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Background: In the last 20 years, studies have shown that large bowel function can be modified by neural stimulation. While still in its infancy, this area of research is beginning to show promise., Methods: This overview brings together systematic reviews and meta-analyses of electrical stimulation used to treat colonic disorders (fecal incontinence, constipation, slow transit constipation [STC], irritable bowel syndrome [IBS-C], and spina bifida-neurogenic bowel). Different methods of electrical stimulation including through sacral nerves, paraspinal, transabdominal, and using electroacupuncture over the ankle or knee and direct stimulation of the bowel are reviewed., Results and Discussion: Most evidence is low level (pilot and small cohort studies) but with more RCTs appearing. Sacral nerve stimulation (SNS) does improve urinary dysfunction and fecal incontinence but not constipation. It is expensive with high rates of reoperation. Transcutaneous stimulation with interferential current (IFC, alternating current at KHz frequency with 2 channels out of phase) does improve constipation and may provide benefit as an adjuvant to behavioral or exercise therapies. Acupuncture and electro-acupuncture (low/very low-level evidence) may have a benefit for constipation., Conclusion: SNS is effective but expensive and limited to extreme patients. Transcutaneous stimulation is noninvasive and cheap and IFC may be effective for constipation, but many parameters need to be optimized and higher level evidence provided from studies (sham, blinding, and larger patient numbers). The next 20 years should be exciting in the field as higher level studies are performed., (© 2020 International Neuromodulation Society.)

Background: Rapid proximal colonic transit with anorectal holdup is a subtype of chronic constipation linked to food intolerance. We aimed to determine the effectiveness of dietary exclusion as a treatment for constipated children with rapid-transit constipation by scintigraphy., Methods: Questionnaires on diet and symptoms were mailed out to 125 children with chronic constipation and rapid proximal colonic transit on nuclear transit study at our institute between 1998 and 2014 years. Patients were given instructions and encouraged to undertake a six-food elimination diet targeting common protein allergens (dairy, wheat, soy, eggs, nuts, seafood). Answers were completed by circling an option or on visual analogue scale. Results were evaluated statistically using GraphPad Prism 6 by a Wilcoxon matched-pairs rank test. P < 0.05 was considered significant., Results: We received 44/125 responses, 26 patients [mean age 11 years (5-21)] had attempted elimination diet and 18 had not. Dairy and wheat were the most common foods eliminated and symptomatic improvement was greater for patients who had completely eliminated foods. Constipation, abdominal pain and pain on defecation were reduced (p < 0.01). Laxative usage decreased, although this was not statistically significant. Families encountered problems with dietary exclusion, particularly expense. Assistance from a dietician or nutritionist was sought by >50 % of families., Conclusion: Dietary exclusion is a promising strategy to treat constipation in children with rapid proximal colonic transit. However, it was hard for many families, demonstrating the need for identifying the cause more specifically and a better set of instructions for the family and/or dietitian to follow.

Purpose: Colonic elongation is reported as a possible cause for slow colonic transit, as it is observed in patients with slow-transit constipation (STC). This study aimed to determine the frequency of colonic elongation in children with STC or anorectal retention using radioimaging. We hypothesized that transverse colon elongation may occur in patients with STC, whereas sigmoid colon elongates in patients with anorectal retention., Methods: Nuclear transit scintigraphy performed for chronic constipation (1999-2011) was analyzed qualitatively for elongated transverse colon or sigmoid colon. Three major colonic transit patterns were identified: slow transit in the proximal colon (STC), normal proximal colonic transit with anorectal retention (NT-AR), and rapid proximal transit ± anorectal retention (RT). χ(2) Test was used for statistical analysis (P < .05 significant)., Results: From 1999 to 2011, 626 children had nuclear transit scintigraphy. Transverse colon elongation occurred more frequently in STC (73/322, or 23%) compared with NT-AR (9/127, or 7%) and RT (5/177, or 3%; P < .0001). Sigmoid colon elongation was equally common in NT-AR (8/127, or 6%) compared with RT (10/177, or 6%) and STC (14/322, or 4%; P < .9)., Conclusion: Transverse colon elongation is more common in STC (23%), whereas sigmoid colon elongation is not more common in anorectal retention. Colonic elongation may be the cause or the result of the underlying slow colonic transit., (Crown Copyright © 2012. Published by Elsevier Inc. All rights reserved.)

Hemokinin-1 (HK-1) is a newly identified tachykinin, originating from the immune system rather than neurons, and may participate in the immune and inflammatory response. In colonic mucosa of patients with inflammatory bowel disease (IBD), up-regulation of the TAC4 gene encoding HK-1 and increased production of prostaglandin E₂ (PGE₂) occur. Our aim was to examine the mechanistic link between human HK-1 and PGE₂ production in normal human colon. Exogenous HK-1 (0.1 μM) for 4 h evoked an increased PGE₂ release from colonic mucosal and muscle explants by 10- and 3.5-fold, respectively, compared with unstimulated time controls. The HK-1-stimulated PGE₂ release was inhibited by the tachykinin receptor antagonists (S)1-2-[3-(3,4-dichlorophenyl)-1-(3-isopropoxyphenylacetyl)piperidin-3-yl]ethyl-4-phenyl-l azonia-bicyclo[2.2.2]octane (SR140333) [neurokinin-1 (NK₁)] and N-[(2S)-4-(4-acetamido-4-phenylpiperidin-1-yl)-2-(3,4-dichlorophenyl)butyl]-N-methylbenzamide (SR48968) [neurokinin-2 (NK₂)] and was also inhibited by the cyclooxygenase (COX)-2 inhibitor N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide) (NS-398) but not by the COX-1 inhibitor 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-trifluoromethylpyrazole (SC-560). A parallel study with substance P showed similar results. Molecular studies with HK-1-treated explants demonstrated a stimulatory effect on COX-2 expression at both transcription and protein levels. It is noteworthy that this was coupled with HK-1-induced down-regulation of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) mRNA and protein expression. Immunoreactivity for 15-PGDH occurred on inflammatory cells, epithelial cells, platelets, and ganglia. This finding provides an additional mechanism for HK-1-evoked PGE₂ increase, in which HK-1 may interfere with the downstream metabolism of PGE₂ by suppressing 15-PGDH expression. In conclusion, our results uncover a novel inflammatory role for HK-1, which signals via NK₁ and NK₂ receptors to regulate PGE₂ release from human colonic tissue, and may further explain a pathological role for HK-1 in IBD when abnormal levels of PGE₂ occur.

Purpose: Transcutaneous electrical stimulation (TES) speeds up colonic transit in children with slow-transit constipation (STC). This study examined if concurrent upper gastrointestinal dysmotility (UGD) affected response to TES., Methods: Radio-nuclear transit studies (NTS) were performed before and after TES treatment of STC as part of a larger randomised controlled trial. UGD was defined as delayed gastric emptying and/or slow small bowel transit. Improvement was defined as increase of ≥1 Geometric Centre (median radiotracer position at each time [small bowel = 1, toilet = 6])., Results: Forty-six subjects completed the trial, 34 had NTS after stimulation (21 M, 8-17 years, mean 11.3 years; symptoms >9 years). Active stimulation increased transit in >50% versus only 25% with sham (p = 0.04). Seventeen children also had UGD. In children with STC and either normal upper GI motility (NUGM) and UGD, NTS improved slightly after 1 month (57 vs. 60%; p = 0.9) and more after 2 months (88 vs. 40%; p = 0.07). However, mean transit rate significantly increased with NUGM, but not UGD (5.0 ± 0.2: 3.6 ± 0.6, p < 0.01)., Conclusion: Transcutaneous electrical stimulation was beneficial for STC, with response weakly associated with UGD. As measured by NTS, STC children with NUGM responded slightly more, but with significantly greater increased transit compared to those with UGD. Higher numbers are needed to determine if the difference is important.

Background: Muscarinic acetylcholine receptors (MR) are involved in multiple intestinal reflexes. The cellular localization of subtypes of MRs within enteric circuits mediating muscle and mucosal reflexes remains to be demonstrated. This study aimed to localize the three functionally significant subtypes of MRs in human colon., Methods: Reverse transcriptase-PCR was used to determine expression levels of muscarinic receptor subtype (MRs) M1Rs, M2Rs and M3Rs in human colon. Indirect immunofluorescence and confocal microscopy was used to localize MRs in cryostat-cut sections of human colon. Sections were double labeled for multiple cellular and neurochemical markers. Western blotting was used to confirm specificity of the muscarinic antisera used., Key Results: All three MR subtypes were expressed in human colon. Immunoreactivity (IR) for M2Rs and M3Rs was most abundant in circular and longitudinal muscle. M1R-IR was most abundant on myenteric and submucosal nerve cells, both cholinergic and nitrergic. M3R-IR was also present on populations on myenteric nerve cell bodies. Immunoreactivity for all three receptors was present on nerve fibers in the circular muscle., Conclusions & Inferences: In the human colon, subtypes of MRs were present on multiple cell types within the enteric circuits underlying motility, secretory and vasoactive reflexes. The cellular distribution for MRs found in this study agrees with data from functional studies, providing insight into the role MRs have in mediating enteric cholinergic neurotransmission.

In guinea-pig ileum, ageing has been associated with a decrease in enteric neurons. This study examined guinea-pig colon and measured changes in gut dimensions, neuron size, density and ganglionic area. Changes in motor nerve fibres in the circular muscle were also measured. Myenteric neurons in whole-mount preparations of mid-colon from 2-week, 6-month, and 2-year-old guinea-pigs were labelled immunohistochemically with the neuronal marker human neuronal protein HuC/HuD, and numbers of neurons mm(-2), neuronal size, ganglionic area mm(-2), gut length, circumference and muscle thickness were measured. Corrected numbers of neurons mm(-2) and ganglionic area mm(-2) accounting for growth of the colon were calculated. Additionally, nerve fibres in circular muscle cross-sections were labelled with antibodies against nitric oxide synthase (NOS) and substance P (SP) and the density of nerve fibres in circular muscle was measured. The numbers of neurons mm(-2) decreased by 56% (from 2 weeks to 2 years) with no change in neuron size. Total neuron numbers decreased by 19% (P = 0.14) when adjusted for changes in length and circumference with age. The percentage area of NOS- and SP-immunoreactive (IR) nerve fibres in the circular muscle decreased (P < 0.001), but the total area of NOS and SP-IR nerve fibres increased (P < 0.01) due to an age-related increase in muscle thickness. The density of myenteric neurons in guinea-pig mid-colon halved from 2 weeks to 2 years, but when the increase in colon dimensions was considered, the number of neurons decreased by only 19%. The percentage area of motor nerve fibres in the circular muscle decreased with no change in total volume of nerve fibres.

The sitz or plastic marker study for colonic transit has been around for many years. It is applicable where an X-ray machine exists, is widely used and is accepted as the gold standard for diagnosing constipation. Recently, radiopharmaceutical methods have been developed. The theme of this review is their possible roles in the assessment of paediatric bowel motility disorders in patients presenting to paediatric surgeons. This review presents data on total and segmental transit in normal adults and children and comparing the two techniques in adults. Reliability and reproducibility are presented. Normative data for colonic transit in adults and children are discussed and parameters for assessing abnormal transit are reviewed. Normal colonic transit takes 20-56 h. Plastic marker studies are more readily accessible, but the assessment may be misleading with current methods. Plastic markers show faster transit than scintigraphy. It is difficult to compare the two techniques because methods of reporting are different. Using scintigraphy, repeatability is good. Separation of normal from slow transit in the ascending colon is apparent at 24 and 48 h, but the determination of transit through the distal colon/rectum in adults may require studies of more than 7 days. In conclusion, plastic marker studies and scintigraphy show similar transit rates in young adults and children. However, scintigraphy has advantages of allowing transit through the stomach and small intestine to be measured and has proved useful in the diagnostic workup of children with intractable constipation.

Background: Slow transit constipation (STC) is a form of chronic constipation characterised by prolonged passage of faecal matter through the colon. It is diagnosed by demonstrating delayed colonic transit on gastrointestinal transit studies. Traditionally, radio-opaque marker studies are performed. Recently, radioisotope nuclear transit studies (NTS) have been used in our centre to assess gastrointestinal transit time. This study aimed to evaluate if there are changes in colonic transit in STC children resistant to standard medical treatment over a prolonged period., Methods: Children with STC resistant to standard medical therapy for > or =2 years who had undergone two separate NTS to assess their colonic transit (where the first study had identified slow colonic transit without anorectal retention) were identified after ethical approval. The geometric centre (GC) of radioisotope activity at 6, 24, 30 and 48 h was compared in the two transit studies to determine if changes occurred., Results: Seven children (4 males) with proven STC resistant to standard medical therapy and two transit studies performed at different times were identified. Mean age was 7.0 years (5.4-10.8 years) at first study, and 11.4 years (9.7-14.2 years) at second study, with a mean of 4.4 years (1-8.5 years) between studies. There was no significant difference in colonic transit at any timepoint in the two tests (paired t test)., Conclusions: We conclude that nuclear transit studies are reproducible in assessing slow colonic transit in children with treatment-resistant STC and demonstrate that conventional medical treatment over many years has no effect on underlying colonic motility.

Unlabelled: Chronic constipation in children is common and produces significant morbidity. Identification of the site of dysmotility in constipation may determine the cause and permit directed management. Scintigraphy differentiates constipated patients with anorectal hold-up from those with colonic slowing. Adults with colonic slowing demonstrate variation in the site of hold-up. However, in children with colonic slowing, variability in the site of hold-up has not been investigated., Purpose: The current study aimed to characterise colonic transit patterns in 64 children with chronic idiopathic constipation., Methods: Scintigraphic images were grouped visually by their transit patterns. Intra-observer variation was assessed. Scintigraphic data were analysed quantitatively., Results: Visual analysis of scintigraphy studies demonstrated normal transit (11/64), anorectal hold-up (7/64) and slow colonic transit (46/64). Transit characteristics in the slow transit group demonstrated three possible subgroups: pancolonic slowing (28/46), discrete hold-up in the transverse colon (10/46) and abnormal small and large bowel transit (8/46). Kappa testing demonstrated consistent characterisation (k = 0.79). Statistical analysis of scintigraphic data demonstrated highly significant differences from normal (P < 0.001) in the subgroups., Conclusion: Scintigraphy demonstrates three possible transit patterns in children with chronic constipation secondary to slow colonic transit.

Background: The physiological basis of slow transit constipation (STC) in children remains poorly understood. We wished to examine pan-colonic motility in a group of children with severe chronic constipation refractory to conservative therapy., Methods: We performed 24 h pan-colonic manometry in 18 children (13 boys, 11.6 +/- 0.9 yr, range 6.6-18.7 yr) with scintigraphically proven STC. A water-perfused, balloon tipped, 8-channel, silicone catheter with a 7.5 cm intersidehole distance was introduced through a previously formed appendicostomy. Comparison data were obtained from nasocolonic motility studies in 16 healthy young adult controls and per-appendicostomy motility studies in eight constipated children with anorectal retention and/or normal transit on scintigraphy (non-STC)., Results: Antegrade propagating sequences (PS) were significantly less frequent (P < 0.01) in subjects with STC (29 +/- 4 per 24 h) compared to adult (53 +/- 4 per 24 h) and non-STC (70 +/- 14 per 24 h) subjects. High amplitude propagating sequences (HAPS) were of a normal frequency in STC subjects. Retrograde propagating sequences were significantly more frequent (P < 0.05) in non-STC subjects compared to STC and adult subjects. High amplitude retrograde propagating sequences were only identified in the STC and non-STC pediatric groups. The normal increase in motility index associated with waking and ingestion of a meal was absent in STC subjects., Conclusions: Prolonged pancolonic manometry in children with STC showed significant impairment in antegrade propagating motor activity and failure to respond to normal physiological stimuli. Despite this, HAPS occurred with normal frequency. These findings suggest significant clinical differences between STC in children and adults.

Interstitial cells of Cajal (ICC) act as pacemaker in gastrointestinal smooth muscle. In animals, small bowel dilatation produces a reduction in ICC numbers and in pacemaker function. With resolution of dilatation, ICC numbers and pacemaking function are partially restored. In human colonic disease states, dilatation is associated with dysmotility. The effect of dilatation on ICC distribution has not previously been examined in the human colon. Tissues from a neonate with colonic atresia and a 17-year-old adolescent with acquired megasigmoid were fixed, sectioned and incubated with anti cKit antibodies followed by fluorescent secondary antibodies. Distended and non-distended segments of colon were examined for ICC distribution using immunohistochemistry to c-Kit. Images were obtained with confocal microscopy. In both patients, there was a marked reduction in cKit-immunoreactive cells in the circular muscle and the myenteric plexus of the distended colon compared to the distal non-distended colon. Dilatation of the human colon is associated with a marked reduction in ICC. A resulting loss of pacemaker function could contribute to dysmotility associated with distension. Further studies assessing pacemaking function in human subjects and investigating reversibility of ICC disruption may allow new therapeutic strategies.

Background: Multiple endocrine neoplasia (MEN) 2B is a rare hereditary syndrome that results from an activating mutation of the RET proto-oncogene. The RET gene is involved in the development of the enteric nervous system. Patients with MEN 2B have enlarged enteric ganglia and may be affected by gastrointestinal dysmotility. A deficiency of the neurotransmitter substance P (SP) has been identified in both pediatric and adult patients with chronic constipation., Methods: Three patients, in whom constipation was the presenting symptom and MEN 2B had been provisionally diagnosed, underwent genetic analysis. Seromuscular colonic biopsies were taken for immunofluorescence imaging in all 3 patients. A retrospective review of the patient notes was undertaken., Results: All 3 patients had constipation refractory to conservative treatment. Genetic analyses in the 3 patients confirmed an identical RET mutation (Met918Thr). Immunofluorescence imaging in all 3 patients identified grossly enlarged myenteric plexus ganglia but surprisingly a low density of SP-labeled nerve fibers in the colonic circular muscle. Nitric oxide synthase and vasoactive intestinal peptide labeling were not reduced., Conclusion: The results show an association between MEN 2B and its most common RET mutation, colonic dysmotility, and low density of SP in the colonic circular muscle. Larger numbers of patients need to be studied to investigate whether low SP is primarily associated with the constipation or RET mutation and if it is a common feature of MEN 2B.

Background: Neurokinin receptors facilitate tachykinin mediated intestinal motility and secretion. Distribution of Substance P (SP) neurokinin 1 receptor (NK1r) immunoreactivity (IR) has been previously characterized in guinea pig ileum, but not colon. This study localizes NK1rs in guinea pig distal colon., Methods: Neurons were double labelled for NK1r and either acetylcholine transferase (ChAT), calbindin (calb), neuropeptide Y (NPY), nitric oxide synthase (NOS) or SP. The NK1r endocytosis was induced by 10(-5) mol L(-1) SP, septide, [SarMet] SP or neurokinin A., Results: In guinea pig distal colon, NK1r-IR was present on 70% of submucosal neurons. Sixty-threepercent of the NK1r-IR submucosal neurons were ChAT-IR, 16% calb/SP-IR, 19% NPY-IR and 14% NOS-IR neurons. The NK1r-IR was present on 5% of myenteric neurons. Of these 63% were ChAT-IR, 16% calb-IR neurons and 25% NOS-IR. The NK1rs were also on myenteric plexus interstitial cells of Cajal and on circular muscle., Conclusion: In guinea pig distal colon, NK1rs were on 70% of submucosal neurons including all three secretomotor neuron subtypes and sensory neurons, suggesting NK1rs have a major role in neuronal control of mucosal reflexes. The NK1rs were on few myenteric neurons but were dense on muscle cells, suggesting NK1rs affect motility through neuro-muscular rather than neuro-neuronal transmission.

Background/purpose: We wish to define colonic motor function in children with slow-transit constipation (STC) using manometry catheters introduced through appendiceal stomas, previously sited for controlling fecal retention by colonic irrigation., Methods: We undertook 24-hour pancolonic manometry of 6 children (5 boys; mean, 11.5 years; SD, 3.0) using a multilumen silastic catheter., Results: were compared to nasocolonic motility studies obtained in healthy young adults., Results: Antegrade propagating sequences (APSs) originated less frequently in the cecum compared to controls. There were fewer APS (mean +/- SEM: STC, 13 +/- 6 per 24 hours; controls, 52 +/- 6 per 24 hours; P < .01) and high-amplitude propagating contractions (HAPCs: STC, 5 +/- 2 per 24 hours; controls, 9.9 +/- 1.4 per 24 hours; P < .05). The amplitude of APS and HAPC was less in STC (APS, 39 +/- 9 mm Hg; controls, 54 +/- 3 per 24 hours; P < .05) (HAPC: STC, 94 +/- 10 mm Hg; control, 117 +/- 3 mm Hg; P < .01), whereas the amplitude of retrograde propagating sequences was greater in STC (43 +/- 6 mm Hg; control, 27 +/- 1 mm Hg; P < .01). The distances propagated by HAPC were significantly less in STC (36 +/- 4.5 vs 47 +/- 2.3 cm, controls; P < .05), and there was no evidence of a region-specific difference in propagation velocity of APS. Neither meal ingestion nor waking significantly increased colonic motor activity in patients with STC., Conclusions: Despite the small numbers available to be studied, we found that children with STC in whom an appendicostomy had been placed show significant abnormalities in pancolonic motor function.

Tachykinins (TKs) colocalize with acetylcholine in excitatory motor neurones supplying human colonic circular muscle (CCM). Some children with slow-transit constipation (STC) have reduced TK-immunoreactivity in nerve terminals in CCM suggesting a deficit in neuromuscular transmission. This study aimed to test this possibility. Seromuscular biopsies of transverse colon were obtained laparoscopically from STC children (37, 17 with low density of TK-immunoreactivity). Specimens of transverse (17) and sigmoid colon (20) were obtained from adults undergoing colonic resection for cancer. CCM contractions were measured isotonically and responses to carbachol, neurokinin A (NKA) and electrical field stimulation (EFS) recorded. Carbachol and NKA-evoked contractions in adult and STC colon. Hyoscine (2 micromol L-1) significantly depressed responses to EFS in all preparations. Blockade of NK2 receptors (SR 48968, 2 micromol L-1) significantly depressed EFS-evoked contractions of adult transverse CCM, but had no effect on STC preparations. Thus, neuromuscular transmission in both adults and STC children is predominantly cholinergic and this component is unimpaired in the latter, indicating that reduced TK-immunoreactivity is not a marker for depressed cholinergic responses. Although pharmacologically responsive TK receptors are present in STC colon, we did not detect neuromuscular transmission mediated by release of TKs in these preparations.