CoNSENSuS Statement E X P E RT C O N S E N S U S D O C U M E N T First translational consensus on terminology and definitions of colonic motility in animals and humans studied by manometric and other techniques Maura Corsetti1,2,16, Marcello Costa3,16, Gabrio Bassotti 4, Adil E. Bharucha5, Osvaldo Borrelli6, Phil Dinning3,7, Carlo Di Lorenzo8, Jan D. Huizinga9, Marcel Jimenez10, Satish Rao11, Robin Spiller 1,2, Nick J. Spencer12, Roger Lentle13, Jasper Pannemans14, Alexander Thys14, Marc Benninga15 and Jan Tack14* Abstract | Alterations in colonic motility are implicated in the pathophysiology of bowel disorders, but high-​resolution manometry of human colonic motor function has revealed that our knowledge of normal motor patterns is limited. Furthermore, various terminologies and definitions have been used to describe colonic motor patterns in children, adults and animals. An example is the distinction between the high-​amplitude propagating contractions in humans and giant contractions in animals. Harmonized terminology and definitions are required that are applicable to the study of colonic motility performed by basic scientists and clinicians, as well as adult and paediatric gastroenterologists. As clinical studies increasingly require adequate animal models to develop and test new therapies, there is a need for rational use of terminology to describe those motor patterns that are equivalent between animals and humans. This Consensus Statement provides the first harmonized interpretation of commonly used terminology to describe colonic motor function and delineates possible similarities between motor patterns observed in animal models and humans in vitro (ex vivo) and in vivo. The consolidated terminology can be an impetus for new research that will considerably improve our understanding of colonic motor function and will facilitate the development and testing of new therapies for colonic motility disorders. The human colon performs several essential functions There is ample agreement that the fundamental including fermentation of nutrients, absorption of water nature of the cellular mechanisms that regulate colonic and electrolytes, and storage and timely expulsion of motor activity is well preserved across mammalian faecal contents1. These functions require a complex, species, including humans, despite the diversity in ana- highly integrated and regulated activity of the colonic tomical features of the colon, and the consumption of muscle that is critical for maintaining health and quality a variety of diets. However, the introduction of high-​ of life. resolution manometry (HRM) to study human colonic Alterations in colonic motor function have been motor function in the past 5 years has revealed that our implicated in the genesis of symptoms associated with current concepts of normal colonic motor activity are various bowel motility disorders, such as functional diar- somewhat limited and might even be flawed6–8. This rhoea or constipation and IBS2,3. The study of colonic problem is further complicated by the fact that, over motility using colonic manometry has been recom- the years, different techniques and protocols have been mended by guidelines and expert reviews to identify applied to study colonic function9. *e-​mail: jan.tack@ med.kuleuven.be colonic motor dysfunction in treatment-​refractory con- Thus, a consensus conference was organized in https://doi.org/10.1038/ stipation in children and adults before consideration of Leuven, Belgium, in September 2016 to critically evalu- s41575-019-0167-1 surgical intervention3–5. ate all aspects of colonic motility from bench to bedside. NATuRe RevIewS | GASTRoENTERology & HEPATology volume 16 | SEPTEMBER 2019 | 559 C o n S e n S u S S tat e m e n t The conference had three objectives: appraise the current years and who were selected and invited to participate knowledge of normal colonic motor patterns (CMPs) in in the process. The selection process took three charac­ humans and in animal models gathered both in vitro teristics into account: diversity in research expertise and in vivo; critically evaluate commonalities and dif- (study of colonic motility in animal models, in human ferences between animal models and humans; and gen- samples in vitro, in adults and children with manometric erate agreement on terminology and definitions that but also nonmanometric techniques); affiliations with can be applied to the study of colonic motility among different societies (United European Gastroenterology, basic scientists and clinicians, as well as among adult and American Gastroenterological Association, European paediatric gastroenterologists (Box 1). and American societies); and diversity in region. All This Consensus Statement provides a conceptual invited participants agreed to participate and were sup- and methodological framework to expand studies on portive of the scope and general aims of the project, colonic motility, both in experimental animals and leading to the consensus group comprising the current humans. This work is intended not only to facilitate the 15 members. development of new drugs to treat common colonic The core group identified five areas of interest, corre- motility disorders, such as chronic constipation and sponding to the main sections of this Expert Consensus irritable bowel syndrome (IBS), but also to pave the way Statement, which were described in a working docu- for the development of appropriate diagnostic and ther- ment. This document was circulated to each member apeutic algorithms for management of paediatric and and it was decided that each group would work on their adult patients. assignments from October 2015 to prepare a review doc- ument to be presented and discussed in a face-​to-face Methods meeting in Leuven in September 2016. Five leaders were The decision to initiate a consensus effort to bring identified to coordinate the work of each group and to together basic scientists and adult and paediatric facilitate the interaction with the core group that coor- gastro­enterologists and conduct the first ‘translational’ dinated the consensus. During this period, the mem- consensus in this area was taken by a small core group bers of each group interacted with each other via e-​mail (M. Corsetti, M. Costa and J. Tack) that prepared and ini- to prepare their document that was then circulated to tiated the process, after a meeting in Rome in September members of the other groups 2 months before the 2015. Because no precedent for such efforts existed and consensus meeting. the topic was not readily amenable to traditional scien- During the face-​to-face meeting, all five documents tific investigation, an approach based on expert-​based were briefly presented, extensively discussed, and revised. consensus was chosen. The core group identified a group Subsequently, the members of the consensus group of eligible contributors who have considerably contrib- drafted five separate text segments, which were merged uted to the current knowledge in this field over several into a first draft of the manuscript which was then cir- culated to all participants in March 2017. All members commented on the content and wording, and areas Author addresses of disagreement were identified, discussed and adapted if required. This process resulted in optimization of the 1 NIHR Nottingham Biomedical Research Centre (BRC), Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK. language, harmonization of terminology and restruc- 2 Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, turing of the manuscript. An updated version of the Nottingham, UK. manuscript was generated and circulated for evaluation 3 Human Physiology and Centre of Neuroscience, College of Medicine, Flinders University, in July 2017. All panel members endorsed this ver- Bedford Park, South Australia, Australia. sion, which was finalized into the document submitted 4 Department of Medicine, University of Perugia Medical School, Perugia, Italy. for publication. 5 Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA. M. Corsetti had the idea of the consensus. M. Corsetti, 6 Department of Paediatric Gastroenterology, Great Ormond Street Hospital for Sick M. Costa and J. Tack organized the consensus, col- Children, London, UK. lated the different parts and provided critical revi- 7 Department of Gastroenterology and Surgery, Flinders Medical Centre, Adelaide, sion of the manuscript. M. Costa, J. D. Huizinga and South Australia, Australia. 8 Department of Pediatric Gastroenterology, Nationwide Children’s Hospital, The Ohio R. Lentle performed the review and wrote the section State University, Columbus, OH, USA. concerning the colonic motility as studied in animals. 9 Department of Medicine, Farncombe Family Digestive Health Research Institute, N. J. Spencer and M. Jimenez performed the review McMaster University, Hamilton, Ontario, Canada. and wrote the section concerning the colonic motil- 10 Department of Cell Physiology, Physiology and Immunology and Neuroscience ity as studied in isolated human colon. M. Corsetti, Institute, Universitat Autònoma de Barcelona, Barcelona, Spain. P. Dinning, G. Bassotti, J. D. Huizinga and S. Rao per- 11 Division of Gastroenterology/Hepatology, Augusta University, Augusta, GA, USA. formed the review and wrote the section concerning the 12 Discipline of Human Physiology, School of Medicine, Flinders University, Bedford Park, colonic motility as studied in adult humans by means South Australia, Australia. of colonic manometry. C. Di Lorenzo, M. Benninga and 13 Digestive Biomechanics Group, College of Health, Massey University, Palmerston North, O. Borrelli performed the review and wrote the sec- New Zealand. 14 Department of Paediatric Gastroenterology and Nutrition, Emma Children’s Hospital/ tion concerning the colonic motility as studied in chil- Academic Medical Centre, Amsterdam, Netherlands. dren by means of colonic manometry. A. E. Bharucha, 15 Translational Research Center for Gastrointestinal disorders (TARGID), Department P. Dinning and R. Spiller performed the review and wrote of Clinical and Experimental Medicine, University of Leuven, Leuven, Belgium. the section concerning the colonic motility as stud- 16 These authors contributed equally: Maura Corsetti, Marcello Costa ied in humans in vivo by means of non-​manometric 560 | SEPTEMBER 2019 | volume 16 www.nature.com/nrgastro C o n S e n S u S S tat e m e n t Box 1 | Fundamental outstanding questions and recording at one location along the colon. When studying CMPs, distinguishing between simply observ- The consensus meeting raised a number of fundamental questions about our current ing motor activities for some period of time (natu- knowledge of the colon and colon motility that are unanswered but are relevant to the ralistic observations) and stimulus-​induced motor successful integration of basic science and clinical science. patterns (experimental physiology) is important. An 1. What is the role of central inputs in colonic movements? example of naturalistic motor activity is the occurrence Propulsion of colon contents and subsequent emptying (defecation) involve different of high-​amplitude propagating contractions (HAPCs) levels of input from the central nervous system depending on diets. Omnivores, such as recorded during colonic manometry. An example of rats and humans, defecate at longer intervals than herbivores, such as rabbits and an experimental physiological motor pattern are the guinea pigs, and have greater dependence on neural inputs from the central nervous HAPCs evoked by intraluminal bisacodyl 14. These system and on environmental and social influences. Hence, the role of extrinsic innervation in humans in the generation of normal motor patterns and pathophysiology two different approaches to investigation are equally needs further study. valid for examining colonic motility, and provide complementary information. 2. What is the nature of haustra? The nomenclature of specific colonic motor events The functional and anatomical nature of haustra in both the animal colon and the human colon remains unclear. Chen et al.21 concluded that “the two definitions come has been widely discussed. Frequently used terms down to seeing haustra as passively formed by contracted taenia or actively formed by include contractions, sequences or pressure waves. circumferential muscle contractions”, which leads to the question whether haustral The consensus panel agreed that any of these terms are boundaries in humans are fixed or are caused by functional slowly advancing circular acceptable and authors are encouraged to indicate the muscle contractions. The persistence of folding at particular sites of the colon after equivalent terms explicitly. death would favour the first hypothesis, whereas the disappearance of the haustrations CMPs can be highly modulated by, or even be during mass movements and their documentation as migrating motor complexes in the dependent on, extrinsic neural connections via visceral proximal colon of herbivores would favour the second hypothesis. sensory pathways and efferent sympathetic and para- 3. What are the characteristics of colonic motility under physiological conditions? sympathetic pathways. To what extent motor patterns Much of our current knowledge on colonic motility in humans has been acquired after a are generated by neurogenic and myogenic mechanisms, bowel preparation and anaesthesia or local sedation that are necessary for the placement even in the absence of extrinsic inputs, is not yet clear. In of manometric catheters. Thus, the challenge of establishing the characteristics of the animals, a far higher number of studies have been per- motor patterns and their role in transit and absorption under more-​physiological formed on isolated preparations (in vitro and ex vivo are conditions remains. used as equivalent terms) than in live animals (in vivo). By contrast, in humans, far more observations have been techniques. J. Pannemans and A. Thys collected the min- made in conscious individuals than in isolated prepa- utes of the consensus meetings, prepared the figures and rations of human colon. Some evidence indicates that the references of the manuscript and helped M. Corsetti, many motor patterns described in vivo, such as neuro- M. Costa and J. Tack. genic peristaltic contractions and slow-​wave-generated myogenic phasic contractions, can be observed in iso- Considerations for techniques lated preparations under suitable conditions15,16. Hence, Suitable recording methods must be applied to estab- the consensus group widely agreed that CMPs could, in lish which processes underlie the generation of different principle, be observed both in vivo and in vitro. motor patterns. Since the development of advanced elec- trophysiological techniques, spatiotemporal mapping Colonic motor patterns in animals techniques and HRM, a considerable body of evidence This section summarizes the different motor patterns has accumulated on the neurogenic (dependent on neu- described in the literature. We propose common termi- ronal pathways) and myogenic (dependent on smooth nology for CMPs and identify areas for further research muscle activity) components of CMPs. Most CMPs are into underlying mechanisms. the result of the interaction between neurogenic and In the colon of omnivores (mouse, rat, dog, pig or myogenic processes, as both neurogenic and myogenic human) the anatomical distinction between the proxi- mechanisms operate concurrently. Depending on the mal and distal colon is less marked than in herbivores17, main process underlying the motor patterns, the terms although a separate caecum is present. The human neurogenic, myogenic or neuro-​myogenic are used in colon is surprisingly more complex than that of other this article. omnivores. It has a relatively small caecum and three The methods that are most frequently used and taeniae, which extend from the proximal colon all the suitable to describe motor patterns include mechanical way to the sigmoid colon, where they fuse to form a recording with isometric or isotonic transducers, strain single longitudinal muscle layer that continues into gauges, intraluminal pressure sensors, and some correla- the rectum17. tions with electrical extracellular or intracellular record- The colons of the rat and mouse do not have separate ings. Methods of recording movements with video, taeniae, and functional differences along their length fluoroscopy or cineradiography, and different forms of are still being investigated. The most detailed analysis analysis of changes in shape of the colonic wall have been of colonic movements and comparisons of differences introduced over the past two decades10–13. in its anatomical components have been performed in Motor patterns can obviously be better described two herbivores: the rabbit and the guinea pig18–21. The using more intact segments of the colon and multi- interest in these two species, particularly in the rabbit, ple recording sites (for example, with spatiotemporal stems from the similarity of its triple taeniated proxi- maps) than when using small tissue strip preparations mal colon to that of the major part of the human colon. NATuRe RevIewS | GASTRoENTERology & HEPATology volume 16 | SEPTEMBER 2019 | 561 C o n S e n S u S S tat e m e n t a b c Oral mm mm 10 28 Fast phasic Slow phasic contractions contractions Ripples Ripples 5 12 20 mm 20 mm 20 mm Anal 60 s 30 s 60 s Fig. 1 | Myogenic motor patterns in animals. The images show graphical representations of wall motion captured by video recordings of a colon segment in an organ bath. Each frame of the video is converted to a greyscale image that maps changes in colon diameter. In these diameter maps (DMaps), darker shading represents an increased diameter (dilation) and lighter regions represent a reduced diameter (contraction). The three DMaps show the three main myogenic (non-neurogenic) patterns of motor activity in the colon of different animal species (in vitro isolated preparations). a | In the colon of most experimental animals, chaotic shallow contractions, termed ripples, are generated by a network of pacemaker cells at the submucous border (interstitial cells of Cajal (ICC) submucosal) acting on the circular muscle to elicit slow waves. In this example from a rabbit distal colon, these ripples become prominent once the neural activity is blocked by tetrodotoxin20. b | In some species, faster ripples have been recorded, which seem to be generated by a net of pacemaker cells located at the myenteric plexus level (ICC myenteric). In this example from the rabbit proximal colon, fast phasic contractions appear following application of hexamethonium, which blocks nicotinic receptors24. c | Slow phasic contractions have been recorded, for example in the rat colon after blocking neural activity with lidocaine and then applying the cholinergic agonist carbachol; whether these slow myogenic contractions exist in all species remains to be determined37. Part a adapted with permission from ref.20, The American Physiological Society. Part b adapted from ref.24, Springer Nature Limited. Part c adapted from ref.37, CC-​BY-4.0 https://creativecommons.org/licenses/by/4.0/. In these two herbivores, the anatomy of the large intes- when the smooth muscle action potential threshold is tine shows marked anatomical variation along its length, reached (Fig. 1). The motor pattern generated is referred with a separate caecum. The shaping of the particulate to as ripples. content of the colonic digesta commences in the prox- D’Antona et al.19 defined ripples in the proximal colon imal colon. By the time it reaches the colonic flexure, in the guinea pig as orally and aborally propagating shal- the solid residue is moulded into recognizable soft faecal low circumferential contractions of the circular muscle, pellets (scibalae). Distal to this transition area, and read- which are insensitive to tetrodotoxin. Lentle et al.24 and ily recognizable in herbivores such as rabbits and guinea Dinning et al.20 also described them in the rabbit proxi- pigs, pellets are found along the entire distal colon and mal and distal colon as contractions with varying levels rectum18,22–24. Although no obvious anatomical correlate of spatial coordination. All investigators who recorded to the flexure in herbivores exists in the human colon, colonic movements either in the conscious rabbit23 or in the structure of the ascending, transverse and descend- isolated rabbit colon preparations8,20,21,24 described rip- ing human colon seems to correspond to the proximal ples within the bulging haustrations, moving in either colon in herbivores. The functional equivalent of the direction, although sometimes they were described as flexure would then correspond to the sigmoid-​rectal being preferentially propagated orally23,24. Ripples in the junction. Compelling evidence for this comparison colon of herbivores seem to be involved in mixing and requires functional confirmation. perhaps in retarding fluid progression, but not in bulk propulsion of contents. Myogenic colonic motor patterns. All the species stud- The complex and chaotic nature of ripples probably ied seem to have at least three pacemaker cell systems results from the spontaneous fluctuation in membrane in their colon. Electrical oscillations in smooth mus- potential generated by contiguous nets of ICC pace- cle are present throughout the digestive tract and are makers that generate different frequencies of oscilla- driven by pacemaker cells, now unequivocally iden- tions within populations located at different sites28. The tified as the interstitial cells of Cajal (ICC)25–27. In the conceptual frame most suitable to describe the nature of colon, the network of ICC located near the submucosal this myogenic motor pattern is an active medium con- border (the ICC of the submucosal plexus (ICC-​SMP) sisting of loosely coupled individually oscillating pace- and the ICC of the submucosa (ICC-​SM)) generates maker cells29. As expected from this conceptual model, electrical oscillations in the circular muscle, also called these oscillations propagate at varying distances along slow waves. Their frequency varies depending on the the colon both aborally and orally and annihilate each species, with increasing frequency in smaller species. other when they collide19,21,30. For example, slow waves occur at 2–6 cycles per min- In the colon, the network of ICC at the boundary ute (cpm) in the human colon, but at 15–18 cpm in the between the circular and longitudinal muscle (variously mouse colon. These electrical oscillations propagate into termed ICC myenteric plexus (ICC-​MP), ICC myenteric the musculature and generate rhythmic contractions (ICC-​M Y) or ICC Auerbach plexus (ICC-​A P)) 562 | SEPTEMBER 2019 | volume 16 www.nature.com/nrgastro C o n S e n S u S S tat e m e n t generates higher frequency oscillations than the ICC-​ between these myogenic processes and enteric neural SMP and ICC-​SM that drive both muscle layers31. These circuits to generate complex motor patterns is likely37. oscillations were originally described as myenteric potential oscillations in dogs and humans31,32. These Neurogenic colonic motor patterns. In all animal species, high-​frequency electrical oscillations of smooth mus- both in vivo and in vitro, strong evidence exists that dis- cle membranes generate rhythmic contractions and are tension of the colon to a suitable extent (regardless of referred to as high-​frequency ripples when they activate content consistency) initiates neurogenic propulsive neighbouring muscle layers to their contractile thresh- movements that propel the contents aborally (Fig. 2). old. High-​frequency ripples, also termed fast propa- In their classic preparation of the colon of dogs, gating contractions in some publications, have been maintained under deep irreversible anaesthesia, Bayliss described in intact segments of the colon in rats and and Starling41 used a solid bolus and described propul- rabbits21,33. They are not abolished by drugs that block sive movements that were evoked as peristaltic contrac- neural activity (for example, tetrodotoxin)24,33. These tions or peristaltic waves. Several investigators have since high-​frequency ripples appear synchronous over some shown colonic propulsion of boluses in isolated prepa- distances and occur at higher frequency than the slow rations in mice42,43, in guinea pigs44,45 and in rabbits46,47, waves in the same species21,24,33. They consist of synchro- as well as in conscious dogs48–53. Similar propulsive con- nous longitudinal and circular contractions24 that do not tractions have also been described in vivo in cats54, in have a ring-​like appearance21. They traverse patterns of monkeys55, in ferrets56 and in rats and mice57,58. Several ripples without annihilating them24, suggesting that of the investigators named such propulsive movements they are driven by a pacing network distinct from the giant contractions. one that generates ripples that are not high frequency. Distension of the proximal colon triggers large prop- Summation (amplitude–amplitude interaction) or phase agating contractions that propel content aborally. These amplitude cross-​frequency coupling between fast oscil- movements have also been termed mass movements lations of the ICC-​MP and slow waves from ICC-​SMP or mass peristalsis24 and are similar in nature to those can occur31,34. Lentle et al.24 suggested that the frequency observed in the rabbit colon in vivo by Ehrlein and col- of high-​frequency ripples seemed to vary spontaneously leagues23. Similar propulsive motor patterns occur in the between several discrete values. proximal and distal colon of guinea pigs when it is mark- The mechanical role of these high-​frequency rip- edly distended by liquid. In these latter studies, the activ- ples in normal movements is uncertain. By themselves, ity was called neural peristalsis or antegrade neurally they are unlikely to be mechanically effective in mix- dependent peristaltic contractions18,19. In the isolated cat ing or propulsion. However, the high-​frequency ripples colon, such propulsive movements were described as net often occur in clusters and might become propulsive6. aboral propulsion59. In the isolated colon of the guinea Furthermore, when slow-​wave-driven ripples occur pig, rat and mouse, fluid distension triggers rapid fluid simultaneously with clusters of high-​frequency ripples, propulsion variously termed neural peristalsis, or long-​ the intraluminal pressure generated becomes greater distance contractions33,42,60,61. A general consensus exists than if either ripple occurs alone20,35. that these propulsive movements, initiated by a bolus or Slow phasic contractions are a third type of much general distention, are generated by enteric neural cir- slower myogenic contractile activity that has been cuits and can therefore be regarded as neural in origin described in some species. Slow phasic contractions are (neurogenic) and are described as peristalsis or the per- caused by cyclic smooth muscle depolarizations that istaltic reflex45,62–67. The term peristaltic reflex has often can be recorded both in the longitudinal and circular been used to refer to the activation of polarised enteric muscle28,36. Slow phasic depolarizations and contrac- reflexes45,68, whereas peristalsis characterizes a sequential tions are recorded in tissue devoid of ICC-​SMP, and activation of the polarised reflexes and should therefore consequently this myogenic activity probably originates be regarded as an ongoing behaviour69,70. Thus, a suitable from within ICC-​MP. Such myogenic contractions have consensus modern term to describe these movements is been well demonstrated in the rat colon28,33,37 and rabbit neural peristalsis. The amplitude and propagation speed colon20,21,24,33. In guinea pigs, similar slow myogenic con- of the contractions underlying these propulsive move- tractions occur at the colonic flexure38. However, slow ments varies depending on the contents (solid, viscous myogenic contractions were not detected in full segments or liquid), as discussed later. of the distal colon of the guinea pig even after direct In 1899, Bayliss and Starling71 proposed that the pro- stimulation of the muscle33. Possibly, these myogenic pulsion of a bolus is a result of the activation of polar- contractions are dependent on specific conditions. ized enteric neural pathways leading to oral contraction The slow phasic contractions are more susceptible and anal relaxation. The displaced content was thought to modification by enteric neural inputs than the slow to be responsible for the subsequent activation of neu- waves39. Inhibitory neurons inhibit slow phasic con- ral pathways further down the intestine ahead of the tractions whereas excitatory neurons enhance them, advancing bolus. This original concept of the peristaltic and slow phasic contractions can possibly be recorded reflex has been modified to incorporate actual evidence inside motor complexes39. The possibility that inter- of polarity of neural activity into what is now proposed acting pacemaker cells could also generate such slow-​ as the neuromechanical loop hypothesis72. This advance frequency contractions has been suggested40. Distension in understanding was made possible through simulta- is probably still required to generate these myogenic con- neous recording of pressure and diameter changes. tractions after neural blockade, and in vivo cooperation This enabled the calculation of the mechanical states of NATuRe RevIewS | GASTRoENTERology & HEPATology volume 16 | SEPTEMBER 2019 | 563 C o n S e n S u S S tat e m e n t a b c Oral mm Long-distance mm mm 5.1 21 Three 14 Propulsive contractions contractions Haustral taeniae boundary contractions Colonic 1.1 6 migrating 5 motor complex Single taenia 50 mm 20 mm 20 mm Anal 300 s 60 s 60 s d Colonic migrating Electrical field stimulation e motor complex mmHg Colonic motor 100 Oral 20 mN complex Proximal 0 20 mN Mid 50 mm 10 mN Distal Anal 120 s 10 min Fig. 2 | Neurogenic motor patterns in animals. Images a–c show examples of neurogenic motor patterns expressed as spatiotemporal maps showing changes in diameter (DMaps) of the excised colon of different animal species in vitro. Two main neurogenic motor patterns have been recognized. The first is neural peristalsis (consensus term) triggered by distension, which was described as propulsive contractions in the guinea pig distal colon33 (part a) and subsequently as long-​distance contractions in the rabbit colon21 (part b). The second motor pattern present in the rabbit proximal colon consists of very slowly propagating contractions, representing the neural colonic motor complex20 (part c) and subsequently as haustral boundary contractions or progression (part b). In the complete mouse colon199 (part d) and in the guinea pig distal colon81 (part e) colonic motor complexes occur in distended segments. Neurogenic peristalsis is triggered and sustained by content, whereas the colonic motor complexes are generated as regular motor activity slowly traversing long segments of colon or appearing even in the absence of any propulsion of contents. Part a adapted with permission from ref.33, The American Physiological Society. Part b adapted with permission from ref.21, The American Physiological Society. Part c adapted with permission from ref.20, The American Physiological Society. Part d adapted with permission from ref.199, Wiley-​VCH. Part e adapted with permission from ref.81, Wiley-​VCH. the intestinal muscle to be established, distinguishing pattern is potentially important, but its function remains active (due to active contraction or relaxation) from pas- largely unclear and will require further investigation. sive changes10. Two components of the neuromechanical loop are distinguished: a bolus-​evoked graded activation Neurogenic colonic motor complexes. Repetitive events of polarized enteric pathways (the neural part) and the of motor activity have been widely reported in the oral contraction and anal relaxation (the mechanical colon of most species (Fig. 2). In 1926, Welch and Plant73 part)10,33. Both neural and mechanical components are showed in the canine colon that periods of contractile adaptable, and this functional loop leads to variable abo- activity existed, lasting 5–15 min and recurring at reg- ral propulsion of the bolus. Distension of a new portion ular intervals of 15–30 min. Numerous other studies in of the gut then initiates a new loop process. The valid- dogs51,74–76, most notably those by Sarna et al.50,77, and ity of this model was demonstrated when it was shown other species, including in rats78,79, in rabbits and in larger that the speed at which the bolus moves was dependent mammals, such as horses80, have shown similar findings. on its size, shape and viscosity18. Thus, colonic propul- Clear examples of repetitive motor activity at a level sion is not simply due to an invariant, stereotyped per- similar to that observed in vivo have been recorded in istaltic reflex; CMPs adapt to the physical properties of isolated preparations of rabbit proximal colon that was the contents. distended by liquid (Krebs solution)23. Overall, repetitive Some descriptions of neural retrograde peristaltic propagating contractions slowly moving anally along the contractions (antiperistalsis; neural retrograde propa- colon have been well described under liquid distension gating contraction) also exist. Antiperistalsis described by three different laboratories, albeit with different ter- by Bayliss and Starling41 in the rabbit colon was demon- minologies (Lentle et al.24: haustral progression; Dinning strated by Dinning et al.20 to be neurogenic but insensi- et al.20: colonic migrating motor complex; Chen et al.21: tive to blockade of nicotinic transmission. This motor haustral boundary contractions). All investigators 564 | SEPTEMBER 2019 | volume 16 www.nature.com/nrgastro C o n S e n S u S S tat e m e n t reported that blocking neural activity abolished this a Low-frequency Ripples motor pattern. This neurogenic activity interacts with the contractions myogenic ripples to give the feature of advancing clusters of rhythmic contractions (motor complexes). Because of this interaction between neurogenic and myogenic mechanisms, the motor patterns can be regarded as neuromyogenic. In guinea pigs, similar slowly migrating motor complexes have been observed in the proximal colon and seem to be involved in the early formation of 1.0g soft pellets81. Based on these findings, the main function of these motor complexes, slowly migrating aborally in herbivores, seems to be initial sequestration and aboral progression of the soft contents of the proximal colon 2min and their transformation into more solid (viscoelastic) b Ripples faecal pellets. Similar motor patterns probably also occur in the colon of other species. 0.1g In most species, fixed distension of the colon with a tethered pellet or localised stretch with an isometric 1min transducer will generate similar neurogenic repet- c High-frequency itive motor events. The best known examples of such contractions motor activity have been originally described as colonic 0.1g migrating motor complexes (CMMCs) that occur in a full-​length isolated mouse colon82 and in the guinea pig 5s colon45,81,83. However, under these conditions of main- tained distension, motor complexes can propagate in Fig. 3 | Motor patterns in isolated strips of the human both retrograde and anterograde directions. In 2017, colon. a | Low-​frequency contractions superimposed the electrical activity in the colonic smooth muscle with intermediate-​frequency motor events or ripples. b | Intermediate-​frequency motor events or ripples. that underlies CMMCs was recorded from isolated c | High-​frequency contractions. Different time and full-​length colon preparations. These cyclical patterns amplitude scales were used to optimally visualise each of myoelectric activity in the mouse colon have been type of contractile activity. referred to as neurogenic spike bursts, which occur at the same frequency as CMMCs84. To preserve neuro- genic spike bursts and CMMCs in vitro, considerable CMPs in isolated colon strips. Most of the studies on small lengths of colon are required. Full neurogenic spike strips of human colon have reported spontaneous con- bursts were only recorded in 30-mm-​long preparations tractions that occur at three different frequencies: high-​ and were absent in 10-mm preparations84. frequency contractions (frequency usually >10 cpm) of In many instances, it is impossible to resolve whether low amplitude probably due to ICC-​MP; intermediate individual motor complexes actually propagate or simul- frequency contractions (~2–4 cpm) probably due to slow taneously occur over a region of the bowel. For example, waves; and low-​frequency high-​amplitude contractions a guinea pig colon distended by a manometric catheter (<1 cpm) that persist in samples devoid of ICC-​SMP, showed repetitive neurogenic increases in intraluminal possibly generated as a result of stretch in ICC-​MP and pressure that propagated in either direction or occupied potentiated by other excitatory inputs39 (Fig. 3; Table 1). up to 25 cm of colon simultaneously81. These three activities are considered the respective cor- As a less committed term that is still descriptive, we relates of high-​frequency ripples, ripples and slow phasic suggest using the generic term colonic motor complexes contractions recorded in the isolated intact colon from to describe any neurogenic repetitive contractions in the animal studies discussed earlier. experimental animals, whether they migrate or not. The term colonic migrating motor complexes should then be CMPs in isolated flat colon preparations. Recordings restricted to complexes that are proven to migrate. of circular muscle contraction in isolated prepara- tions of human colon that were opened lengthwise and CMPs in the isolated human colon mounted flat showed slow spontaneous contractions, The human colon is one of the least understood organs termed slow phasic contractions85, occurring at inter- of the body, largely because of difficulty with access, both vals of 0.5–5 min. Electrical activation of enteric neural in vivo and in terms of availability of human resection pathways could initiate these contractions prematurely, specimens for experimental studies. Most studies on resetting their rhythmicity 85,86. Similar slow phasic isolated human colon have used very small segments of contractions persisted following blockade of all neural colon, typically from 1 to 2 mm to a few centimetres activity with tetrodotoxin86. in length32. These small segments are useful for study- ing the myogenic activity in the colon but are less use- CMPs in the isolated colon. Two studies have recorded ful for understanding the neurogenic motor patterns, activity from the isolated human colon in vitro86,87. as they are of an insufficient length to determine the These studies show two major types of motor activity: characteristics of propagation. repetitive sequences and single propagating sequences NATuRe RevIewS | GASTRoENTERology & HEPATology volume 16 | SEPTEMBER 2019 | 565 C o n S e n S u S S tat e m e n t Table 1 | Motor patterns in isolated strips of human colon Name of the colonic pattern Rae et al. Carbone et al. Mane et al. Possible origin Correlation with (1998)32 (2013)85 (2015)200 animal studies High-​frequency contractions 15–18 cpm 20 cpm Not identified • ICC-​MP High-​frequency ripples (low amplitude) • Myenteric potential oscillations Intermediate-​frequency 1.6–3 cpm 3.8 cpm 2–4 cpm • ICC-​SMP Ripples contractions (low amplitude) • Slow waves Low-​frequency contractions 0.5–0.9 cpm 1 cpm 0.3–0.6 cpm • ICC-​MP Slow phasic contractions (high amplitude) • Cyclic depolarizations cpm, cycles per minute; ICC, interstitial cells of Cajal; ICC-​MP, ICC myenteric plexus; ICC-​SMP, ICC submucosal plexus. (Fig. 4) . To establish a harmonized terminology, we same simultaneous pressure increases were recorded suggest using the terms repetitive motor patterns and in studies that used HRM to concurrently evaluate single motor pattern (Table 2). Both sequences can be colonic and anal sphincteric activity 7 (Fig. 5). With initiated at any site along the colon and propagate over HRM, the pressure increases were recorded across all considerable distances in either anterograde, retrograde manometry channels and were temporally associated or both anterograde and retrograde directions. They can with relaxation of the anal sphincter. Importantly, no readily be evoked by enteric nerve stimuli or luminal accompanying changes in abdominal wall electromy- distension86. They are considered the correlates of the ography activity were recorded6–8. By contrast, colonic previously described colonic motor complexes recorded lumen pressure increases that were associated with in animal studies discussed earlier. contractions in the abdominal wall or other artefacts were associated with pressure increases in the anal CMPs in adults by manometry sphincter and with electromyographic activity in the Previous studies, using manometric catheters with abdominal wall7. The simultaneous pressure increases recording sites at ≥7.5-cm spacings, have demonstrated associated with anal sphincter relaxations were termed that colonic motor activity in healthy individuals is colonic pressurizations. In some colonic manometry represented mainly by nonpropagating activity, inter- studies in healthy adults, these colonic pressurizations spersed with propagating contractions of low amplitude were the most commonly recorded motor pattern and and of high amplitude occurring in limited numbers were associated with a desire to evacuate gas and/or of 2.4 ± 0.1 and 0.4 ± 0.1 events per hour, respectively88,89. gas expulsion7,8. These simultaneous pressure increases Both nonpropagating and propagating activity is redu­ might be equivalent to the colonic motor complexes ced in patients with chronic idiopathic constipation90,91. observed in the colon of mice and guinea pigs during However, as no qualitative or quantitative data exist maintained distension. that unequivocally differentiate normal from abnormal colonic function5,92, the role of colonic manometry in the Haustral boundary pressure transients. This motor pat- management of these patients remains unclear5. tern consists of sequences of highly rhythmic (3 cpm) Surprisingly limited knowledge exists regarding transient pressure increases, which are recorded by sin- the anatomical or functional nature of the haustra gle sensors but repeated at around every five sensors in the human colon. It has previously been argued (hence, around every 5 cm) moving across these sen- that they are fixed anatomical features, or that they sors8. They seem to represent haustral boundary con- are transient contractions of the intertaeniae circular tractions, corresponding to CMMCs in mice, in rabbits muscle, resulting in the typical triangular narrowing (also called haustral boundary progression24 or haustral observed in colonoscopies93. However, as the haus- boundary contractions21) and in guinea pigs (also called trations disappear during mass movements94,95, they proximal colon migrating motor complex18). However, are probably functional contractions rather than fixed as limited knowledge exists regarding the haustra in anatomical features. the human colon, further work is needed to determine The introduction of HRM, in which the distance whether this activity corresponds to actual movements between the intraluminal pressure sensors has been of haustrations. decreased to one sensor every 1–2.5 cm, has been found The fact that rhythmic changes in intraluminal to increase the accuracy of detection of CMPs, in par- pressure in the human colon sometimes occur with a ticular that of low-​amplitude propagating activity96. frequency of ~3 cpm suggests that they are due to the Currently, only a few studies have used HRM to mon- myogenic contractile activity termed ripples8. The rhyth- itor colonic motility in adult humans. Hence, the fol- mic pattern commonly occupied ≤5 consecutive sensors lowing section summarizes CMPs identified in healthy and could, therefore, have been occurring within a sin- individuals both by conventional manometry and by gle haustrum. The individual pressure wave sometimes HRM (Table 3). propagated at 2 ± 1 cm/s in either an antegrade or a retrograde direction, consistent with its genesis in the Simultaneous pressure increases. These CMPs were propagation of slow waves8. Hence, these are likely to identified using conventional manometry but were ten- be intrahaustral myogenic contractions8 (intrahaustral tatively considered to be artefacts caused by contrac- activity), that is, ripples responsible for segmental tions in the wall of the abdomen97–101. However, the activity as also described in the rabbit colon21. 566 | SEPTEMBER 2019 | volume 16 www.nature.com/nrgastro C o n S e n S u S S tat e m e n t Cyclic propagating motor pattern. This CMP was the Low-​amplitude single propagating contractions. These most commonly recorded propagating motor pattern CMPs were identified in conventional manometric in studies of the healthy adult colon using fibreop- studies and are characterized as elevations in pressure tic HRM6. The individual propagating contractions <50 mmHg, propagating over at least three consecutive within this motor pattern had a frequency of 2–6 per recording ports, usually in an aboral direction88,100,101,105. minute, which suggests they result from ripples gener- These motor patterns were recorded more commonly ated by myogenic slow waves amplified by neural excit- during the day and occurred at an approximate rate atory inputs. Activity of a similar frequency has been of 61 events per 24 h. They have been reported to be recorded in the rectum using conventional manome- associated with the transport of luminal content, expul- try and was termed periodic rectal motor activity, as sion of intestinal gas and relaxation of the anal sphinc- well as in the colon where it was termed segmental ter89,106. Subsequent colonic HRM studies characterized activity88,98,102–104. Each sequence of propagating con- three subtypes. tractions within the cyclic motor pattern travelled The short single motor pattern is a propagating predominantly in a retrograde direction. Cyclic motor motor pattern that occurs in isolation, separated from patterns were observed in the proximal and descend- other propagating motor patterns by intervals >1 min ing colon, but the majority (76%) were identified in the (refs6,7). This motor pattern could propagate in both rectosigmoid colon. anterograde and retrograde directions over short lengths of colon (~7 cm) at a velocity of 0.5 ± 0.3 cm/s. It origi- nated primarily in the proximal colon (42%) or sigmoid a colon (43%), and made up 24.2% of all propagating motor patterns. Long single motor patterns comprise single pres- sure events that propagate over long distances6,7. These events are always separated by intervals >1 min when Manometric they occur repetitively. Most originate in the proximal catheter colon (76%) and the remaining 24% originate in the proximal region of the descending colon. These con- tractions usually propagate in an anterograde direction. They can be distinguished from short single motor Sigmoid colon patterns since they propagate over considerably longer distances along the colon (40.8 ± 8.4 cm), often as far as the distal descending or sigmoid colon. Their inci- dence is increased by polyethylene glycol and linaclo- tide107,108. These events might be the correlates of the long-​distance contractions or neural peristalsis observed in animal studies. Slow retrograde motor patterns are rare but dis- Oral 5cm Anal tinctive propagating motor patterns that are typically observed during fasting6,7. They travel at <0.5 cm/s and propagate over distances generally >40 cm, starting in the b sigmoid colon and entering the transverse colon. They make up only 0.3% of all propagating motor patterns. High-​amplitude propagating contractions. These CMPS are prominent and of diagnostic importance, but only occur between 4 and 23 times over the course of 24 h. This motor pattern consists of powerful propagating contractions that are associated with the mass movement of colonic content and with defecation88,89,98,100,109–111. Over the years, this motor pattern has been variously defined as pressure waves with amplitudes varying between 50 and >136 mmHg, lasting 10–30 s (refs6,112). This motor pattern extends at least 10–30 cm along the length of the colon and mostly originates in the proximal 60s colon6,112. These events are probably the correlate of the neural peristalsis described in animal studies. Fig. 4 | Colonic motor patterns of an excised section of human sigmoid colon. The stimuli that generate these contractions remain a | The excised sigmoid colon is placed into an organ bath filled with an oxygenated Krebs solution maintained at 37°C. Motor patterns are recorded by a high-​resolution unclear. They might be triggered by distension of the manometric catheter attached to a rod at the base of the preparation. b | A series lumen caused by intraluminal accumulation of colonic of propagating pressure waves recorded from the section of the colon. Three large content. A postprandial increase in the number of propagating contractions start at the oral end and move towards the anal end of HAPCs has been demonstrated in healthy adults in a the segment. number of studies. However, the number of postprandial NATuRe RevIewS | GASTRoENTERology & HEPATology volume 16 | SEPTEMBER 2019 | 567 C o n S e n S u S S tat e m e n t HAPCs that are generated seems to depend on a number for either Hirschsprung’s disease or other anorectal of factors. Studies performed within hours of a bowel abnormalities120. preparation and catheter placement reported low num- Until 2013, most data about childhood colonic motil- bers of postprandial HAPCs even in healthy subjects113. ity patterns had been accrued using water-​perfused cath- Once the colon begins to fill again by the following day, eters with six to eight recording sites spaced 10–15 cm the postprandial count of HAPCs increases114. Ileal prop- apart121. The analysis of the resulting motor events has agating activity has been reported to continue through- focused traditionally on the presence or absence of a out the night115, and might augment colonic filling postprandial increase in overall motility and on the pres- and activate the enteric circuits that generate HAPCs. ence, absence and extent of propagation of HAPCs120. As HAPCs are suppressed during sleep, suggesting that their healthy children cannot be studied for ethical reasons, incidence is influenced by the central nervous system116. the conclusion about what constitutes normal motility Various pharmacological interventions influence the in children has been derived from studies in paediat- incidence of HAPCs in humans. Blocking the adrener- ric patients who in retrospect (based on their clinical gic alpha-2 receptor with yohimbine in a study applying characteristics and treatment outcome) are deemed to colonic distension controlled by an electronic barostat have functional constipation. Functional constipation increased the number of HAPCs112. Intraluminal appli- in children is considered a consequence of a disordered cation of glycerol, oleic acid or bisacodyl can also increase behaviour in individuals who have developed stool with- the incidence of this motor pattern112. Neither the admin- holding in response to the urge to defecate after experi- istration of granisetron (a 5-hydroxytryptamine 3 receptor encing an unpleasant defecation. The colon is thought to antagonist) intravenously or octreotide (a somatostatin have a completely normal motor function in these chil- analogue) subcutaneously affected the number or charac­ dren and the problem is usually resolved once the child teristics of HAPCs, whereas intraluminal lidocaine and realizes that it is more comfortable to release colonic intravenous phloroglucinol inhibited HAPCs induced content than to withhold it122. Some of these children, by intraluminal glycerol117. Intravenous atropine did not especially those refractory to behavioural and medical inhibit spontaneous postprandial HAPCs118 and HAPCs therapy, have received colonic manometry testing and were not elicited by powerful cholinergic stimulation the data from these patients have been reviewed induced by intravenous edrophonium chloride119. and ana­lysed to describe normal colonic motility in chil- dren of different ages123. This section reports how these CMPs in children by manometry established findings, which have been used in the past Among the diagnostic tools available for the assess- 25 years to study children in clinical practice, integrate ment of children with constipation that do not respond with more recent descriptions of other motor events to medical and behavioural management, colonic measured by HRM. manometry is currently advocated as the most inform- ative modality for evaluating colonic neuromuscular High-​amplitude propagating contractions. The gener- function3. This test has been used in children to clarify ally accepted definition for HAPCs in children is con- colonic pathophysiology and direct clinical care for the tractions with an amplitude of greater than 75 mmHg, a past 25 years. Colonic manometry is also among the tests duration of greater than 10 s and propagation distance required for accomplishing level II training in paediat- of 30 cm or more92,124–126 (Fig. 6). Normal HAPCs are ric neurogastroenterology and motility in the United expected not to propagate beyond the junction between States4. Minimum standards to be used in performing the sigmoid colon and the rectum and are often asso- this test were suggested almost two decades ago120. ciated with a relaxation of the anal sphincter (coloanal In children, colonic manometry is currently indicated reflex)127. They typically occur following meals and upon to discriminate between colonic neuromuscular disor- waking, and can be induced by bisacodyl128. Octreotide ders and functional constipation to guide the surgical and erythromycin do not induce HAPCs129–131. approach in those patients refractory to conventional HAPCs are generally classified based on their dis- medical treatment, to evaluate the colonic involvement tance of propagation: fully propagating, when HAPCs in children with chronic intestinal pseudo-​obstruction, reach the sigmoid colon; partially propagating, when to determine whether a diverted colon is suitable for HAPCs stop at the level of the splenic flexure or the reconnection and to clarify the underlying mechanisms descending colon; and absent, when no HAPCs are responsible for the persistence of symptoms after surgery observed in the entire colon125,132,133. HAPCs can be Table 2 | Motor patterns in isolated human colon86 Name of the Interval Directionality of Extent of Site of initiation Trigger Stimulus colonic pattern between events propagation propagation Repetitive motor 4.0 ± 0.6 min Anterograde, Variable; Variable; at different Spontaneous Enteric nerve stimulation pattern (0.25 cpm) retrograde or usually >20 cm sites along the length simultaneous of the colon Single motor Single event Anterograde or Variable; Variable; at different Spontaneous Enteric nerve stimulation pattern retrograde usually >20 cm sites along the length and balloon distension of the colon cpm, cycles per minute. 568 | SEPTEMBER 2019 | volume 16 www.nature.com/nrgastro C o n S e n S u S S tat e m e n t Table 3 | Colonic motor patterns in healthy humans6,7,109,111 Name of the colonic pattern Amplitude Frequency Response Response to Stimulant Suppressant to waking meal Simultaneous pressure increases Low ≤1–2 cpm if Increase Increase (meal of Neostigmine (i.v.), Not known repetitive ~400 kcal) prucalopride (p.o.) Haustral boundary pressure transients Low 3 cpm Not known Not known Not known Not known Intrahaustral activity Low 3 cpm Not known Increase Not known Not known Cyclic propagating motor pattern Low; mainly 2–6 cpm Not known Increase (meal of Not known Not known retrograde ~700 kcal) Short single motor pattern Low Not repetitive Increase Increase Not known Not known Long single motor pattern Low 1 cpm if Not known Not influenced Polyethylene glycol Not known repetitive (p.o.) and linaclotide (p.o.) Slow retrograde motor pattern Low Not repetitive Not known Not influenced Not known Not known High-​amplitude propagating >75 mmHg Can be Increase Increase (~1–2 h Yohimbine (i.v.), glycerol Lidocaine contractions repetitive after meal) (i.c.), oleic acid (i.c.) and (i.c.) and bisacodyl (i.c. and p.o.) phloroglucinol (i.v.) cpm, cycles per minute; i.c., intracolonic; i.v., intravenous; p.o., per os. further classified as normal or abnormal based on the Patterns detected by HRM in children. Reports on using morphology of pressure waves within the contraction HRM to study colonic motility in children have only sequences. Abnormal HAPCs have either two or more started to be published in the past 4 years. Several motility pressure peaks or a duration exceeding 30 s. Several patterns other than HAPCs and low-​amplitude propagat- aspects of HAPCs have been established based on pae- ing sequences in children presenting with constipation diatric studies92,123–125,127,134–143. They are reliably identi- were described in 2016 (refs121,146,147). The characteristics fied by different observers (with minimal interindividual of colonic motility in children with constipation were eval­ variability)134 and are more common in younger children u­ated using HRM water-​perfused catheters and were clas- (their frequency is inversely correlated to age in a group sified on the basis of definitions similar to those used in of children aged 1–17 years)123. They are more common adults. The authors identified antegrade and retrograde in patients who have had a distal colonic resection, such cyclic propagating motor patterns, short single ante- as after surgery for Hirschsprung’s disease, probably grade and retrograde motor patterns, and preprandial owing to the disruption of the inhibitory recto–colonic and postprandial long single motor patterns147. Similar reflex125,135. HAPCs can be induced through infusion of to adults with constipation, children with constipation saline and distention of the right colon136,137. Their pres- did not show the normal postprandial increase in the ence suggests intact colonic neuromuscular function cyclic retrograde propagating motor pattern147. In addi- and studies based on the characteristics of HAPCs have tion, paediatric patients showed greater numbers of the been found to be predictive of medical and surgical out- antegrade propagating long single motor pattern during come132,137–139. For example, patients with intact HAPCs the preprandial phase147. The clinical significance of these are more likely to respond well to the administration of findings is currently unclear. In one study, the presence antegrade enemas or to the surgical resection of a dys- of simultaneous pressure increases like those reported in motile colonic segment. Abnormalities in HAPCs have adults was also observed in children with constipation121. been used to explain the pathophysiology of defecatory difficulties in various different medical conditions, Human colonic motility by other techniques such as imperforate anus, Hirschsprung’s disease, The major limitations of manometry are that pressure pseudo-​obstruction and chronic constipation92,124,140–143. changes might not accurately represent colonic contrac- Bisacodyl-​induced HAPCs are quantitatively and tions or might not be associated with movement of intra- qualitatively similar to naturally occurring HAPCs127. luminal content. Hence, the techniques to assess colonic transit, tone and wall motion, which are relevant to Low-​amplitude propagating sequences. Low-​amplitude colonic motor function, are evaluated here. Radiopaque propagating sequences typically have an amplitude markers, scintigraphy, a wireless pH and pressure record- <50 mmHg and occur 40 to 120 times in a 24-h period in ing capsule (SmartPill; Medtronics) and a telemetric adults144. They occur considerably more often during the capsule system (3D-​Transit; Motilis Medica SA) have all day than at night, and, similar to HAPCs, they increase been used to assess colonic transit. The SmartPill also in frequency following meals and upon waking. They measures pressure activity using a single sensor built into have also been described in children and a considerable the device. The barostat balloon can measure colonic difference was found between patients with slow-​transit tone and phasic contractions. Over the past 4 years, MRI constipation and healthy controls in the mean number has been used to noninvasively assess unique parameters of ascending, transverse and descending low-​amplitude of colonic function that were previously inaccessible for propagating sequences121,145. measurement. NATuRe RevIewS | GASTRoENTERology & HEPATology volume 16 | SEPTEMBER 2019 | 569 C o n S e n S u S S tat e m e n t a Pan-colonic pressurizations b Hepatic flexure mmHg Right colon 100 Transverse colon mmHg Splenic flexure 60 50 1 min 30 Anal sphincter 0 Anal sphincter relaxations Recto- c Hepatic sigmoid junction 0 flexure mmHg 60 1 min Cyclic propagating motor pattern Splenic d flexure Clustered activity 30 5 cm Recto- sigmoid 0 junction 2 min 1 min Fig. 5 | Colonic motor patterns frequently identified by HRM in adults. The introduction of high-​resolution manometry (HRM) increased the accuracy of the detection of colonic motor patterns. The most frequently detected patterns in adults are simultaneous pressure increases, cyclic propagating motor patterns and haustral activity. a | Examples of simultaneous pressure increases (pan-​colonic pressurizations)7. These are characterized by simultaneous pressure increases recorded across all recording sensors and are associated with relaxation of the anal sphincter. b | The cyclic propagating motor pattern, shown as a spatiotemporal colour plot, recorded in a healthy adult colon. This activity increases after a meal, originates at the rectosigmoid junction and propagates primarily in a retrograde direction (anal to oral). c | Cyclic propagating motor patterns can also occur in clusters spaced at 1–4-min intervals. These clusters appear after the consumption of a high-​calorie meal. d | Intrahaustral activity often has a frequency of ~3 cpm in ≤5 consecutive sensors and, therefore, seems to be activity within a haustrum8. Part d adapted from ref.8, CC-​BY-4.0 https://creativecommons.org/ licenses/by/4.0/. Radiopaque markers. Whole-​gut transit time and seg- regional colonic transit149. Beginning with the original mental colonic transit time can be estimated by counting reports of slow-​transit constipation150,151, markers have the number of ingested markers remaining in the abdo- been widely used to evaluate colonic transit in patients men on abdominal X-​rays. These techniques have been with constipation, and to a lesser extent in those with reviewed elsewhere148. The estimated whole-​gut transit diarrhoea152. Markers have also been used to evaluate the time also includes gastric and small bowel transit, which correlation between colonic transit and stool weight153, constitute a small proportion of the whole-​gut transit and the effects of supplementing dietary fibre as well as time in healthy individuals and in patients with isolated physical exercise on colonic transit154,155. slow-​transit constipation, but constitute a larger propor- tion of the whole-​gut transit time in patients who also Scintigraphy. Colonic transit scintigraphy is per- have severely delayed gastric emptying (for example, in formed after patients swallow a capsule containing a patients with diabetic gastroparesis). Hence, radiopaque radioisotope, typically indium (111In), which is tagged markers can provide a surrogate measure of colonic to charcoal pellets156. The capsule has a methacrylate transit. They remain the criterion standard, the cheap- coating that dissolves at a pH of 7.2–7.4, generally in est and perhaps the most widely used technique to assess the terminal ileum, releasing the isotope in the cae- colonic transit in constipated patients. cum157. Scintigraphy has been widely used to evaluate Radiopaque markers, scintigraphy and the wireless the effects of drugs and diseases on colonic transit. motility capsule (SmartPill) provide comparable results Measuring colonic transit with radiopaque markers regarding colonic transit. However, transit through the takes 6 days compared with 48 h for scintigraphy. By ascending and transverse colon was considerably shorter integrating two isotopes, gastric, small intestinal and when measured by the radiomarker technique than by colonic transit can be simultaneously evaluated with scintigraphy, probably because particle size influences scintigraphy158–160 (Fig. 7). 570 | SEPTEMBER 2019 | volume 16 www.nature.com/nrgastro C o n S e n S u S S tat e m e n t a b c Fig. 6 | HAPCs in children. Normally and abnormally propagating high-​amplitude propagating contractions (HAPCs) have been identified by high-​resolution manometry in children. a | In normal HAPCs, the amplitude is >75 mmHg and the contractions propagate distally to the rectosigmoid junction. The anal sphincter relaxes concurrently to the HAPC. b | In abnormally propagating HAPCs, the contractions do not propagate beyond the transverse colon. c | An abnormal configuration of HAPCs with multipeaked waveforms and prolonged duration. This configuration has been associated with histological evidence of colonic neuropathy121. Early studies in humans that evaluated the relation- absorption, retard colonic transit and, therefore, reduce ship between colonic motor events and transit with stool frequency. simultaneous manometry and scintigraphy might have missed subtle movements because they used relatively Wireless motility capsule. After ingestion, this capsule, slow scintigraphic acquisition rates, for example every which is 26 mm by 13 mm in size, measures pH, pressure minute161 or every 5 minutes162,163. Studies over the past and temperature within the gastrointestinal tract. Data 10 years have used faster image acquisition rates, for are wirelessly transmitted to a recorder worn externally. example every 10–15 s, with visual detection or quan- It is the only method that simultaneously records colonic titative assessment of colonic isotope movement89,164. pressure activity and transit165. In a large study, overall These studies showed that movement of colonic con- agreement between capsule and radiopaque marker tent occurs in a stepwise manner over short distances, measurements of colonic transit categorized as normal in both antegrade and retrograde directions, associ- or slow was 87%166,167. ated with propagating sequences88,164. In humans, 93% The ambulatory system enables studies to be com- of propagated contractions were associated with pro- pleted at home. The capsule can reliably distinguish pulsion of content88,164. Low-​amplitude propagating between normal and slow colonic transit. Colonic sequences with amplitudes of 2–5 mmHg were as likely pressure activity is on average greater in constipation-​ to be associated with movement of content as higher predominant IBS than in functional constipation168, but amplitude propagating sequences. However, of all the there is considerable overlap between groups. Colonic episodes of propulsion, fewer than half were associated pressure activity increases as the capsule moves distally with detectable propagating sequences. This finding through the colon169. As the location of the capsule in might suggest that pressure waves are not essential for the colon is not monitored during its passage, the pres- propulsion. The strength of this pressure–flow relation- sure cannot be attributed to a specific colonic region. ship seems to be region-​dependent, being stronger in Because pressures are recorded at only a single location, the transverse colon than in the caecum and ascend- propagation of motor events cannot be assessed. ing colon. In theory, the movement of colonic contents that is not accompanied by propagating colonic con- Electromagnetic capsules. This equipment (3D-​Transit; tractions might be explained by contractions at points Motilis Medica SA) comprises a magnetic pill (a silicon-​ remote from the recording sites, or motor events that coated capsule, which is 21 mm by 9.8 mm in size, con- do not substantially affect intraluminal pressure, such taining a permanent cylindrical magnet), a detection as longitudinal muscle shortening, nonlumen-​occluding matrix (4 × 4 magnetic field sensors) that detects move- circular muscle contractions, or alterations in regional ments of the pill, and dedicated software. The matrix wall tone. Importantly, these combined manometry maps the location and movement of the pill within the and scintigraphy studies used low-resolution manom- colon by plotting the x, y and z coordinates and two etry with recording sensors spaced at >7 cm intervals, inclination angles170. which is much less accurate than HRM (sensors at 1 cm The technique enables the calculation of both ante- intervals) for identifying colonic propagating motor pat- grade and retrograde movement and the speed of that terns96. Hence, the lack of association might also reflect, movement in real time. By detecting pill rotation, the at least in part, technical constraints. frequency of contractile events can be determined. Retrograde sequences are generally associated with Gastrointestinal transit times assessed by 3D-​Transit retrograde movements of colonic content. However, capsules and standard radiopaque markers strongly ~90% of retrograde flow episodes occur in the absence correlate171. Currently, the use of this tool is limited to of retrograde sequences. About half of the retrograde research studies. Colonic retention times have been flow events follow immediately after an antegrade move- evaluated in healthy adults170–172 and in patients with ment, indicating frequent reflux of content back into active ulcerative colitis173. All studies were conducted the region from which it had just moved164. This subtle in Europe. The ambulatory system enables studies to be ‘to and fro’ motion is likely to help maintain maximal completed at home. NATuRe RevIewS | GASTRoENTERology & HEPATology volume 16 | SEPTEMBER 2019 | 571 C o n S e n S u S S tat e m e n t a b to defecate and to postprandial abdominal discomfort Stomach in IBS. When the colonic diameter exceeds 5.6 cm, a baro­ 2 stat is more sensitive than manometry for recording 99m Tc-labelled polystyrene pellets nonocclu­sive contractions182. A barostat can also record in standardized meal 1 colonic relaxation, whereas manometry can only directly 3 record contraction176. However, in contrast to manometry, a barostat cannot evaluate spatial patterns or propaga- tion. Another aspect of the barostat is its ability to record colonic pressure–volume relationships and perception 4 of distention183,184. Pressure–volume relationships are useful for assessing colonic biomechanical properties in health and disease and in response to pharmacological modulation. In-labelled 111 charcoal in MRI. MRI differs from other nonmanometric techniques delayed-release 5 as it does not require ionising radiation or invasive pro- Colon Small intestine capsules cedures, or the use of special contrast agents. It can be Fig. 7 | Scintigraphic assessment of gastrointestinal transit. a | Gastric emptying and used to measure gastric, small intestinal and colonic small intestinal transit are assessed with 99mTc-​labelled polystyrene pellets, whereas volumes185, the physical chemical characteristics of colonic transit is measured with 111In-​labelled charcoal in delayed-​release capsules. the lumen environment186, transit rate, and to quantify b | Proportion of 111In counts in each of four colonic regions of interest and stool is multiplied by the appropriate weighting factor, ranging from 1 to 5. motility, as reviewed elsewhere187. Cine imaging, or the ability to acquire multiple, temporally-​resolved, images, enables the visual appreciation of wall movement; direct Barostat. The barostat was initially used to measure gas- comparison with manometry showed good correlation tric174,175 and subsequently colonic motor function118,176. between luminal occlusive contractions induced by bisa- A highly compliant polyethylene balloon is placed into the codyl and high amplitude propagated contractions188. cleansed colon using endoscopy and fluoroscopy. This Cine MRI can also readily detect the strong propulsive balloon is connected to a barostat, which is a computer-​ contractions induced by luminal distension with the controlled, motor-​driven piston within a cylinder92 that osmotic laxative polyethylene glycol as fluid enters and can regulate and measure balloon pressure and volume. distends the ascending colon. Thus, in the future, cine When the colon contracts against a balloon inflated to a MRI could be relevant in the clinical assessment of con- fixed pressure, air is expelled from the balloon into the stipation given that cine MRI requires only the ability barostat. Conversely, when the colon relaxes, the barostat to operate an MRI scanner, which is much more widely adds air to the balloon to maintain a constant pressure. prevalent than expertise in manometry. Application in Another option is to distend the balloon across a range clinical practice is only just beginning, but increased of pressures and measure volume to derive pressure– motility after ingestion of polyethylene glycol has been volume relationships. Generally, a barostat balloon is demonstrated using a semiquantitative subjective assess- combined with manometry pressure sensors177 (Fig. 8). ment where motility was greater in healthy controls and Unique to a barostat is its ability to detect colonic tone, patients with constipation-​predominant IBS than in nonlumen-​occluding contractions, pressure–volume those with functional constipation189. A more objective relationships, sensation and relaxation. Tone is crucial to colonic mixing and propulsion. In particular, the right colon has a propensity to relax. Baseline tone is a pre- requisite for relaxation. Colonic distention to low pres- Polyethylene sure by a barostat does not alter motor activity recorded balloon by manometric sensors. However, the possibility that Manometric a balloon distended to a low pressure might stimulate sensor low threshold mucosal afferents cannot be excluded. Eating increases tone to a lesser extent in the proximal colon than in the distal colon178,179. Eating also increases Barostat colonic phasic pressure activity. The response can begin device within a few seconds after eating and generally lasts up to 1 h. Meal composition and caloric content are both important; a mixed meal containing >500 kcal predicta- bly elicits a response178,179. Gastric distention and chemi- Fig. 8 | Assessment of colonic motility using a barostat. The barostat–manometric assembly is positioned in the cal stimulation by nutrients elicit comparable responses; descending colon with a polyethylene balloon in apposition lipids are the most potent stimuli, whereas amino acids to the colonic mucosa. The device maintains the balloon have an inhibitory effect180. In addition to augmenting at a pressure that ensures that the colonic wall is not tonic and phasic motor activity, feeding also increases distended. Contractions of the colonic wall induce a colonic sensation and affects recto–colonic reflexes181. decrease in the baseline balloon volume, which is recorded This reflex might contribute to the postprandial urge by the barostat. 572 | SEPTEMBER 2019 | volume 16 www.nature.com/nrgastro C o n S e n S u S S tat e m e n t method has also been developed, which confirmed the subjective assessments189, using a dual registration of abdominal motion (DRAM) technique to correct for respiratory artefacts. This correction is necessary when prolonged recordings are to be made (more than a single breath hold)189,190. Imaging the undistended colon using the contrasting signal between the colonic wall and its contents is possible but is less distinct and the anatomy is more variable, particularly in the sigmoid area com- pared with the distended colon. Hence, assessment that is more detailed requires further development of this technique. A very promising MRI tagging technique was reported in 2017 that enables observing movement of colonic contents191 (Fig. 9). This method shows axial flow of contents with minimal movements adjacent to the colonic wall, possibly reflecting impedance to flow by the haustra191. Although the length of MRI recordings in practice has no limit, the duration of recordings is often short (5–30 min) owing to a combination of expense and patient discomfort from close confinement in the scan- ner. This limitation makes this technique most suitable Fig. 9 | MRI assessment of colonic wall movement. for studying short-​lived provoked motility, for example MRI enables the measurement of various characteristics after a laxative or pharmacological stimulant such as of the gastrointestinal tract, such as organ volumes, transit neostigmine or bisacodyl. Thus, at present, MRI should rate and motility. In this MRI of a sagittal section of the be seen as a complementary technique rather than as a ascending colon, the horizontal lines define the colonic substitute for manometry. lumen. During cine MRI, changes in the lengths of the lines provide a measure of transverse wall velocity, which Conclusions enables the calculation of a motility index (the percentage In this Expert Consensus Statement, we report the results of data points at which the wall velocity is >0.5 mm/s). of the first translational consensus on colonic motility. To our knowledge, basic scientists and adult and paedi- atric gastroenterologists met for the first time with the meeting (Table 5). Despite the very different experi- aim of reviewing the current literature in conjunction mental conditions used in animal and human studies, with their own studies to find a common conceptual similarities in the cellular mechanisms are sufficient understanding of colonic motility and reach an agree- to expect similarities in the motor patterns. Further ment on terminology and the definitions of CMPs. The research is needed to conclusively determine which participants were selected based on their contribution human motor patterns might correspond to the motor to the current knowledge of these patterns in human patterns described in experimental animals190. The and animal studies, both in vitro and in vivo. This effort motor patterns in animals summarized in this article was particularly useful, as it was immediately clear to all include myogenic ripples, myogenic high-​frequency participants that concepts, terminology and definitions ripples, myogenic slow phasic contractions, neurogenic applied by basic scientists were frequently misinter- colonic motor complexes and neural peristalsis. preted by clinicians and vice versa. The data presented The most obvious similarity is that between neural in this manuscript represent the agreement reached peristalsis that propels the contents in animals when dis- by the consensus group with the main aim of further- tended and the HAPCs and long single motor patterns ing knowledge about colonic motility from a common in humans. In both the animal bowel and the human understanding of the current state of the art, and to bowel, these motor patterns are dependent on the activa- introduce uniformity in the different terminologies used tion of enteric neural circuits by the bowel contents with in different laboratories (Table 4). greater or lesser dependence from extrinsic excitatory The introduction of colonic HRM has enabled us to neural inputs. Defecation in omnivores is sensitive to redefine knowledge of the normal CMPs in humans. environmental conditions, whereas pellet excretion in In particular, it has enabled us to better identify low-​ herbivores is clearly quasi-​continuous192–195. amplitude activity and to obtain simultaneous record- Less clear is the homology between the various types ings of both colonic and anorectal motor activity, which and descriptions of CMCs in experimental animals and was previously not possible owing to the thickness of the similar patterns in humans. In animals, the CMC seems required catheter and the large distance between record- to originate from the interaction between neurogenic ing sensors. HRM has demonstrated that the colonic excitatory activity that occurs at intervals close to 1 min pressurizations or simultaneous pressure increases, the and the myogenic ripples. In the proximal colon of her- retrograde cyclic activity and the intrahaustral activity bivores, the slow propagation of haustral boundaries are important and common CMPs in adult humans. that facilitates the formation of faecal pellets is driven The comparison of data on animal and human motor by neurogenic, slowly propagating CMCs. Neurogenic patterns was an important aspect of the consensus slow propagation of haustrations might also occur in NATuRe RevIewS | GASTRoENTERology & HEPATology volume 16 | SEPTEMBER 2019 | 573 C o n S e n S u S S tat e m e n t humans but has not yet been convincingly demon- described in the isolated human colon in vitro86,87 and strated. The neurogenic CMC elicited by continuous dis- to the repetitive pan-​colonic simultaneous events (pres- tension of the animal colon42,81 might correspond to the surizations) described in humans in vivo that occur at a simultaneous and quasi-​simultaneous motor complexes frequency of ~1 per minute7,8,196. Table 4 | Suggested terminology of colonic motor patterns Consensus term Previous terms Definition Animal colon Neural peristalsis Long-​distance contractions Anterograde propulsive movements triggered by distension segments (in vitro) with liquids or solids; can be repetitive if stimulus persists Ripples Ripples Myogenic contractions generated by non-​neuronal pacemaker cells; can be retrograde, anterograde or nonpropagating (chaotic) Colonic motor complex Colonic migrating motor Neurogenic repetitive peaks of pressure and/or electrical complexes; cyclic motor activity; can be migrating or nonmigrating complexes; haustral progression; haustral boundary contractions Neural retrograde propagating Retrograde propagating Neurogenic retrogradely propagating contractions contraction contraction Human isolated Repetitive motor pattern Repetitive propagating Anterograde, retrograde or simultaneous pressure events colon (in vitro) sequences triggered by enteric nerve stimulation or spontaneous Single motor pattern Single propagating sequences Anterograde or retrograde pressure events triggered by enteric nerve stimulation, balloon distension or spontaneous Adult colonic Simultaneous pressure Simultaneous contractions; Simultaneous pressure increases across multiple recording recording (in vivo) increases pan-​colonic pressurizations; sites; may be associated with internal anal sphincter common cavity relaxation Haustral boundary pressure Haustral boundary pressure Rhythmic or continuous pressure increases that can occur transients transients (movement of haustra in isolation at a single location or at spacings of 4–5 cm, not conclusively demonstrated) moving across these sensors Intrahaustral activity Intrahaustral segmental activity Pressure waves propagating in both directions at ~3 cpm Cyclic propagating motor Segmental contraction; Repetitive propagating pressure events with a frequency pattern nonpropagating activity of 2–6 cpm; can propagate retrogradely, anterogradely or occur simultaneously across ≥2 channels Short single motor pattern Low-​amplitude propagating Isolated propagating contractions separated by intervals contraction of >1 min; propagating anterogradely or retrogradely; typically spanning between 3 and 10 cm Long single motor pattern Low-​amplitude propagating Isolated propagating contractions separated by intervals contraction of >1 min; propagating rapidly (>2 cm/s) primarily anterogradely for >30 cm Slow retrograde motor pattern Not previously defined A slow (<0.5 cm/s) retrogradely propagating contraction spanning >40 cm High-​amplitude propagating High-​propagating sequences; An array of pressure waves, with the majority having a contractions giant migrating contractions; trough-​to-peak amplitude of >100 mmHg, that extend >20 high-​amplitude propagating cm along the colon pressure waves Paediatric colonic Simultaneous pressure Simultaneous contraction Same as in adults recording (in vivo) increases Haustral boundary pressure Not previously defined Not previously defined transients Intrahaustral activity Not previously defined Not previously defined Cyclic propagating motor Segmental contraction; Same as in adults pattern nonpropagating activity Short single motor pattern Low-​amplitude propagating Same as in adults contraction Long single motor pattern Low-​amplitude propagating Same as in adults contraction Slow retrograde motor pattern Not previously defined Same as in adults High-​amplitude propagating High-​propagating sequences Same as in adults contractions Definitions of in vivo recordings are based on high-​resolution manometry. cpm, cycles per minute. 574 | SEPTEMBER 2019 | volume 16 www.nature.com/nrgastro C o n S e n S u S S tat e m e n t Table 5 | Possible correspondence between colonic motor patterns in different settings Animal colon segments Human isolated colon Adult colonic recording (in vivo) Paediatric colonic recording (in vivo) (in vitro) (in vitro) Neural peristalsis Not yet studied High-​amplitude propagating contractions; High-​amplitude propagating contraction; long or short single motor pattern long or short single motor pattern Ripples Not yet studied Cyclic propagating motor pattern; Cyclic propagating motor pattern intrahaustral activity Colonic motor complex Repetitive motor pattern Simultaneous pressure increases Simultaneous pressure increases Colonic migrating motor Not yet studied Haustral boundary pressure transients Not observed complex Neural retrograde propagating Not observed Slow retrograde motor pattern Not observed contraction Isolated human colonic strips do not contain the entire neural circuits to generate complex motor patterns, but are useful to understand myogenic mechanisms, such as ripples associated with slow wave activity and slow phasic contractions and their modulation by neural inputs. The widely described ripples in the colon of animals, considered in the decision making for adults. The sole generated by slow waves, have also been identified focus on HAPCs will probably be replaced by a more in vitro in the human colon where they generate regular detailed assessment, including the identification and contractions at 2–6 cpm, and are termed intermediate-​ quantification of other motor patterns and differential frequency contractions. In animals, the ripples are assessment of regional motor activity. Thus, we clearly generated by the pacemaker system located at the need to further expand our knowledge about normal submucous side of the circular muscle (ICC-​SMP). In motor patterns and ultimately establish a uniform pro- humans, these ripples are present in vivo throughout tocol by which to perform and analyse colonic motility the colon and seem to be part of the cyclic propagat- studies in both children and adults. This harmonization ing motor pattern. HRM recordings from the human of protocols would enable the pooling of multicentre sigmoid colon have demonstrated a retrograde propa- results and modification of treatment outcomes. gation of the cyclic motor activity, perhaps indicating The review of the literature regarding the use of non- a mechanism that prevents premature rectal filling197. manometric techniques indicates that colonic scintig- Extrinsic excitatory neural inputs observed after feeding raphy has the potential to clarify the inter-​relationship can increase the amplitudes of the colonic ripples, which between the various patterns of motility and the tran- might then become mechanically more effective6. The sit of digesta, and that barostatic studies have the intrasegmental activity reported in humans8 as pressure ability to quantify colonic tone and wall compliance. waves propagating in both directions at ~3 cpm is also However, scintigraphy involves exposure to radiation likely to represent myogenic ripples. and the barostat can assess activity only over a localized No clear evidence exists from human colonic area. The wireless motility, pH and pressure capsule manometry studies regarding the occurrence of the (SmartPill) has the disadvantage that it cannot assess high-​frequency ripples that are commonly observed the propagation of motor events and, as the location in animals, although a similar underlying pacemaker of the capsule in the colon is unknown, the pressure system (the ICC-​MP) exists in humans that generates registration cannot be attributed to a specific colonic the electrical myenteric potential oscillations at a higher region. Promising techniques seem to be the 3D-​Transit frequency than that of the slow waves. Slow phasic electromagnetic capsules that can assess the move- myogenic contractions might correspond to the low-​ ments of colonic contents, and MRI that can measure frequency contractions described in human samples different colonic and noncolonic parameters simultane- in vitro and have been observed in isolated preparations ously (gastric, small intestinal and colonic volumes, the from animals. In summary, a number of similarities exist physical and chemical environment, transit and motility). between motor patterns described in animals and those The current literature regarding colonic motility in in the human colon, both in vitro and in vivo. humans has many deficiencies. In general, the studies The review and discussion concerning the CMPs applying colonic manometry included low numbers of recorded in vivo in children has been particularly illumi- individuals and often highly selected patients. Future nating. The findings from HRM studies on what should manometric studies in larger populations of healthy indi- be considered normal in healthy adults have raised ques- viduals are needed to confirm the findings with HRM tions regarding the manometric criteria in protocols for and to establish more reliable normal ranges. Combined surgical intervention in children with refractory consti- manometric and transit studies could help to determine pation. Healthy children cannot be studied for ethical the functional role of particular motor patterns. Future reasons. Moreover, the characteristics of propagating research should also focus on the possible mechanisms CMCs that lead to mass movements, notably HAPCs, are that control these patterns and elucidate possible phar- regarded as key features in paediatric clinical decision-​ macological strategies for therapeutic modulation. making because some studies in children suggest that Further studies, ideally multicentre studies, are needed the characteristics of HAPCs can predict the response to re-​evaluate the utility of colonic manometry in deci- to treatment. However, these characteristics are not sion making in clinical practice. For example, in patients NATuRe RevIewS | GASTRoENTERology & HEPATology volume 16 | SEPTEMBER 2019 | 575 C o n S e n S u S S tat e m e n t with chronic constipation who have failed to respond to are followed by simultaneous increases in pressure is less current treatments, HRM could give a more complete clear (Fig. 6b). Do simultaneous increases result from a description of motor patterns to subtype constipation, ‘common cavity’ phenomenon or do they represent true enabling treatment around that subtyping198. simultaneous contractile activity? Unlike a contractile Medical and surgical decisions for children are cur- event, a common cavity was hypothesized to occur when rently based on colonic manometry studies, but no stud- a propagating contraction in the proximal regions of ies have conclusively demonstrated that characterizing the colon moves content (gaseous, liquid or solid) into the and quantifying CMPs improves long-​term outcome. distal regions. The propagating contraction ends and, if This aim could be achieved only if colonic manometric the anal sphincters remain closed, the content moving procedures are standardized between centres. Adult and ahead of the propulsive motor pattern causes a simulta- paediatric gastroenterologists who perform such proce- neous rise in pressure throughout the distal regions of dures and scientists with expertise in colonic physiology the colon. Is the consistent failure of the colonic segment should work together to achieve such standardization. to develop propagated contractions the primary cause Both in children and adults, the relevance of poorly (and is the disorder, therefore, amenable to surgical propagating HAPCs in disorders of motility needs to resection) or is it a secondary effect of the patient’s severe be clarified. A total absence of propagated contractions constipation? Finally, the clinical relevance of the CMPs in response to colonic stimulants can be considered a identified by HRM in children needs to be assessed. reliable indicator of colonic inertia, but the clinical sig- nificance of HAPCs that propagate only partially and Published online 11 July 2019 1. Phillips, S. F. Functions of the large bowel: an overview. guinea-​pig colon. Neurogastroenterol. Motil. 27, layers of canine proximal colon. Am. J. Physiol. 258, Scand. J. Gastroenterol. Suppl. 93, 1–12 (1984). 1466–1477 (2015). G484–G491 (1990). 2. Mearin, F. et al. Bowel disorders. Gastroenterology 19. D’Antona, G., Hennig, G. W., Costa, M., 35. Quan, X., Yang, Z., Xue, M., Chen, J. H. & Huizinga, J. D. 150, 1393–1407 (2016). Humphreys, C. M. & Brookes, S. J. Analysis of motor Relationships between motor patterns and intraluminal 3. Tabbers, M. M. et al. Evaluation and treatment patterns in the isolated guinea-​pig large intestine by pressure in the 3-taeniated proximal colon of the rabbit. of functional constipation in infants and children: spatio-​temporal maps. Neurogastroenterol. Motil. 13, Sci. Rep. 7, 42293 (2017). evidence-​based recommendations from ESPGHAN 483–492 (2001). 36. Yoneda, S., Takano, H., Takaki, M. & Suzuki, H. and NASPGHAN. J. Pediatr. Gastroenterol. Nutr. 58, 20. Dinning, P. G., Costa, M., Brookes, S. J. & Spencer, N. J. Properties of spontaneously active cells distributed 258–274 (2014). Neurogenic and myogenic motor patterns of rabbit in the submucosal layer of mouse proximal colon. 4. Rudolph, C. D. & Winter, H. S. NASPGN guidelines proximal, mid, and distal colon. Am. J. Physiol. J. Physiol. 542, 887–897 (2002). for training in pediatric gastroenterology. NASPGN Gastrointest. Liver Physiol. 303, G83–G92 (2012). 37. Huizinga, J. D. et al. Two independent networks of Executive Council, NASPGN Training and Education 21. Chen, J. H., Yang, Z., Yu, Y. & Huizinga, J. D. Haustral interstitial cells of cajal work cooperatively with the Committee. J. Pediatr. Gastroenterol. Nutr. 29, boundary contractions in the proximal 3-taeniated enteric nervous system to create colonic motor patterns. S1–S26 (1999). rabbit colon. Am. J. Physiol. Gastrointest. Liver Physiol. Front. Neurosci. 5, 93 (2011). 5. Bharucha, A. E., Pemberton, J. H. & Locke, G. R. 310, G181–G192 (2016). 38. Fujimoto, H., Shigemasa, Y. & Suzuki, H. Properties of 3rd American Gastroenterological Association 22. Ehrlein, H. J., Reich, H. & Schwinger, M. Physiological spontaneous contractions and their modulation by technical review on constipation. Gastroenterology significance of the contractions of the rabbit proximal transmural nerve stimulation in circular smooth muscle 144, 218–238 (2013). colon. Q. J. Exp. Physiol. 67, 407–417 (1982). isolated from the pacemaker area in the flexure region 6. Dinning, P. G. et al. Quantification of in vivo colonic 23. Ehrlein, H. J., Reich, H. & Schwinger, M. Colonic motility of the guinea-​pig colon. J. Smooth Muscle Res. 46, motor patterns in healthy humans before and after a and transit of digesta during hard and soft faeces 293–308 (2010). meal revealed by high-​resolution fiber-​optic manometry. formation in rabbits. J. Physiol. 338, 75–86 (1983). 39. Mane, N. et al. Dynamics of inhibitory co-​transmission, Neurogastroenterol. Motil. 26, 1443–1457 (2014). 24. Lentle, R. G. et al. High-​definition spatiotemporal membrane potential and pacemaker activity determine 7. Corsetti, M. et al. Pan-​colonic pressurizations associated mapping of contractile activity in the isolated neuromyogenic function in the rat colon. Pflugers Arch. with relaxation of the anal sphincter in health and proximal colon of the rabbit. J. Comp. Physiol. B 178, 466, 2305–2321 (2014). disease: a new colonic motor pattern identified using 257–268 (2008). 40. Huizinga, J. D. et al. Motor patterns of the small high-​resolution manometry. Am. J. Gastroenterol. 112, 25. Dickens, E. J., Hirst, G. D. & Tomita, T. Identification intestine explained by phase-​amplitude coupling of 479–489 (2017). of rhythmically active cells in guinea-​pig stomach. two pacemaker activities: the critical importance of 8. Chen, J. H. et al. Intraluminal pressure patterns in the J. Physiol. 514, 515–531 (1999). propagation velocity. Am. J. Physiol. Cell Physiol. 309, human colon assessed by high-​resolution manometry. 26. Huizinga, J. D., Robinson, T. L. & Thomsen, L. C403–C414 (2015). Sci. Rep. 7, 41436 (2017). The search for the origin of rhythmicity in intestinal 41. Bayliss, W. M. & Starling, E. H. The movements and 9. Dinning, P. G., Carrington, E. V. & Scott, S. M. The use contraction; from tissue to single cells. the innervation of the large intestine. J. Physiol. 26, of colonic and anorectal high-​resolution manometry Neurogastroenterol. Motil. 12, 3–9 (2000). 107–118 (1900). and its place in clinical work and in research. 27. Sanders, K. M., Ward, S. M. & Koh, S. D. Interstitial 42. Barnes, K. J., Beckett, E. A., Brookes, S. J., Sia, T. C. Neurogastroenterol. Motil. 27, 1693–1708 (2015). cells: regulators of smooth muscle function. Physiol. Rev. & Spencer, N. J. Control of intrinsic pacemaker 10. Costa, M. et al. An experimental method to identify 94, 859–907 (2014). frequency and velocity of colonic migrating motor neurogenic and myogenic active mechanical states of 28. Pluja, L. et al. Evidence supporting presence of two complexes in mouse. Front. Neurosci. 8, 96 (2014). intestinal motility. Front. Syst. Neurosci. 7, 7 (2013). pacemakers in rat colon. Am. J. Physiol. Gastrointest. 43. Brann, L. & Wood, J. D. Motility of the large intestine 11. Hennig, G. W., Costa, M., Chen, B. N. & Brookes, S. J. Liver Physiol. 281, G255–G266 (2001). of piebald-​lethal mice. Am. J. Dig. Dis. 21, 633–640 Quantitative analysis of peristalsis in the guinea-​pig 29. Parsons, S. P. & Huizinga, J. D. Effects of gap junction (1976). small intestine using spatio-​temporal maps. J. Physiol. inhibition on contraction waves in the murine small 44. Crema, A., Frigo, G. M. & Lecchini, S. A pharmacological 517, 575–590 (1999). intestine in relation to coupled oscillator theory. Am. J. analysis of the peristaltic reflex in the isolated colon of 12. Janssen, W. M. P. & Lentle, R. in New Advances in Physiol. Gastrointest. Liver Physiol. 308, G287–G297 the guinea-​pig or cat. Br. J. Pharmacol. 39, 334–345 Gastrointestinal Motility Research (eds Cheng, L. K., (2015). (1970). Pullan, A. J. & Farrugia, G.) 219–241 (Springer, 2013). 30. Hennig, G. W., Gregory, S., Brookes, S. J. & Costa, M. 45. Costa, M. & Furness, J. B. The peristaltic reflex: an 13. Cheng, L. K. & Farrugia, G. in New Advances in Non-​peristaltic patterns of motor activity in the analysis of the nerve pathways and their pharmacology. Gastrointestinal Motility Research (eds Cheng, L. K., guinea-​pig proximal colon. Neurogastroenterol. Motil. Naunyn Schmiedebergs Arch. Pharmacol. 294, 47–60 Pullan, A. J. & Farrugia, G.) 1–6 (Springer, 2013). 22, e207–e217 (2010). (1976). 14. Hardcastle, J. D. & Mann, C. V. Study of large bowel 31. Smith, T. K., Reed, J. B. & Sanders, K. M. Interaction 46. Auer, J. & Krueger, H. Experimental study of peristalsis. Gut 9, 512–520 (1968). of two electrical pacemakers in muscularis of canine antiperistaltic and peristaltic motor and inhibitory 15. Lecci, A., Giuliani, S., Tramontana, M., Giorgio, R. D. proximal colon. Am. J. Physiol. 252, C290–C299 phenomena. Am. J. Physiol. 148, 350–357 (1947). & Maggi, C. A. The role of tachykinin NK1 and NK2 (1987). 47. Bozler, E. Myenteric reflex. Am. J. Physiol. 157, receptors in atropine-​resistant colonic propulsion in 32. Rae, M. G., Fleming, N., McGregor, D. B., Sanders, K. M. 329–337 (1949). anaesthetized guinea-​pigs. Br. J. Pharmacol. 124, & Keef, K. D. Control of motility patterns in the human 48. Karaus, M. & Sarna, S. K. Giant migrating contractions 27–34 (1998). colonic circular muscle layer by pacemaker activity. during defecation in the dog colon. Gastroenterology 16. Frigo, G. M. & Lecchini, S. An improved method for J. Physiol. 510, 309–320 (1998). 92, 925–933 (1987). studying the peristaltic reflex in the isolated colon. 33. Costa, M. et al. Neurogenic and myogenic motor 49. Sethi, A. K. & Sarna, S. K. Contractile mechanisms of Br. J. Pharmacol. 39, 346–356 (1970). activity in the colon of the guinea pig, mouse, rabbit, canine colonic propulsion. Am. J. Physiol. Gastrointest. 17. Christensen, J. Gross and Microscopic Anatomy of the and rat. Am. J. Physiol. Gastrointest. Liver Physiol. Liver Physiol. 268, G530–G538 (1995). Large Intestine (Raven Press, 1991). 305, G749–G759 (2013). 50. Sarna, S. K. Myoelectric correlates of colonic motor 18. Costa, M. et al. Neuromechanical factors involved in 34. Sabourin, P. J., Kingma, Y. J. & Bowes, K. L. Electrical complexes and contractile activity. Am. J. Physiol. the formation and propulsion of fecal pellets in the and mechanical interactions between the muscle 250, G213–G220 (1986). 576 | SEPTEMBER 2019 | volume 16 www.nature.com/nrgastro C o n S e n S u S S tat e m e n t 51. Scott, S. M., Pilot, M. A., Barnett, T. G. & Williams, N. S. 78. Ferre, J. P. & Ruckebusch, Y. Myoelectrical activity and 104. Rao, S. S. & Welcher, K. Periodic rectal motor activity: Prolonged ambulatory canine colonic motility. Am. J. propulsion in the large intestine of fed and fasted rats. the intrinsic colonic gatekeeper? Am. J. Gastroenterol. Physiol. 268, G650–G662 (1995). J. Physiol. 362, 93–106 (1985). 91, 890–897 (1996). 52. Quigley, E. M. & Phillips, S. F. The ileocecal (ileocolonic) 79. Du, C., Ferre, J. P. & Ruckebusch, Y. Spinal cord 105. Bassotti, G., Clementi, M., Antonelli, E., Pelli, M. A. sphincter. Z. Gastroenterol. 21, 47–55 (1983). influences on the colonic myoelectrical activity of fed & Tonini, M. Low-​amplitude propagated contractile 53. Adler, H. F. & Templeton, R. D. The correlation of and fasted rats. J. Physiol. 383, 395–404 (1987). waves: a relevant propulsive mechanism of human activity and transportation in the colon of the dog. 80. Roger, T. & Ruckebusch, Y. Pharmacological colon. Dig. Liver Dis. 33, 36–40 (2001). Am. J. Physiol. 128, 514–520 (1940). modulation of postprandial colonic motor activity in the 106. Bassotti, G., Germani, U. & Morelli, A. Flatus-​related 54. De Vos, W. C. Migrating spike complex in the small pony. J. Vet. Pharmacol. Ther. 10, 273–282 (1987). colorectal and anal motor events. Dig. Dis. Sci. 41, intestine of the fasting cat. Am. J. Physiol. 265, 81. Costa, M. et al. New insights into neurogenic cyclic 335–338 (1996). G619–G627 (1993). motor activity in the isolated guinea-​pig colon. 107. Corsetti, M. et al. Effect of linaclotide on colonic 55. Zhu, Y. R., Cowles, V. E., Herranz, E. S., Schulte, W. J. Neurogastroenterol. Motil. 29, 1–13 (2017). motility assessed with intraluminal colonic high-​ & Condon, R. E. Arginine vasopressin inhibits phasic 82. Spencer, N. J. Control of migrating motor activity in resolution manometry in healthy subjects: preliminary contractions and stimulates giant contractions in the colon. Curr. Opin. Pharmacol. 1, 604–610 (2001). results [abstract Sa1376]. Gastroenterology 148, monkey colon. Gastroenterology 102, 868–874 83. Smith, T. K. et al. A smooth muscle tone-​dependent S-308 (2015). (1992). stretch-​activated migrating motor pattern in isolated 108. Corsetti, M. et al. Comparison of the effect of 56. Nagakura, Y., Sohda, K., Ito, H. & Miyata, K. guinea-​pig distal colon. J. Physiol. 551, 955–969 polyethylene glycol 3350, prucalopride, bisacodyl and Gastrointestinal motor activity in conscious ferrets. (2003). placebo on colonic motility assessed with intraluminal Eur. J. Pharmacol. 321, 53–57 (1997). 84. Hibberd, T. J. et al. Neurogenic and myogenic patterns colonic high-​resolution manometry in healthy subjects: 57. Li, M., Johnson, C. P., Adams, M. B. & Sarna, S. K. of electrical activity in isolated intact mouse colon. the quantitative analysis. United European. Cholinergic and nitrergic regulation of in vivo giant Neurogastroenterol. Motil. 29, 1–12 (2017). Gastroenterol. J. 2, A104 (2014). migrating contractions in rat colon. Am. J. Physiol. 85. Carbone, S. E. et al. Ascending excitatory neural 109. Bassotti, G., Betti, C., Fusaro, C. & Morelli, A. Colonic Gastrointest. Liver Physiol. 283, G544–G552 (2002). pathways modulate slow phasic myogenic contractions high-​amplitude propagated contractions (mass 58. Gourcerol, G. et al. Cholinergic giant migrating in the isolated human colon. Neurogastroenterol. movements): repeated 24-h manometric studies in contractions in conscious mouse colon assessed by Motil. 25, 670–676 (2013). healthy volunteers. Neurogastroenterol. Motil. 4, using a novel noninvasive solid-​state manometry 86. Spencer, N. J. et al. Characterization of motor patterns 187–191 (1992). method: modulation by stressors. Am. J. Physiol. in isolated human colon: are there differences in 110. Bassotti, G. & Gaburri, M. Manometric investigation Gastrointest. Liver Physiol. 296, G992–G1002 patients with slow-​transit constipation? Am. J. Physiol. of high-​amplitude propagated contractile activity of (2009). Gastrointest. Liver Physiol. 302, G34–G43 (2012). the human colon. Am. J. Physiol. 255, G660–G664 59. Weems, W. A. & Weisbrodt, N. W. Ileal and colonic 87. Dinning, P. G. et al. High-​resolution colonic motility (1988). propulsive behavior: contribution of enteric neural recordings in vivo compared with ex vivo recordings 111. Crowell, M. D., Bassotti, G., Cheskin, L. J., circuits. Am. J. Physiol. 250, G653–G659 (1986). after colectomy, in patients with slow transit Schuster, M. M. & Whitehead, W. E. Method for 60. Spencer, N. J. et al. Mechanisms underlying distension-​ constipation. Neurogastroenterol. Motil. 28, prolonged ambulatory monitoring of high-​amplitude evoked peristalsis in guinea pig distal colon: is there a 1824–1835 (2016). propagated contractions from colon. Am. J. Physiol. role for enterochromaffin cells? Am. J. Physiol. 88. Bampton, P. A. et al. Spatial and temporal organization 261, G263–G268 (1991). Gastrointest. Liver Physiol. 301, G519–G527 (2011). of pressure patterns throughout the unprepared colon 112. Bharucha, A. E. High amplitude propagated 61. Chen, J. H. et al. Neurogenic and myogenic properties during spontaneous defecation. Am. J. Gastroenterol. contractions. Neurogastroenterol. Motil. 24, 977–982 of pan-​colonic motor patterns and their spatiotemporal 95, 1027–1035 (2000). (2012). organization in rats. PLOS ONE 8, e60474 (2013). 89. Cook, I. J., Furukawa, Y., Panagopoulos, V., Collins, P. J. 113. De Schryver, A. M., Samsom, M. & Smout, A. I. Effects 62. Bulbring, E. & Crema, A. Observations concerning the & Dent, J. Relationships between spatial patterns of of a meal and bisacodyl on colonic motility in healthy action of 5-hydroxytryptamine on the peristaltic reflex. colonic pressure and individual movements of content. volunteers and patients with slow-​transit constipation. Br. J. Pharmacol. Chemother. 13, 444–457 (1958). Am. J. Physiol. Gastrointest. Liver Physiol. 278, Dig. Dis. Sci. 48, 1206–1212 (2003). 63. Davenport, H. W. Comprehensive Physiology: G329–G341 (2000). 114. Dinning, P. G. et al. Bowel preparation affects the Supplement 16. Handbook of Physiology. 90. Dinning, P. G. et al. Pancolonic spatiotemporal mapping amplitude and spatiotemporal organization of colonic Gastrointestinal Physiology, 1895–1975: Motility reveals regional deficiencies in, and disorganization of propagating sequences. Neurogastroenterol. Motil. (ed. Terjung, R.) (American Physiological Society, 2011). colonic propagating pressure waves in severe 22, 633-e176 (2010). 64. Hukuhara, T. & Miyake, T. The intrinsic reflexes in the constipation. Neurogastroenterol. Motil. 22, 115. Dinning, P. G., Bampton, P. A., Kennedy, M. L. colon. Jpn J. Physiol. 9, 49–55 (1959). e340–e349 (2010). & Cook, I. J. Relationship between terminal ileal 65. Christensen, J. Comprehensive Physiology: 91. Bassotti, G. et al. Colonic mass movements in idiopathic pressure waves and propagating proximal Supplement 16. Handbook of Physiology. Colonic chronic constipation. Gut 29, 1173–1179 (1988). colonic pressure waves. Am. J. Physiol. 277, Motility (ed. Terjung, R.) (American Physiological 92. Camilleri, M. et al. American Neurogastroenterology G983–G992 (1999). Society, 2011). and Motility Society consensus statement on 116. Furukawa, Y. et al. Relationship between sleep 66. Grider, J. R. Identification of neurotransmitters intraluminal measurement of gastrointestinal and patterns and human colonic motor patterns. regulating intestinal peristaltic reflex in humans. colonic motility in clinical practice. Neurogastroenterol. Gastroenterology 107, 1372–1381 (1994). Gastroenterology 97, 1414–1419 (1989). Motil. 20, 1269–1282 (2008). 117. Louvel, D. et al. Intracolonic injection of glycerol: 67. Kunze, W. A. & Furness, J. B. The enteric nervous 93. Hawkins, C. F. & Hardy, T. L. On the nature of a model for abdominal pain in irritable bowel system and regulation of intestinal motility. Annu. Rev. haustration of the colon. J. Fac. Radiol. 2, 95–98 syndrome? Gastroenterology 110, 351–361 (1996). Physiol. 61, 117–142 (1999). (1950). 118. Steadman, C. J. et al. Control of muscle tone in the 68. Furness, J. B. The enteric nervous system and 94. Holzknechtg, G. Die normale Peristaltlik des Kolon human colon. Gut 33, 541–546 (1992). neurogastroenterology. Nat. Rev. Gastroenterol. [German]. Munch. Med. Wochenschr. 47, 2401–2403 119. Bassotti, G. et al. Edrophonium chloride for testing Hepatol. 9, 286–294 (2012). (1909). colonic contractile activity in man. Acta Physiol. Scand. 69. Tonini, M., Costa, M., Brookes, S. J. & Humphreys, C. M. 95. Alvarez, W. An Introduction to Gastroenterology 141, 289–293 (1991). Dissociation of the ascending excitatory reflex from (Butterworth-​Heinemann, 1948). 120. Di Lorenzo, C. et al. Manometry studies in children: peristalsis in the guinea-​pig small intestine. 96. Dinning, P. G. et al. Low-​resolution colonic manometry minimum standards for procedures. Neurogastroenterol. Neuroscience 73, 287–297 (1996). leads to a gross misinterpretation of the frequency Motil. 14, 411–420 (2002). 70. Wood, J. D. Enteric nervous system: reflexes, pattern and polarity of propagating sequences: initial results 121. Giorgio, V. et al. High-​resolution colonic manometry generators and motility. Curr. Opin. Gastroenterol. 24, from fiber-​optic high-​resolution manometry studies. accurately predicts colonic neuromuscular 149–158 (2008). Neurogastroenterol. Motil. 25, e640–e649 (2013). pathological phenotype in pediatric slow transit 71. Bayliss, W. M. & Starling, E. H. The movements and 97. Daly, J., Bergin, A., Sun, W. M. & Read, N. W. Effect constipation. Neurogastroenterol. Motil. 25, 70-e9 innervation of the small intestine. J. Physiol. 24, of food and anti-​cholinergic drugs on the pattern of (2013). 99–143 (1899). rectosigmoid contractions. Gut 34, 799–802 (1993). 122. Solzi, G. & Di Lorenzo, C. Are constipated children 72. Dinning, P. G. et al. Neural mechanisms of peristalsis 98. Narducci, F., Bassotti, G., Gaburri, M. & Morelli, A. different from constipated adults? Dig. Dis. 17, in the isolated rabbit distal colon: a neuromechanical Twenty four hour manometric recording of colonic 308–315 (1999). loop hypothesis. Front. Neurosci. 8, 75 (2014). motor activity in healthy man. Gut 28, 17–25 (1987). 123. Di Lorenzo, C., Flores, A. F. & Hyman, P. E. Age-​related 73. Welch, B. P. & Plant, H. O. A. Graphic study of the 99. Moreno-​Osset, E. et al. Association between changes in colon motility. J. Pediatr. 127, 593–596 muscular activity of the colon, with special reference postprandial changes in colonic intraluminal pressure (1995). to its response to feeding. Am. J. Med. Sci. 172, and transit. Gastroenterology 96, 1265–1273 (1989). 124. Di Lorenzo, C., Flores, A. F., Reddy, S. N. & Hyman, P. E. 261–261 (1926). 100. Rao, S. S., Sadeghi, P., Beaty, J., Kavlock, R. Use of colonic manometry to differentiate causes of 74. Cherbut, C. & Ruckebusch, Y. The effect of indigestible & Ackerson, K. Ambulatory 24-h colonic manometry in intractable constipation in children. J. Pediatr. 120, particles on digestive transit time and colonic motility healthy humans. Am. J. Physiol. Gastrointest. Liver 690–695 (1992). in dogs and pigs. Br. J. Nutr. 53, 549–557 (1985). Physiol. 280, G629–G639 (2001). 125. Di Lorenzo, C. et al. Colonic manometry in children 75. Schuurkes, J. A. & Tukker, J. J. The interdigestive 101. De Schryver, A. M., Samsom, M. & Smout, A. J. In with chronic intestinal pseudo-​obstruction. Gut 34, colonic motor complex of the dog. Arch. Int. search of objective manometric criteria for colonic 803–807 (1993). Pharmacodyn. Ther. 247, 329–334 (1980). high-​amplitude propagated pressure waves. 126. Di Lorenzo, C., Solzi, G. F., Flores, A. F., Schwankovsky, L. 76. Shibata, C., Sasaki, I., Matsuno, S., Mizumoto, A. Neurogastroenterol. Motil. 14, 375–381 (2002). & Hyman, P. E. Colonic motility after surgery for & Itoh, Z. Colonic motility in innervated and 102. Patton, V., Wiklendt, L., Arkwright, J. W., Lubowski, D. Z. Hirschsprung’s disease. Am. J. Gastroenterol. 95, extrinsically denervated loops in dogs. & Dinning, P. G. The effect of sacral nerve stimulation on 1759–1764 (2000). Gastroenterology 101, 1571–1578 (1991). distal colonic motility in patients with faecal 127. Rodriguez, L., Siddiqui, A. & Nurko, S. Internal anal 77. Sarna, S. K., Condon, R. & Cowles, V. Colonic incontinence. Br. J. Surg. 100, 959–968 (2013). sphincter relaxation associated with bisacodyl-​induced migrating and nonmigrating motor complexes in dogs. 103. Bassotti, G., Bucaneve, G., Pelli, M. A. & Morelli, A. colonic high amplitude propagating contractions in Am. J. Physiol. Gastrointest. Liver Physiol. 9, Contractile frequency patterns of the human colon. children with constipation: a colo-​anal reflex? G355–G360 (1984). Neurogastroenterol. Motil. 2, 73–78 (1990). Neurogastroenterol. Motil. 24, 1023-e545 (2012). NATuRe RevIewS | GASTRoENTERology & HEPATology volume 16 | SEPTEMBER 2019 | 577 C o n S e n S u S S tat e m e n t 128. Hamid, S. A., Di Lorenzo, C., Reddy, S. N., Flores, A. F. 151. Preston, D. M. & Lennard-​Jones, J. E. Severe chronic 172. Haase, A. M. et al. Gastrointestinal motility during & Hyman, P. E. Bisacodyl and high-​amplitude- constipation of young women: ‘idiopathic slow transit sleep assessed by tracking of telemetric capsules propagating colonic contractions in children. J. Pediatr. constipation’. Gut 27, 41–48 (1986). combined with polysomnography — a pilot study. Gastroenterol. Nutr. 27, 398–402 (1998). 152. Sadik, R., Abrahamsson, H., Ung, K. A. & Stotzer, P. O. Clin. Exp. Gastroenterol. 8, 327–332 (2015). 129. Venkatasubramani, N., Rudolph, C. D. & Sood, M. R. Accelerated regional bowel transit and overweight 173. Haase, A. M. et al. Regional gastrointestinal transit Erythromycin lacks colon prokinetic effect in children shown in idiopathic bile acid malabsorption. Am. J. times in severe ulcerative colitis. Neurogastroenterol. with functional gastrointestinal disorders: a Gastroenterol. 99, 711–718 (2004). Motil. 28, 217–224 (2016). retrospective study. BMC Gastroenterol. 8, 38 153. Hoverstad, T. & Bjorneklett, A. Short-​chain fatty acids 174. Azpiroz, F. & Malagelada, J. R. Gastric tone measured (2008). and bowel functions in man. Scand. J. Gastroenterol. by an electronic barostat in health and postsurgical 130. Dranove, J., Horn, D., Reddy, S. N. & Croffie, J. Effect 19, 1059–1065 (1984). gastroparesis. Gastroenterology 92, 934–943 of intravenous erythromycin on the colonic motility of 154. Bingham, S. A. & Cummings, J. H. Effect of exercise (1987). children and young adults during colonic manometry. and physical fitness on large intestinal function. 175. Azpiroz, F. & Malagelada, J. R. Physiological J. Pediatr. Surg. 45, 777–783 (2010). Gastroenterology 97, 1389–1399 (1989). variations in canine gastric tone measured by an 131. Parashette, K. R., Waseem, S., Horn, D., Shah, A. 155. VanSoest, P. J., Robertson, J. B. & Levitsky, D. A. electronic barostat. Am. J. Physiol. 248, G229–G237 & Croffie, J. Effect of octreotide on the colonic motility Comparison of the effects of psyllium and wheat (1985). in pediatric patients with chronic recalcitrant bran on gastrointestinal transit time and stool 176. Steadman, C. J., Phillips, S. F., Camilleri, M., constipation. J. Pediatr. Gastroenterol. Nutr. 61, characteristics. J. Am. Diet. Assoc. 88, 323–326 Haddad, A. C. & Hanson, R. B. Variation of muscle 626–629 (2015). (1988). tone in the human colon. Gastroenterology 101, 132. van den Berg, M. M. et al. Colonic manometry as 156. Krevsky, B., Malmud, L. S., D’Ercole, F., Maurer, A. H. 373–381 (1991). predictor of cecostomy success in children with & Fisher, R. S. Colonic transit scintigraphy. A 177. Ravi, K. et al. Phenotypic variation of colonic motor defecation disorders. J. Pediatr. Surg. 41, 730–736 physiologic approach to the quantitative measurement functions in chronic constipation. Gastroenterology (2006). of colonic transit in humans. Gastroenterology 91, 138, 89–97 (2010). 133. Aspirot, A., Fernandez, S., Di Lorenzo, C., Skaggs, B. 1102–1112 (1986). 178. Ford, M. J., Camilleri, M., Wiste, J. A. & Hanson, R. B. & Mousa, H. Antegrade enemas for defecation 157. Southwell, B. R., Clarke, M. C., Sutcliffe, J. Differences in colonic tone and phasic response to a disorders: do they improve the colonic motility? & Hutson, J. M. Colonic transit studies: normal values meal in the transverse and sigmoid human colon. Gut J. Pediatr. Surg. 44, 1575–1580 (2009). for adults and children with comparison of radiological 37, 264–269 (1995). 134. Sood, M. R. et al. Interobserver variability in the and scintigraphic methods. Pediatr. Surg. Int. 25, 179. Jouet, P. et al. Tonic and phasic motor activity in the interpretation of colon manometry studies in 559–572 (2009). proximal and distal colon of healthy humans. Am. J. children. J. Pediatr. Gastroenterol. Nutr. 55, 548–551 158. Jian, R., Najean, Y. & Bernier, J. J. Measurement of Physiol. 274, G459–G464 (1998). (2012). intestinal progression of a meal and its residues in 180. Wiley, J., Tatum, D., Keinath, R. & Chung, O. Y. 135. Kaul, A. et al. Colonic hyperactivity results in frequent normal subjects and patients with functional diarrhoea Participation of gastric mechanoreceptors and fecal soiling in a subset of children after surgery for by a dual isotope technique. Gut 25, 728–731 intestinal chemoreceptors in the gastrocolonic Hirschsprung disease. J. Pediatr. Gastroenterol. Nutr. (1984). response. Gastroenterology 94, 1144–1149 52, 433–436 (2011). 159. Camilleri, M., Zinsmeister, A. R., Greydanus, M. P., (1988). 136. Liem, O. et al. Distention of the colon is associated Brown, M. L. & Proano, M. Towards a less costly but 181. Van Der Veek, P. P. J. et al. Recto-​colonic reflex with initiation of propagated contractions in children. accurate test of gastric emptying and small bowel is impaired in patients with irritable bowel Neurogastroenterol. Motil. 22, 19–23 (2010). transit. Dig. Dis. Sci. 36, 609–615 (1991). syndrome. Neurogastroenterol. Motil. 19, 653–659 137. Gomez, R., Mousa, H., Liem, O., Hayes, J. & Di 160. Proano, M., Camilleri, M., Phillips, S. F., Brown, M. L. (2007). Lorenzo, C. How do antegrade enemas work? Colonic & Thomforde, G. M. Transit of solids through 182. Von Der Ohe, M. R., Hanson, R. B. & Camilleri, M. motility in response to administration of normal saline the human colon: regional quantification in the Comparison of simultaneous recordings of human solution into the proximal colon. J. Pediatr. unprepared bowel. Am. J. Physiol. 258, G856–G862 colonic contractions by manometry and a barostat. Gastroenterol. Nutr. 51, 741–746 (2010). (1990). Neurogastroenterol. Motil. 6, 213–222 (1994). 138. Rodriguez, L., Nurko, S. & Flores, A. Factors associated 161. Reddy, S. N. et al. Colonic motility and transit in 183. Bharucha, A. E., Camilleri, M., Zinsmeister, A. R. with successful decrease and discontinuation of health and ulcerative colitis. Gastroenterology 101, & Hanson, R. B. Adrenergic modulation of human antegrade continence enemas (ACE) in children with 1289–1297 (1991). colonic motor and sensory function. Am. J. Physiol. defecation disorders: a study evaluating the effect of 162. Bazzocchi, G. et al. Postprandial colonic transit 273, G997–G1006 (1997). ACE on colon motility. Neurogastroenterol. Motil. 25, and motor activity in chronic constipation. 184. Bharucha, A. E., Hubmayr, R. D., Ferber, I. J. 140-e81 (2013). Gastroenterology 98, 686–693 (1990). & Zinsmeister, A. R. Viscoelastic properties of the 139. Youssef, N. N., Pensabene, L., Barksdale, E. Jr & 163. Bazzocchi, G. et al. Effect of eating on colonic motility human colon. Am. J. Physiol. Gastrointest. Liver Di Lorenzo, C. Is there a role for surgery beyond and transit in patients with functional diarrhea. Physiol. 281, G459–G466 (2001). colonic aganglionosis and anorectal malformations in Simultaneous scintigraphic and manometric 185. Nilsson, M. et al. Quantification and variability in children with intractable constipation? J. Pediatr. Surg. evaluations. Gastroenterology 101, 1298–1306 colonic volume with a novel magnetic resonance 39, 73–77 (2004). (1991). imaging method. Neurogastroenterol. Motil. 27, 140. Pensabene, L., Youssef, N. N., Griffiths, J. M. 164. Dinning, P. G., Szczesniak, M. M. & Cook, I. J. 1755–1763 (2015). & Di Lorenzo, C. Colonic manometry in children Proximal colonic propagating pressure waves 186. Murray, K. et al. Novel MRI techniques and with defecatory disorders. Role in diagnosis and sequences and their relationship with parameters for assessing the impact of laxatives on management. Am. J. Gastroenterol. 98, 1052–1057 movements of content in the proximal human the human colon [abstract Su2056]. Gastroenterology (2003). colon. Neurogastroenterol. Motil. 20, 512–520 146, S-534 (2014). 141. King, S. K. et al. 24-Hour colonic manometry in (2008). 187. Alyami, J., Spiller, R. C. & Marciani, L. Magnetic pediatric slow transit constipation shows significant 165. Wang, Y. T. et al. Regional gastrointestinal transit resonance imaging to evaluate gastrointestinal reductions in antegrade propagation. Am. J. and pH studied in 215 healthy volunteers using function. Neurogastroenterol. Motil. 27, 1687–1692 Gastroenterol. 103, 2083–2091 (2008). the wireless motility capsule: influence of age, (2015). 142. Liem, O. et al. Prolonged colonic manometry in children gender, study country and testing protocol. 188. Kirchhoff, S. et al. Assessment of colon motility using with defecatory disorders. J. Pediatr. Gastroenterol. Aliment. Pharmacol. Ther. 42, 761–772 (2015). simultaneous manometric and functional cine-​MRI Nutr. 59, 748–753 (2014). 166. Camilleri, M. et al. Wireless pH-​motility capsule analysis: preliminary results. Abdom. Imaging 36, 143. Heikenen, J. B. et al. Colonic motility in children for colonic transit: prospective comparison with 24–30 (2011). with repaired imperforate anus. Dig. Dis. Sci. 44, radiopaque markers in chronic constipation. 189. Lam, C. et al. Colonic response to laxative ingestion 1288–1292 (1999). Neurogastroenterol. Motil. 22, 874–882 (2010). as assessed by MRI differs in constipated irritable 144. Palit, S., Lunniss, P. J. & Scott, S. M. The physiology of 167. Rao, S. S., Mysore, K., Attaluri, A. & Valestin, J. bowel syndrome compared to functional constipation. human defecation. Dig. Dis. Sci. 57, 1445–1464 Diagnostic utility of wireless motility capsule in Neurogastroenterol. Motil. 28, 861–870 (2016). (2012). gastrointestinal dysmotility. J. Clin. Gastroenterol. 45, 190. Spencer, N. J., Dinning, P. G., Brookes, S. J. 145. Scott, S. M. Manometric techniques for the 684–690 (2011). & Costa, M. Insights into the mechanisms underlying evaluation of colonic motor activity: current status. 168. Monthira, M., Saab, R., Hasler, W., Kuo, B. colonic motor patterns. J. Physiol. 594, 4099–4116 Neurogastroenterol. Motil. 15, 483–513 (2003). & Chey, W. D. Do circadian changes in colonic motility (2016). 146. El-​Chammas, K. I., Tipnis, N. A., Simpson, P. M. differ between healthy volunteers and patients with 191. Pritchard, S. E. et al. Assessment of motion of & Sood, M. R. Colon high-​resolution manometry: chronic constipation? Insights yielded by a colonic contents in the human colon using MRI using pressure topography plots to evaluate pediatric noninvasive, wireless pH and motility capsule. tagging. Neurogastroenterol. Motil. 29, e13091 colon motility. J. Pediatr. Gastroenterol. Nutr. 59, Neurogastroenterol. Motil. 21, 37 (2009). (2017). 500–504 (2014). 169. Hasler, W. L. et al. Heightened colon motor activity 192. Hall, C. S. Emotional behavior in the rat. I. Defecation 147. Wessel, S. et al. Characterizing colonic motility in measured by a wireless capsule in patients with and urination as measures of individual differences children with chronic intractable constipation: a look constipation: relation to colon transit and IBS. Am. J. in emotionality. J. Comp. Psychol. 18, 385–403 beyond high-​amplitude propagating sequences. Physiol. Gastrointest. Liver Physiol. 297, (1934). Neurogastroenterol. Motil. 28, 743–757 (2016). G1107–G1114 (2009). 193. Barone, F. C. et al. Cold-​restraint stress increases rat 148. Bouchoucha, M. et al. How many segments are 170. Hiroz, P., Schlageter, V., Givel, J. C. & Kucera, P. fecal pellet output and colonic transit. Am. J. Physiol. necessary to characterize delayed colonic transit time? Colonic movements in healthy subjects as monitored 258, G329–G337 (1990). Int. J. Colorectal Dis. 30, 1381–1389 (2015). by a magnet tracking system. Neurogastroenterol. 194. Enck, P. & Holtmann, G. Stress and gastrointestinal 149. Stivland, T. et al. Scintigraphic measurement of Motil. 21, 838-e57 (2009). motility in animals: a review of the literature. regional gut transit in idiopathic constipation. 171. Haase, A. M. et al. Pilot study trialling a new Neurogastroenterol. Motil. 4, 83–90 (1992). Gastroenterology 101, 107–115 (1991). ambulatory method for the clinical assessment of 195. Nagano, M., Ishimizu, Y., Saitoh, S., Okada, H. & 150. Watier, A. et al. Constipation with colonic inertia. regional gastrointestinal transit using multiple Fukuda, H. The defecation reflex in rats: fundamental A manifestation of systemic disease? Dig. Dis. Sci. 28, electromagnetic capsules. Neurogastroenterol. Motil. properties and the reflex center. Auton. Neurosci. 111, 1025–1033 (1983). 26, 1783–1791 (2014). 48–56 (2004). 578 | SEPTEMBER 2019 | volume 16 www.nature.com/nrgastro C o n S e n S u S S tat e m e n t 196. Corsetti, M. et al. Pan-​colonic pressurizations 200. Mane, N., Martinez-​Cutillas, M., Gallego, D. & Publisher’s note associated with relaxation of the anal sphincter in Jimenez, M. Enteric motor pattern generators involve Springer Nature remains neutral with regard to jurisdictional man: a highly prevalent colonic motor event identified both myogenic and neurogenic mechanisms in the claims in published maps and institutional affiliations. using high-​resolution manometry and associated with human colon. Front. Physiol. 6, 205 (2015). feeling and desire to evacuate gas. Gastroenterology Open Access This article is licensed under 148, S192 (2015). Acknowledgements a Creative Commons Attribution 4.0 197. Lin, A. Y. et al. High-​resolution anatomic correlation of M.B. and J.T. contributed equally as senior authors to this International License, which permits use, cyclic motor patterns in the human colon: evidence manuscript. Individual authors thank the following funders for sharing, adaptation, distribution and reproduction in any of a rectosigmoid brake. Am. J. Physiol. Gastrointest. research support: National Institute of Diabetes, Digestive and medium or format, as long as you give appropriate credit to Liver Physiol. 312, G508–G515 (2017). Kidney Diseases (NIDDK) of the National Institutes of Health the original author(s) and the source, provide a link to the 198. Corsetti, M. et al. Colonic motor responses to a meal under award numbers R01 DK78924 (A.E.B.), 5R21DK104127- Creative Commons license, and indicate if changes were and to bisacodyl, evaluated by high-​resolution 02 and U-34, 1434-DK109191-01 (S.R.). made. The images or other third party material in this article manometry (HRM), differ between laxative-​refractory are included in the article’s Creative Commons license, slow transit constipation with or without pain Author contributions unless indicated otherwise in a credit line to the material. [abstract Su1584]. Gastroenterology 150, All authors researched data for the article, made substantial If material is not included in the article’s Creative Commons S533–S534 (2016). contributions to discussion of its content, wrote and reviewed license and your intended use is not permitted by statutory 199. Spencer, N. J., Bywater, R. A. Enteric nerve stimulation and/or edited the manuscript before submission. regulation or exceeds the permitted use, you will need to evokes a premature colonic migrating motor complex obtain permission directly from the copyright holder. To view in mouse. Neurogastroenterol. Motil. 14, 657–665 Competing interests a copy of this license, visit http://creativecommons.org/ (2002). The authors declare no competing interests. licenses/by/4.0/. NATuRe RevIewS | GASTRoENTERology & HEPATology volume 16 | SEPTEMBER 2019 | 579