanical studies are beginning to elucidate the pathophysiological role of ICC and the pacemaker system in this condition. Receptors and ion channels that play a role in ICC function are being discovered and characterized, which paves the way for pharmacological interventions in gut motility disorders through ICC.

Neurogenic and myogenic properties of pan-colonic motor patterns and their spatiotemporal organization in rats.

Background and Aims Better understanding of intrinsic control mechanisms of colonic motility will lead to better treatment options for colonic dysmotility. The aim was to investigate neurogenic and myogenic control mechanisms underlying pan-colonic motor patterns. Methods Analysis of in vitro video recordings of whole rat colon motility was used to explore motor patterns and their spatiotemporal organizations and to identify mechanisms of neurogenic and myogenic control using pharmacological tools. Results Study of the pan-colonic spatiotemporal organization of motor patterns revealed: fluid-induced or spontaneous rhythmic propulsive long distance contractions (LDCs, 0.4–1.5/min, involving the whole colon), rhythmic propulsive motor complexes (RPMCs) (0.8–2.5/min, dominant in distal colon), ripples (10–14/min, dominant in proximal colon), segmentation and retrograde contractions (0.1–0.8/min, prominent in distal and mid colon). Spontaneous rhythmic LDCs were the dominant pattern, blocked by tetrodotoxin, lidocaine or blockers of cholinergic, nitrergic or serotonergic pathways. Change from propulsion to segmentation and distal retrograde contractions was most prominent after blocking 5-HT3 receptors. In the presence of all neural blockers, bethanechol consistently evoked rhythmic LDC-like propulsive contractions in the same frequency range as the LDCs, indicating the existence of myogenic mechanisms of initiation and propulsion. Conclusions Neurogenic and myogenic control systems orchestrate distinct and variable motor patterns at different regions of the pan-colon. Cholinergic, nitrergic and serotonergic pathways are essential for rhythmic LDCs to develop. Rhythmic motor patterns in presence of neural blockade indicate the involvement of myogenic control systems and suggest a role for the networks of interstitial cells of Cajal as pacemakers.

Actions of hydrogen sulfide and ATP-sensitive potassium channels on colonic hypermotility in a rat model of chronic stress.

Objective To investigate the potential role of hydrogen sulphide (H2S) and ATP-sensitive potassium (KATP) channels in chronic stress-induced colonic hypermotility. Methods Male Wistar rats were submitted daily to 1 h of water avoidance stress (WAS) or sham WAS (SWAS) for 10 consecutive days. Organ bath recordings, H2S production, immunohistochemistry and western blotting were performed on rat colonic samples to investigate the role of endogenous H2S in repeated WAS-induced hypermotility. Organ bath recordings and western blotting were used to detect the role of KATP channels in repeated WAS. Results Repeated WAS increased the number of fecal pellets per hour and the area under the curve of the spontaneous contractions of colonic strips, and decreased the endogenous production of H2S and the expression of H2S-producing enzymes in the colon devoid of mucosa and submucosa. Inhibitors of H2S-producing enzymes increased the contractile activity of colonic strips in the SWAS rats. NaHS concentration-dependently inhibited the spontaneous contractions of the strips and the NaHS IC50 for the WAS rats was significantly lower than that for the SWAS rats. The inhibitory effect of NaHS was significantly reduced by glybenclamide. Repeated WAS treatment resulted in up-regulation of Kir6.1 and SUR2B of KATP channels in the colon devoid of mucosa and submucosa. Conclusion The colonic hypermotility induced by repeated WAS may be associated with the decreased production of endogenous H2S. The increased expression of the subunits of KATP channels in colonic smooth muscle cells may be a defensive response to repeated WAS. H2S donor may have potential clinical utility in treating chronic stress- induced colonic hypermotility.

Motor patterns of the small intestine explained by phase-amplitude coupling of two pacemaker activities: the critical importance of propagation velocity

Phase-amplitude coupling of two pacemaker activities of the small intestine, the omnipresent slow wave activity generated by interstitial cells of Cajal of the myenteric plexus (ICC-MP) and the stimulus-dependent rhythmic transient depolarizations generated by ICC of the deep muscular plexus (ICC-DMP), was recently hypothesized to underlie the orchestration of the segmentation motor pattern. The aim of the present study was to increase our understanding of phase-amplitude coupling through modeling. In particular the importance of propagation velocity of the ICC-DMP component was investigated. The outcome of the modeling was compared with motor patterns recorded from the rat or mouse intestine from which propagation velocities within the different patterns were measured. The results show that the classical segmentation motor pattern occurs when the ICC-DMP component has a low propagation velocity (<0.05 cm/s). When the ICC-DMP component has a propagation velocity in the same order of magnitude as that of the slow wave activity (∼1 cm/s), cluster type propulsive activity occurs which is in fact the dominant propulsive activity of the intestine. Hence, the only difference between the generation of propagating cluster contractions and the Cannon-type segmentation motor pattern is the propagation velocity of the low-frequency component, the rhythmic transient depolarizations originating from the ICC-DMP. Importantly, the proposed mechanism explains why both motor patterns have distinct rhythmic waxing and waning of the amplitude of contractions. The hypothesis is brought forward that the velocity is modulated by neural regulation of gap junction conductance within the ICC-DMP network.

Discrepancies between c-Kit positive and Ano1 positive ICC-SMP in the W/Wv and wild-type mouse colon; relationships with motor patterns and calcium transients

Interstitial cells of Cajal associated with the submuscular plexus (ICC‐SMP) generate omnipresent slow‐wave activity in the colon and are associated with prominent motor patterns. Our aim was to investigate colon motor dysfunction in W/Wv mice in which the ICC are reportedly reduced.

The myogenic and neurogenic components of the rhythmic segmentation motor patterns of the intestine

Almost all motor patterns in gut organs have as primary function the mixing of content. Although classical peristalsis is equated with propulsion, and this is certainly the case in the esophagus, the predominant effect in all other organs is mixing and exposing the content optimally to the mucosal surface, because the propulsion ends somewhere and the content is moving back; only very rarely does propulsion end with evacuation of content from the body. The segmentation motor pattern is different from peristalsis in that it contains only stationary or very short distance propagating contractions and hence is considered a specialized motor pattern for mixing and absorption. The segmentation motor pattern was described and illustrated by Cannon in 1902 based on X-ray observations and shown to be extremely rhythmic (Cannon, 1902). Alvarez was the first to find that the frequency of rhythmic segmenting contractions occurred at the frequency of a myogenic pacemaker and that in various regions of the intestine the frequency decreased in the same way as the pacemaker frequency decreased (Alvarez, 1914), suggesting a firm relationship between slow waves and segmentation. In 1968, Code and co-workers also recognized the role of slow waves in segmentation (Code et al., 1968); the slow waves were thought to go in and out of excitable regions of smooth muscle fibers. Ehrlein noted in 1987 that there were no electrical or mechanical features known that could distinguish peristaltic and segmental motor patterns (Ehrlein et al., 1987). In 2006, two major reviews on control of motility only very briefly mentioned segmentation: “The most basic small intestinal contractile pattern, segmentation, results from reciprocal inhibition and dis-inhibition of adjacent circular muscle” (Hasler, 2006) and “Oscillation of membrane potential through the slow wave cycle results in periods of high and low open probability for Ca2+ channels, and this naturally organizes the contractile pattern into a series of phasic contractions contributing to motility patterns such as peristalsis and segmentation” (Sanders et al., 2006). Recently, it was shown that spontaneous segmentation or decanoic acid-induced segmentation is associated with a waxing and waning of the slow wave activity that can occur prominently in the presence of nerve conduction block (Huizinga et al., 2014). Evidence was provided that waxing and waning developed when low frequency rhythmic transient depolarizations originating from interstitial cells of Cajal (ICC) associated with the deep muscular plexus (ICC-DMP) interacted with the omnipresent slow wave activity originating from ICC associated with the myenteric plexus (ICC-MP) through phase–amplitude coupling. That is, the phase of the low frequency activity modulated the amplitude of the higher frequency slow wave activity. Hence interacting myogenic electrical activities were seen to underlie the segmentation motor pattern. The segmentation motor pattern appeared to be associated with the induction of a low frequency component, causing minute rhythm clusters of contractions and a waxing and waning of the amplitudes of the individual contractions within a cluster (Huizinga et al., 2014). These clusters occurred prominently after decanoic acid in rats (Huizinga et al., 2014) or oleic acid in dogs (Ehrlein et al., 1987). In human small intestine studies, the post-prandial motility pattern can be quite variable but regular “cluster contractions” are often reported and seen to be mainly stationary (Hellstrom, 1995). In a study by Husebye (1999), the clusters were shown to have a minute rhythm, the contraction amplitudes within the clusters had a waxing and waning appearance with a frequency of ~10/min, hence occurring at the slow wave frequency (Husebye, 1999; Gallego et al., 2014). When a nutrient solution was given to healthy volunteers with or without 40 g/l ethanol, it was ethanol in particular that induced a low frequency component, the clustered contractions; the clusters occurred at 1 per 2–3 min and the individual contractions within the clusters at ~12/min with waxing and waning amplitudes (Schmidt et al., 1997). Hence also in the human small intestine, the slow wave frequency, as well as an additional lower frequency component, are reported in the post-prandial intestinal motor activity.

Editorial: Irritable Bowel Syndrome and the Elusive Mast Cells

Irritable bowel syndrome (IBS) is the most common condition seen by gastroenterologists. It presents with alternating symptoms of bowel dysfunction that often worsens with stress. The cause of these symptoms eludes investigators and many attempts have been made to discover an underlying pathology. This is a daunting task since symptoms come and go, and change characteristics. Furthermore, the pathology of IBS is unlikely to be identical in all patients. In addition, all symptoms and all features studied thus far have a strong overlap with healthy volunteers. Elsewhere in this issue, Braak et al. report a well-designed clinical investigation in patients with IBS and come to the conclusion that IBS is not characterized by mast cell or other immune cell proliferation, but by immune dysregulation in the colon. Is this the final answer?

Involvement of 5-HT3 and 5-HT4 receptors in colonic motor patterns in rats.

Colonic migrating motor complexes in the rat constitute two distinct propulsive motor patterns, pan‐colonic rhythmic long distance contractions (LDCs), and rhythmic propulsive motor complexes (RPMCs) occurring primarily in the mid/distal colon. Interstitial cells of Cajal govern their rhythmicity, but their occurrence is dependent on neural programs. Our aim was to investigate the involvement of 5‐HT3 and 5‐HT4 receptors in the generation and pharmacological control of the motor patterns.

On the origin of rhythmic contractile activity of the esophagus in early achalasia, a clinical case study

A patient with early achalasia presented spontaneous strong rhythmic non-propulsive contractions at ~7/min, independent of swallows. Our aim was to evaluate characteristics of the rhythmic contractions, provide data on the structure of pacemaker cells in the esophagus and discuss a potential role for interstitial cells of Cajal (ICC) in the origin of rhythmicity. We hypothesize that intramuscular ICC (ICC-IM) are the primary pacemaker cells. The frequency but not the amplitude of the rhythmic contractions was inhibited by the phosphodiesterase inhibitor drotaverine consistent with cAMP inhibiting pacemaker currents in ICC-IM. The frequency increased by wet swallows but not dry swallows, consistent with stretch causing increase in slow wave frequency in ICC-IM. New studies on archival material showed that ICC-IM were present throughout the human esophageal musculature and were not diminished in early achalasia. Although ICC-IM exhibited a low density, they were connected to PDGFRα-positive fibroblast-like cells with whom they formed a dense gap junction coupled network. Nitrergic innervation of ICC was strongly diminished in early achalasia because of the loss of nitrergic nerves. It therefore appears possibly that ICC-IM function as pacemaker cells in the esophagus and that the network of ICC and PDGFRα-positive cells allows for coupling and propagation of the pacemaker activity. Loss of nitrergic innervation to ICC in achalasia may render them more excitable such that its pacemaker activity is more easily expressed. Loss of propagation in achalasia may be due to loss of contraction-induced aboral nitrergic inhibition.