Physiology of the Colon and Its Measurement

CHAPTER

144 

Physiology of the Colon and Its Measurement Adil E. Bharucha 

|

  Michael Camilleri

T

he human colon serves to absorb water and electrolytes, store intraluminal contents until elimination is socially convenient, and salvage nutrients after bacterial metabolism of carbohydrates that have not been absorbed in the small intestine. These functions are dependent on the colon’s ability to control the distal progression of contents; in healthy adults, colonic transit normally requires several hours to almost 3 days for completion. There are differences in colonic structure and function even among mammals1; unless otherwise stated, this chapter will focus on the physiology of colonic function in humans. Although the colon is regarded as a single organ, there are regional differences between the right and left colon, indicated in Table 144.1. The right and left colon are derived from the embryologic midgut and hindgut, and the junction is located just proximal to the splenic flexure.

ANATOMY GROSS ANATOMY In adult cadavers the colon is approximately 1.5 m long. The musculature in the colonic wall is composed of outer longitudinal and inner circular layers. From the cecum to the rectosigmoid junction, the longitudinal layer is organized in three thick bands, the taeniae, with a thin layer of longitudinal muscle in between these bands.2 At the rectosigmoid junction, the three taeniae broaden to form a uniformly thick layer throughout the rectum. In the anal canal, the longitudinal muscle layer extends into a plane between the external anal sphincter and the circular muscle layer that thickens to become the internal anal sphincter to insert on the perianal skin as the corrugator cutis ani muscle. Other than humans, only primates, horses, guinea pigs, and rabbits have taeniae coli3; the taeniae coli are thought to function as suspension cables upon which the circular muscle arcs are suspended, facilitating efficient contraction of the circular muscle. Thus a 17% contraction of circular muscle reduces the luminal diameter of the colon by two-thirds.4 If the longitudinal muscles were arranged concentrically, an identical contraction of circular muscle would reduce luminal diameter by only one-third. Whether or not longitudinal and circular muscles contract synchronously during peristalsis is controversial. The colon is suspended from the posterior abdominal wall by a mesentery. The mesentery is relatively narrow, restricting mobility of the cecum and ascending and descending colon. Around the transverse and sigmoid colon, the mesentery is broader, permitting considerable movement and contributing to the tendency in some individuals to have a pendulous transverse colon or a

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floppy sigmoid colon. This contributes to the looping of the colonoscope during examination.

ENTERIC NERVOUS SYSTEM Colonic neurons, interstitial cells of Cajal (ICC), and smooth muscle work in concert to effectuate colonic contraction. The enteric nervous system possesses afferent neurons, interneurons, and motor neurons that can initiate physiologic motor activity in the absence of extrinsic input. The ICC form extensive networks in the myenteric plexus (ICCMY), which is situated between longitudinal and circular muscle layers, and the submucosal plexus (ICCSM) deep to the circular muscle layer (see Fig. 144.5), from where it regulates mucosal absorption. A separate layer—the intramuscular ICC (ICCIM)—is found in the septa that separate bundles of circular muscle cells. ICCMY and ICCSM form extensive networks along the colon and are electrically coupled to one another, the smooth muscle cells, and enteric motor neurons. ICC regulate colonic motility via several mechanisms. They generate electrical slow waves, which then propagate through smooth muscle cells via gap junctions5 and influence the smooth muscle membrane potential and membrane potential gradient,6 and they partly mediate mechanosensitivity in smooth muscle.7 They may also mediate neurotransmission from axons of enteric motor neurons to the smooth muscle,5 although this has recently been questioned.8,9

CELLULAR BASIS FOR MOTILITY Contraction of smooth muscle results from interactions between smooth muscle, the ICC, the intrinsic or enteric nervous system, and the extrinsic nervous system. ICC are the pacemaker cells, responsible for generating slow wave activity that drives smooth muscle contraction. ICC also amplify neuronal input, act as mechanotransducers, and regulate smooth muscle membrane potential. The three basic electrical events recorded from human colonic circular smooth muscle in vitro are10: (1) slow wave activity with a frequency of two to four contractions/minute, originating along the submucosal plexus border of the circular muscle layer; (2) membrane potential oscillations (MPOs), with a frequency of approximately 18 contractions/ minute, originating in the myenteric plexus border of circular muscle; and (3) action potentials superimposed upon slow waves and MPOs. Slow waves and MPOs summate in the central region of circular muscle producing a complex pattern of activity that regulates contractile amplitude and frequency. The predominant contractile rhythm recorded from the human colon in vitro and in vivo corresponds to the slow wave frequency of two to four/minute. Repolarization of membrane potential during slow waves results in opening of L-type calcium channels and, when a firing threshold

Physiology of the Colon and Its Measurement  CHAPTER 144 1676.e1

ABSTRACT The human colon serves to absorb water and electrolytes, store intraluminal contents until elimination is socially convenient, and salvage nutrients after bacterial metabolism of carbohydrates that have not been absorbed in the small intestine. These functions are dependent on the colon’s ability to control the distal progression of contents; in healthy adults, colonic transit normally requires several hours to almost 3 days for completion. There are differences in colonic structure and function even among mammals1; unless otherwise stated, this chapter will focus on the physiology of colonic function in humans. Although the colon is regarded as a single organ, there are regional differences between the right and left colon, indicated in Table 144.1. The right and left colon are derived from the embryologic midgut and hindgut, and the junction is located just proximal to the splenic flexure.

KEYWORDS Human colon; Physiology; Measurement of colon motility

Physiology of the Colon and Its Measurement  CHAPTER 144 

TABLE 144.1  Comparison of Right and Left Colon Feature

Right Colon

Left Colon

Embryologic origin Blood supply

Midgut Superior mesenteric vessels

Hindgut Inferior mesenteric vessels

EXTRINSIC NERVE SUPPLY Parasympathetic

Vagus

Sympathetic

Superior mesenteric ganglion Mixing and storage

Function

Pelvic nerves from sacral S2-S4 segments Inferior mesenteric ganglion Conduit

is reached, action potentials. The result is Ca2+ influx through voltage-dependent dihydropyridine-sensitive L-type Ca2+ channels. Calcium phosphorylates the myosin light chains in the contractile apparatus to trigger crossbridge cycling and smooth muscle contraction. Action potentials superimposed upon slow waves greatly augment Ca2+ entry. Between slow waves, the open probability for Ca2+ channels is low, so action potentials and powerful muscle contractions do not occur. Colonic slow waves may also trigger sufficient Ca2+ influx to activate the contractile apparatus. Strain gauge transducers used in older studies were too insensitive to detect small contractile events.11 L-type Ca2+ channels are blocked by nifedipine. In the presence of nifedipine, smooth muscle contraction is inhibited and action potentials are absent. Tonic contractions are generated by continuous action potentials. In contrast to regular cyclical contractile activity in the stomach and small intestine, colonic motility is markedly irregular. This irregularity is partly attributable to the variable frequency and duration of action potentials but is not well understood.

EXTRINSIC NERVE SUPPLY TO THE COLON The extrinsic innervation includes sympathetic and parasympathetic components. The vagus (parasympathetic) innervates the proximal colon. The parasympathetic input to the distal colon is derived from the sacral (S2-S4) segments of the spinal cord via the pelvic plexus. After entering the colon, these fibers form the ascending colonic nerves, traveling orad in the plane of the myenteric plexus to supply a variable portion of the left colon. The sympathetic fibers originate in the paravertebral “chain” ganglion, segments from the T12 to L4 levels of the spinal cord, and are conveyed to the colon via arterial arcades of the superior and inferior mesenteric vessels. The sympathetic nervous system provides excitatory input to the sphincters and a tonic inhibitory input to nonsphincteric muscle. Norepinephrine is the major neurotransmitter released by sympathetic nerves throughout the small and large intestine. The extrinsic nerves modulate the intrinsic neural activity. For example, sympathetic nervous system exerts a tonic inhibitory input on colonic motor function, primarily via stimulation of α2-adrenergic receptors, which hyperpolarize cholinergic neurons in the myenteric plexus.

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Thus the α2 agonist clonidine decreases colonic tone, whereas the α2 antagonist yohimbine increases colonic tone in humans12; clonidine also enhances mucosal absorption of fluid and salt.

FUNCTIONS REGIONAL HETEROGENEITY IN COLONIC FUNCTION The right colon functions primarily as a reservoir for mixing and storage processes, the left colon as a conduit, and the rectum and anal canal enable defecation and continence. The ileocolonic sphincter regulates the intermittent aborad transfer of ileal contents into the colon, mainly after meals, and prevents reflux of bacteria into the ileum. The rate of delivery of liquids into the proximal colon can influence colonic transit. Thus a liquid marker injected directly into the proximal colon is emptied more rapidly than after oral ingestion of the same marker.13 There is evidence for adaptation in these regional functions. Within 6 months after a right hemicolectomy, isotope movement from the small to large bowel normalizes in response to the augmented storage capacity in the residual transverse and descending colon.14 In humans the ileocolonic sphincter plays only a minor role in regulating ileocolonic transit.

COLONIC FLUID AND ELECTROLYTE TRANSPORT Under basal conditions, the healthy colon receives approximately 1500 mL of chyme over 24 hours, absorbing all but 100 mL of fluid and 1 mEq of sodium and chloride, which are lost in the feces.15 Colonic absorptive capacity can increase to 5 to 6 L and 800 to 1000 mEq of sodium and chloride daily when challenged by larger fluid loads entering the cecum, as long as there is a slow infusion rate (i.e., 1 to 2 mL/minute). In addition to the ascending and transverse colon, the rectosigmoid may also participate in this compensatory absorptive response.16 Absorptive mechanisms are constitutively expressed in crypt epithelial cells; secretion is regulated by one or more neurohumoral agonists released from lamina propria cells, including myofibroblasts.17 When the colon is perfused with a plasma-like solution, water, sodium, and chloride are absorbed, and potassium and bicarbonate are secreted into the colon.18 Absorption of sodium and secretion of bicarbonate in the colon are active processes occurring against an electrochemical gradient. There are several different active (transcellular) processes for absorbing sodium, and these show considerable segmental heterogeneity in the human colon. The regional differentiation of colonic mucosal absorption is also demonstrated by regional effects of glucocorticoids and mineralocorticoids on sodium and water fluxes. For example, in the distal colon, epithelial Na+, K+, and ATPase are activated by mineralocorticoids.19 On the other hand, the Na+/H+ exchange is activated in proximal colonic epithelium by the mineralocorticoid, aldosterone.20 Specific channels are involved in water transport across surfaces and epithelia. These water channels, or aquaporins (AQPs), are a diverse family of proteins, of which AQP8 is expressed preferentially in colonic epithelium and small intestinal villus tip cells.

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SECTION IV  Colon, Rectum, and Anus

Potassium is absorbed and secreted by active processes; it is unclear if chloride is absorbed by an active process. In contrast to the small intestine, glucose and amino acids are not absorbed in the colon. Colonic conservation of sodium is vital to fluid and electrolyte balance, particularly during dehydration, when it is enhanced by aldosterone.21 Patients with ileostomies are susceptible to dehydration, particularly when placed on a low sodium diet or during an intercurrent illness. In addition to glucocorticoids and mineralocorticoids (aldosterone), other factors enhancing active sodium transport include somatostatin, α2-adrenergic agents, and short-chain fatty acids (SCFAs). Clonidine mimics the effects of adrenergic innervation by stimulating α2 receptors on colonocytes. In contrast, stimulation of mucosal muscarinic cholinergic receptors inhibits active NaCl absorption and stimulates active chloride secretion. Somatostatin, a peptide released by submucosal and myenteric nerves, also has potent antisecretory effects.

abundance of Firmicutes over Bacteroidetes28 and accelerates colonic transit, particularly in irritable bowel syndrome (IBS).11 Alternatively, it is conceivable that faster transit is associated with lesser production of secondary bile acids, which may alter the microbiota. Small intestinal bacterial overgrowth is a recognized complication of intestinal motility disorders (e.g., intestinal pseudoobstruction, scleroderma, radiation enteropathy). During a lactulose-hydrogen breath test, some patients with IBS have increased breath hydrogen excretion. This has erroneously been attributed to small intestinal bacterial overgrowth.29,30 Rather, in many patients the increased breath hydrogen excretion is explained by rapid small intestinal transit, hence colon delivery, and bacterial metabolism of lactulose.31 Thus lactulose and glucose hydrogen breath tests are not recommended for identifying small intestinal bacterial overgrowth.32

COLONIC METABOLISM

Assessment of Colonic Motor Function Colonic Transit Radiopaque Marker Methods.  Since the original description by Hinton et al., there have been several refinements to the radiopaque marker technique for measuring colonic transit.5 A widely used approach is to give a capsule containing 24 radiopaque markers on days 1, 2, and 3 and count remaining markers on a plain abdominal x-ray on days 4 and 7.6 With this technique a total of 68 or fewer markers remaining in the colon is normal, whereas more than 68 markers is slow transit (Fig. 144.1).6

In the proximal colon, bacteria ferment organic carbohydrates to SCFAs, predominantly acetate, propionate, and butyrate.22 There is a low, normal rate of SCFA production from malabsorbed (up to 10% of ingested) carbohydrates; diets high in fiber, beans, resistant starches, and complex carbohydrates increase the production of SCFA. SCFA are rapidly absorbed from the colon, augment sodium, chloride, and water absorption and constitute the preferred metabolic fuel for colonocytes. SCFA may also serve to regulate proliferation, differentiation, gene expression, immune function, and wound healing in the colon.

COLONIC MOTILITY

COLONIC MICROFLORA The human intestinal tract contains a large variety of microorganisms, of which bacteria are the most dominant and diverse. Contrary to earlier estimates that suggested that the number of bacteria exceeded human cells by a factor of 100,23 a revised estimate suggests that the number of bacteria and cells in humans is similar (i.e., approximately 39 trillion).24 Three bacterial divisions, the Firmicutes (gram positive), Bacteroidetes (gram negative), and Actinobacteria (gram positive), dominate the adult human gut microbiota. Among other multifaceted effects, microflora can affect gastrointestinal (GI) motility by releasing bacterial substances or end products of bacterial fermentation (e.g., SCFA), affecting intestinal neuroendocrine factors, and by modulating immunity. 25 The composition of microbiota is associated with stool consistency. 26 Moreover, the profile of the colonic mucosal microbiota differed between constipated patients and healthy people, independent of colonic transit, and discriminated between patients with constipation and controls with 94% accuracy.27 Genera from Bacteroidetes were more abundant in the colonic mucosal microbiota of patients with constipation. In contrast, the fecal microbiota were associated with colonic transit and were not different between constipation and health. Genera from Firmicutes (Faecalibacterium, Lactococcus, and Roseburia) were correlated with faster colonic transit. Perhaps this association is mediated by cholic acid, which increases the relative

FIGURE 144.1  Abdominal radiograph demonstrating radiopaque markers and lines used to demarcate markers in the left, right, and sigmoid colon/rectum.

Physiology of the Colon and Its Measurement  CHAPTER 144 

99mTc

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Geometric center (GC)

in egg meal

2

Gamma camera

1

3

FIGURE 144.2  Scintigraphic assessment of 0 111 In-charcoal

4

Stool

111 In-charcoal

in capsule coated with pH-sensitive methacrylate

A

B

Scintigraphic Techniques.  Colonic transit can also be assessed by scintigraphy (Fig. 144.2).5 To avoid dispersion of the radiolabel during passage through the GI tract, the isotope is delivered into the colon by orocecal intubation or a delayed-release capsule. The delayed-release capsule contains activated charcoal or polystrene pellets radiolabeled with technetium 99m (99mTc) or indium 111 (111In) and covered with a single coating of a pH-sensitive polymer, methacrylate. The capsule dissolves at a pH between 7.2 and 7.4, generally within the distal ileum, releasing the radioisotope within the ascending colon. The colonic distribution of radioisotope on scans taken 4, 24, and 48 hours after administration of the capsule is highly sensitive and specific for identifying rapid or slow colonic transit. The proportion of counts in each of four colonic regions of interest (i.e., ascending, transverse, descending, and rectosigmoid colon) and stool is multiplied by a specific weighting factor, which ranges from 1 (for the ascending colon) to 5 (for stool). The aggregate of these products (proportion of counts × weighting factor) provides the geometric center of overall colonic transit. A low geometric center implies that most radiolabel is close to the cecum, whereas a high geometric center implies that most radiolabel is close to stool. pH-Pressure Capsule.  Colonic transit can also be recorded by an ingested capsule that measures pH, pressure, and temperature as it traverses the GI tract. The pH rises abruptly (by >2 units) when the capsule exits the stomach and drops rapidly (by >1 unit) when it crosses the ileocecal valve. In the largest studies to date, overall agreement between capsule and radiopaque markers for characterizing colonic transit was 87%.7,8 Although the capsule can also assess gastric emptying and small intestinal transit, its sensitivity for detecting delayed gastric emptying (i.e., gastroparesis), as defined by gastric emptying measured by scintigraphy at 4 hours, is limited (i.e., 44%).9 In summary, allowing for differences in particle size, all three techniques probably provide comparable assessments of colonic transit. Scintigraphy and radiopaque marker techniques entail similar total body radiation exposure (i.e., 0.08 rad) for the radioactive capsule and for each abdominal radiograph. Scintigraphy is a useful

5

gastrointestinal transit. (A) Gastric emptying and small intestinal transit are assessed with technetium 99m–labeled polystyrene pellets, whereas indium 111 (111In)–labeled charcoal in delayed-release capsules measures colonic transit. (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.

research tool that allows more thorough assessment of regional colonic functions. Colonic Motility Recording Techniques.  Colonic motor activity can be assessed by recording electrical signals or variations in luminal pressure by pressure transducers, either water perfused or solid state, or a balloon controlled by a barostat.33,34 There are several limitations to recording colonic motor activity in humans. Intraluminal colonic recording devices can only be positioned using flexible colonoscopy, per-oral or per-nasal intubation techniques. Cleansing of the rectosigmoid and occasionally the entire colon is necessary to facilitate placement and accurate recording. Cleansing can accelerate colonic transit, but does not, with the exception of more frequent highamplitude propagated contractions (HAPCs), fundamentally alter motor activity.35 Recording myoelectrical activity with serosal, mucosal, or intraluminal electrodes is fraught with technical difficulties and has fallen out of favor. Manometry can identify the colonic motor response to a meal (see later) or to a stimulatory agent, such as neostigmine or bisacodyl. However, intraluminal pressure changes may not necessarily reflect colonic contractions. Moreover, it can be challenging to assess propagation with traditional manometry catheters because of the distance, typically 10 cm, between manometric sensors. In high-resolution manometry catheters, sensors are spaced at 1-cm intervals; assessing propagation is simpler.36 In contrast to manometry, barostat assessments by an infinitely compliant polyethylene balloon continuously apposed to the colonic mucosa can identify colonic contraction and relaxation (Fig. 144.3). The barostat is a rigid piston within a cylinder that can adjust either the pressure or volume within the bag using a servomechanism. When the balloon is inflated to a low constant pressure, colonic contraction is accompanied by expulsion of air from the balloon into the barostat. Conversely, when the colon relaxes, the balloon volume increases to maintain a constant pressure. The advantages of the barostatic balloon over manometry are greater sensitivity for

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SECTION IV  Colon, Rectum, and Anus Interneurons

Manometric sensors Balloon Excitatory motor neurons

Inhibitory motor neurons

Acetylcholine Tachykinins Barostat machine

Ascending contraction

Vasoactive intestinal peptide Nitric oxide

Descending relaxation

Intrinsic primary afferent neuron

Volume pressure

FIGURE 144.3  Barostat-manometric assembly positioned in the descending colon with polyethylene balloon in apposition with colonic mucosa.

recording contractions that do not occlude the lumen, particularly when the colonic diameter is greater than 5.6 cm.37 Moreover, a barostat can record changes in baseline balloon volume and phasic fluctuations, colonic relaxation, and colonic pressure-volume relationships. Thus the barostat is primarily a research tool that has been introduced into clinical practice in selected centers. The barostat measurement is the only currently available technique to measure colonic tone, and it has been shown to characterize the primary motor problem in chronic megacolon.38 Peristalsis Distention of a viscus evokes the peristaltic reflex, characterized by coordinated contraction of the orad segment and relaxation of the distal gut, facilitating propulsion. The neural pathways and neurotransmitters mediating this reflex are depicted in Fig. 144.4. In the human colon the principal excitatory neurotransmitter is acetylcholine, whereas in vitro studies suggest that nitric oxide and adenosine triphosphate are inhibitory neurotransmitters in the human colon. Colonic Motor Function in Health.  Contractile activity in the human colon is not cyclical. Colonic motor activity may vary from no activity or quiescence, isolated contractions, bursts of contractions, or propagated contractions. Irregular phasic activity constitutes a major proportion of colonic motor activity and probably serves to segment and mix intraluminal contents. Combined assessments of motor activity and transit in the cleansed colon of healthy subjects reveal that transit is associated with nonpropagated and propagated contractions; propagated contractions propel contents over longer distances than nonpropagated contractions.39 However only one-third of propagated contractions are accompanied by propulsion of colonic contents. Propagated contractions are subclassified as low (5 to 40 mm Hg) or high amplitude (>75 mm Hg). In ambulatory, prolonged colonic manometry studies, HAPCs occur on an average of 6 times/day, originate predominantly in the cecum/ascending colon, and migrate over a variable distance. These HAPCs are probably responsible

Distention by bolus

FIGURE 144.4  Schematic representation of major neurotransmitters mediating peristaltic reflex. Mechanical distention activates sensory neurons while interneurons transmit messages between sensory and motor neurons. (Modified from work by Grider and Makhlouf; Furness and Costa.)

Manometry Descending colon 50 mm Hg 0 Sigmoid colon Pneumobelt Barostat Colon pressure Colon volume Rectal pressure

250

Rectal volume Neostigmine (1.5 mg IV)

mL 5 min

0

FIGURE 144.5  High-amplitude propagated contractions induced by neostigmine. (From Law NM, Bharucha AE, Undale AS, Zinsmeister AR. Am J Physiol. 1997;281:G1228–G1237.)

for mass movement of colonic contents. HAPCs occur more frequently after awakening and after meals and may account for the urge to defecate in healthy subjects and in patients with IBS (Fig. 144.5). The mechanisms that underlie HAPCs are poorly understood. In addition to occurring spontaneously, HAPCs can be induced by luminal distention, by the parenteral administration of cholinesterase inhibitor neostigmine, or by intraluminal stimuli (i.e., glycerol, bisacodyl, and oleic acid). Eating is accompanied by a brisk increase in tone and phasic activity throughout the colon (Fig. 144.6).40 Because this response is preserved even after a gastrectomy, the term “colonic motor response to eating” is preferred to “gastrocolonic reflex.” The response may begin within a few seconds after eating and last, to a varying degree, for up to 2.5 hours. A biphasic response with early (first 60

Physiology of the Colon and Its Measurement  CHAPTER 144 

Manometry Descending colon

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Colonic HAPC ±

Sigmoid colon

Stool enters rectum

50 mm Hg 0

Rectal distention

Pneumobelt Barostat Colonic pressure Colonic volume

100 0

Meal

Desire to defecate

mL

30 min

FIGURE 144.6  Colonic motor response to a 1000-kcal meal. Note the increased phasic pressure activity recorded by manometric sensors and reduction in barostat balloon volume maintained at constant pressure, indicating increased tone.

minutes) and late (120 and 150 minutes) components has also been described.41 Meal composition and caloric content both influence the response. A mixed meal containing greater than 500 kcal predictably elicits a response. Gastric distention and chemical stimulation by nutrients elicit comparable responses; lipids are the most potent stimuli, whereas amino acids appear to inhibit the response.42 The precise mechanisms mediating the response are uncertain, but neural and hormonal mechanisms have been implicated. It is conceivable that different mechanisms regulate the early and late components.43 The early, particularly the immediate, component is likely to be neurally mediated. The later component temporally coincides with arrival of chyme into the ileum and may be mediated by humoral factors, such as peptide YY, neuropeptide Y, and neurotensin released from the ileal mucosa. Although serum levels of gastrin and cholecystokinin rise after a meal, intravenous cholecystokinin actually induces colonic relaxation.44 Atropine, naloxone, and the 5-hydroxytryptamine type 3 (5-HT3) antagonist ondansetron inhibit the response indicating that cholinergic, opiate, and serotoninergic 5-HT3 receptors may be involved in mediating the response.45 There is also evidence to suggest that efferent vagal fibers contribute to the colonic motor response in primates.46 The colon relaxes during sleep, after intraluminal administration of SCFAs or glycerol, during balloon distention of the rectum, and in response to parenterally administered pharmacologic agents. In addition to clonidine (an α2-adrenergic agonist), morphine, atropine, buspirone (a 5-HT1A agonist),5 and sumatriptan (a 5-HT1D agonist), all reduce colonic tone in humans.47–49 Rectal distention by a balloon to subnoxious levels induces colonic relaxation in humans.50 Colocolonic reflexes mediated via local nervous pathways through the prevertebral ganglia and independent of central nervous system activity have been well characterized in animal preparations.51 This propensity for colonic relaxation, particularly that induced by sympathetic stimulation and opiates, may be relevant to the pathophysiology of acute colonic dilatation or pseudoobstruction.52 Colonic relaxation induced

Involuntary • Internal sphincter relaxes • ? rectal contraction

Voluntary • Appropriate posture • Abdominal muscles contract → ↑ intraabdominal pressure • Puborectalis and external sphincter relax

Fecal expulsion

FIGURE 144.7  Schematic representation of events preceding defecation. HAPCs, High-amplitude propagated contractions.

by rectal distention may explain left-sided colonic transit delays in patients with obstructed defecation because restoration of normal defecation tends to restore colonic motility to normal.53 There are regional and age-related differences in biomechanical properties of the colon.4 These biomechanical properties can be assessed by stress-strain relationships in vitro and by the pressure-volume relationships during balloon distention by a barostat in vivo. In ex vivo and in vivo studies, stiffness declines from the rectum to the transverse colon. These observations are probably relevant to the segmental heterogeneity in function depicted in Table 144.1 and to the pathophysiology of diverticulosis, as discussed later. Thus the compliant ascending and transverse colon are ideally suited to function as a reservoir. Conversely, the descending and sigmoid colonic segments are suited to function as conduits, tend to have lower compliances, and are the primary sites of diverticula because intraluminal pressures are transmitted to weak points in the colonic wall.

DEFECATION In health, rectal distention evokes the desire to defecate and reflex relaxation of the internal anal sphincter (Fig. 144.7). If social circumstances are conducive, defecation is accomplished by adoption of a suitable posture and contraction of the diaphragm and abdominal muscles to raise intraabdominal pressure. Concomitant relaxation of the puborectalis and external anal sphincter, both striated muscles, enables widening of the anorectal angle by 15 degrees or more and reduction of pressure within the anal canal and perineal descent. Appropriate coordination between abdominal contraction and pelvic floor

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SECTION IV  Colon, Rectum, and Anus Thalamus Hypothalamus Cortex Third-order neuron Reticular formation Dorsal root ganglion (first-order neuron)

Dorsal horn neuron (second-order neuron)

FIGURE 144.8  Visceral sensory pathways include reflexes mediated through prevertebral and other autonomic ganglia and a third-order neuron chain that ultimately projects to supraspinal centers. Convergence of visceral and somatic afferents at the dorsal horn explains referral of visceral discomfort to the body surface. Third-order neurons originating in thalamus project to the cerebral cortex; those from the reticular formation to the thalamus and hypothalamus. (From Camilleri M, Saslow SB, Bharucha AE. Gastrointestinal sensation. Mechanisms and relation to functional gastrointestinal disorders. Gastroenterol Clin North Am. 1996;25:247–258.)

TABLE 144.2  Visceral Afferent Pathways Functions

Discriminative

Affective-Motivational

Afferent fibers

Rapidly conducting Aδ fibers Lateral Somatosensory cortex

Unmyelinated C fibers Medial Frontal, parietal, and limbic regions

Thalamic nuclei Cortical area

relaxation is crucial to normal fecal expulsion. In addition, there is evidence to suggest that these somatic processes are integrated with visceral components, such as colonic HAPCs during defecation.54

COLONIC SENSATION Healthy individuals, for the most part, do not perceive physiologic processes within the gut except for the sensation of fullness and the desire to defecate. Over the past few years, it has been proposed that symptoms associated with functional GI disorders are partly related to enhanced sensory perception.55 Visceral sensation is perceived in peripheral receptors and conveyed centrally by a threeneuron chain (Fig. 144.8).56 Although visceral afferents can respond to one or more stimulus modality (e.g., tension, temperature, osmolarity), mechanoreceptors are particularly important in the context of functional GI diseases. Mucosal mechanoreceptors respond to mucosal pinching or stroking, whereas serosal mechanoreceptors respond to movement or strong distention of a viscus. Visceral perception is characterized by discriminative (localizing, precise) and affective motivational (diffuse, emotional) aspects, which are conveyed by discrete mechanisms, demonstrated in Table 144.2.

Afferent Prevertebral ganglia (reflex modulation)

Efferent

The predominant afferent fibers are rapidly conducting myelinated Aδ fibers and slowly conducting unmyelinated C fibers. The Aδ fibers convey the sensation of first pain, which is well localized and lasts as long as the stimulus. The C fibers convey the “second” pain, which is diffuse, lasts longer than the duration of the stimulus, and is associated with the affective-motivational aspects of pain. In the spinal cord, visceral afferents project centrally via spinothalamic, spinoreticular tracts, and a nociceptive dorsal column. The spinothalamic tracts project to the medial and lateral thalamic nuclei, which are associated with affective-motivational and discriminative aspects of pain, respectively. These thalamic nuclei project to the cortical areas indicated in Table 144.2. Descending (chiefly serotoninergic and adrenergic) pathways originating in the frontal cortex, hypothalamus, and brainstem reticular formation inhibit spinal cord dorsal horn neurons, thereby reducing pain perception. In humans, colonic (and rectal) perception is assessed during balloon distention. The rate and pattern of balloon distention are important parameters. Perception is assessed by asking subjects to indicate when they perceive a given sensation (i.e., first threshold, desire to defecate, or discomfort). The contractile response is more pronounced during fast than during slow distention. It is conceivable that this partly explains why rapid rectal distention is more likely than slow distention to be perceived in healthy subjects and to evoke visceral hypersensitivity in IBS.57,58 An alternative method involves asking patients to rate the intensity of perception during balloon distentions of standardized intensity delivered in random order.59 Perceptual intensity is recorded on separate visual analog scales for gas, desire to defecate, and discomfort. Subjective perceptual ratings are proportional to the intensity of the stimulus. Psychologic stress60 and meals61,62 increase perception of colonic distention and may explain why

Physiology of the Colon and Its Measurement  CHAPTER 144 

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Interview and physical examination

Metabolic and structural evaluation, baseline labs

Therapeutic trial – fiber ± laxatives

Inadequate response

Anorectal manometry balloon expulsion test

Inconclusive

Normal

Abnormal

FIGURE 144.9  Diagnostic tests in Barium or MR defecography

Colonic transit

Slow

Normal Normal

Slow transit constipation

Abnormal

Normal transit constipation (? IBS)

these factors induce symptoms in IBS. Conversely, mental relaxation reduced perception of colonic distention in healthy people.59 In humans, balloon distention of the left colon evokes abdominal discomfort in the midline or left iliac fossa. The rectum is more sensitive than the colon and can distinguish between flatus and feces. Rectal distention induces rectal or sacral discomfort, akin to the desire to defecate or urgency. The anal canal is exquisitely sensitive, with sensitivity to touch, pain, and temperature comparable to the dorsum of the hand.

PERTURBATIONS OF COLONIC PHYSIOLOGY IN DISEASE STATES The following are examples of illnesses that derange colonic physiology. Constipation Constipation may result from slow colonic transit and/ or pelvic floor function, also known as defecatory disorders (DDs) (Fig. 144.9).63,64 Among constipated patients who have not responded to simple laxatives, anorectal functions should be evaluated, generally with an anorectal manometry and a rectal balloon expulsion test (see Fig. 144.9). Colonic transit may be delayed not only due to colonic motor dysfunction but also in patients with DDs. Hence colonic transit is assessed only after excluding or managing DDs. Patients with normal transit constipation usually respond to dietary fiber supplementation65; those with slow transit constipation frequently require judiciously administered

Defecatory disorder

management of constipated patients in clinical practice. Note these simple tests permit categorization of patients and choice of therapy. IBS, Irritable bowel syndrome; MR, magnetic resonance. (From Bharucha AE, Dorn SD, Lembo A, Pressman A. American Gastroenterological Association Medical position statement on constipation. Gastroenterology. 2013;144:211–217.)

laxatives, and pelvic floor retraining is necessary to reverse pelvic floor dysfunction in patients with DDs. Colonic motor assessments should be considered in patients with medically refractory chronic constipation, particularly when surgery (i.e., total colectomy with ileorectostomy) is considered. Intraluminal measurements are useful for confirming or excluding severe colonic motor dysfunction, manifest as a reduction in the number of colonic HAPCs, and/or a reduced colonic motor response to eating.66 In patients who have the most severe dysfunction, responses to such a stimulant as bisacodyl or neostigmine are also blunted (i.e., colonic inertia).54 The primary reason to consider colonic motility testing instead of colonic transit times is that barostat assessments of colonic tone reveal reduced fasting colonic tone and/or postprandial colonic tonic responses in many patients with normal transit and normal motor responses in many patients with isolated slow transit constipation.67 Moreover, some patients with chronic constipation, particularly those with constipationpredominant IBS, have increased colonic motor activity, especially in the sigmoid colon.67,68 Increased sigmoid colonic phasic pressure activity (“spastic colon”) has been implicated to retard colonic transit in chronic constipation.69,70 Detailed histopathologic studies with special stains reveal a marked loss of nerves and ICC throughout the colon in slow transit constipation and megacolon (Fig. 144.10).71 Rarely, constipation may be the presenting manifestation of a generalized GI motility disorder resulting from a paraneoplastic syndrome (e.g., due to small cell carcinoma of the lung).72

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BOX 144.1  Diagnostic Tests for Defecatory Disorders (During Simulated Defecation)*

LM

ANORECTAL MANOMETRY/ANAL SPHINCTER ELECTROMYOGRAPHY

MY

Failure of anal canal pressure/electromyography activity to decline

BALLOON EXPULSION Inability to expel rectal balloon within specified normal time

BARIUM OR MR DEFECOGRAPHY Reduced widening of rectoanal angle Reduced or excessive perineal descent Reduced rectal evacuation CM

Sub

*Precise criteria vary among tests.

100 µm

FIGURE 144.10  Distribution of interstitial cells of Cajal as demonstrated by c-Kit–positive immunoreactivity, shown in red, in the normal human sigmoid colon. Sections were cut parallel to the longitudinal muscle layer for both panels. CM, Circular muscle; LM, longitudinal muscle; MY, myenteric plexus region; Sub, submucosal border.

Defecatory Disorders Patients with DDs strain excessively to overcome the functional obstruction caused by inadequate relaxation of the external anal sphincter and/or puborectalis muscle sling.73 Dyssynergic defecation, anismus, and puborectalis dysfunction are some other terms used to describe this condition. Such symptoms as excessive straining, a sensation of incomplete evacuation, dyschezia, and digital evacuation of feces suggest but cannot be used to conclusively diagnose DDs.74 The physical examination may reveal high resting anal sphincter tone, failure of puborectalis relaxation, and/or perineal descent during simulated defecation, or anatomic abnormalities, such as anal fissure or rectocele. The latter may occur alone or may be accompanied by pelvic floor laxity and organ prolapse (descending perineum syndrome). The clinical impression can be corroborated by objective assessments of pelvic floor function, beginning with anal manometry and a rectal balloon expulsion test (Box 144.1). With anal manometry or sphincter electromyography, paradoxical sphincter contraction or anismus can be observed in a substantial proportion of healthy subjects with no symptoms of DDs. This underscores the importance of considering clinical features and not basing the diagnosis of DDs on manometry alone.75,76 The rectal balloon expulsion test, performed by measuring the time required to expel, or external traction

required to facilitate expulsion of a rectal balloon filled with water or air, is a useful, highly sensitive (89%) and specific (84%) test for evacuation disorders.77,78 The balloon expulsion test is a useful screening test but does not define the mechanism of disordered defecation nor does a normal balloon expulsion study always exclude a functional defecation disorder.79 Anal manometry and an abnormal balloon expulsion test suffice to confirm the diagnosis of an evacuation disorder in most patients with typical symptoms and reduced perineal descent (i.e., <1 cm) at clinical examination. However, if the results of anal manometry and the rectal balloon expulsion test are discrepant or conflict with the clinical impression, then evaluation of rectal and pelvic floor motion during attempted defecation by barium or magnetic resonance (MR) defecography may be necessary to clarify the diagnosis. Defecography can detect structural abnormalities (rectocele, enterocele, rectal prolapse) and assess functional parameters (anorectal angle at rest and during straining, perineal descent, anal diameter, indentation of the puborectalis in the posterior aspect of the rectoanal junction, degree of rectal emptying).80,81 The diagnostic value of defecography has been questioned primarily because normal ranges for quantified measures are inadequately defined and because some parameters, such as the anorectal angle, cannot be measured reliably because of anatomic variations in rectal contour and location (e.g., in the presence of perianal discomfort). Magnetic resonance imaging (MRI) is the only imaging modality that can visualize both anal sphincter anatomy and global pelvic floor motion (anterior, middle, and posterior compartments) in real time without radiation exposure. Dynamic MRI depicts the heterogeneity in functional defecation disorders and may be useful for clarifying the diagnosis in selected patients.82,83 Patients with obstructed defecation may also have delayed left colonic transit, attributable to obstruction of luminal contents by retained stool, colonic motor dysfunction unrelated to obstructed defecation, rectocolonic inhibition, or decreased colonic motor response to a meal. The latter is reversible after biofeedback therapy.53 Acute Colonic Pseudoobstruction (Ogilvie Syndrome) In acute megacolon (Ogilvie syndrome), colonic dilatation is attributed to a sympathetically mediated reflex response

Physiology of the Colon and Its Measurement  CHAPTER 144 

to a number of serious medical or surgical conditions in older patients.52 Cholinesterase inhibitors, such as neostigmine, enhance colonic contractility, reducing colonic distention in patients with acute colonic pseudoobstruction by increasing the availability of acetylcholine in myenteric plexus and neuromuscular junction.84 Chronic Megacolon Chronic megacolon may be congenital (due to Hirschsprung disease; lack of distal or total colonic myenteric nerve plexus and presents as toxic megacolon in infancy or adult severe constipation due to a short segment of denervated internal sphincter) or may present later in life after a long history of refractory constipation. Confirming the diagnosis, plain or contrast radiographs or a colonic barostat study may reveal colonic distention.38 The initial treatment for Hirschsprung disease is surgery. In chronic idiopathic megacolon, such medical measures as colonic evacuation with enemas, fiber supplementation, and laxatives do not usually suffice; if severe motor dysfunction is confined to the colon, a subtotal colectomy with an ileorectal anastomosis or an ileostomy may be necessary. Chronic megacolon may also result from multiple endocrine neoplasia type 2B (MEN2B), which is associated with ganglioneuroma formation in the colon.85 Functional Diarrhea or Diarrhea-Predominant Irritable Bowel Syndrome The etiopathogenesis of IBS is still incompletely understood. There is considerable evidence for peripheral disturbances, such as low-grade, microscopic, inflammation that persists after acute gastroenteritis.86 A role for intraluminal intestinal irritants, such as maldigested carbohydrates (producing SCFAs) or fats, an excess of bile acids, and gluten intolerance; alterations in the microbiome; enteroendocrine cell products; and genetic susceptibility to inflammation or altered bile acid synthesis has also been implicated. These luminal and mucosal irritants can alter mucosal permeability and cause immune activation or inflammation, which in turn activates local reflexes that alter intestinal motility or secretion. The irritants also stimulate sensory mechanisms, leading to visceral hypersensitivity and pain. Psychosocial issues (e.g., anxiety, depression, stress, and abuse) are also important. In a prospective study, hypochondriasis or a recent stressful life event predicted which patients would have abnormal colonic physiology and IBS symptoms after an attack of acute gastroenteritis.87 A subset of patients with IBS have accelerated proximal colonic transit,88 more frequent HAPCs,89 and an exaggerated colonic motor response to eating. These result in postprandial abdominal discomfort and urgency to defecate in some patients with diarrhea-predominant IBS. Other studies have shown that approximately 50% of patients with diarrhea-predominant IBS have rectal hypersensitivity or project sensation to a wider cutaneous area during balloon distention. Although the significance of visceral hypersensitivity during balloon distention to symptoms in patients with IBS is unclear,90 visceral hypersensitivity has been associated with abdominal pain and bloating. 91 However, rectal hypersensitivity does not accurately predict the response to therapy. Because bile

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acids can induce colonic secretion and propulsive contractions and increase epithelial permeability, bile acid malabsorption may contribute to diarrhea after cholecystectomy and in patients with idiopathic bile acid malabsorption.92,93 Small intestinal bacterial overgrowth, as detected by breath hydrogen testing, has also been implicated as a cause for IBS. However, using a standard definition of bacterial overgrowth (i.e., ≥105 colonic organisms/mL in jejunal cultures), only 4% of IBS patients and asymptomatic controls had small intestinal bacterial overgrowth.31 Of unclear significance, a higher proportion of IBS patients than controls (43% vs. 12%) had mildly increased bacterial counts (≥5 × 103/mL). Controlled studies suggest that a short course of antibiotics (e.g., rifaximin) may be beneficial in patients with IBS.94 The therapeutic benefit was modest (e.g., 40.2% of the rifaximin group vs. 30.3% of placebo reported adequate relief of bloating at 3 months after a 2-week course of treatment). However, the data have been replicated in two phase III randomized controlled studies.95 Further studies evaluating the long-term risk-benefit ratio of repeating antibiotic therapy need to be evaluated.

OTHER DIARRHEAL ILLNESSES In carcinoid syndrome, there is accelerated small intestinal transit and increased jejunal secretion. However, there is also evidence for altered colonic physiology. Increased delivery of contents to the colon is compounded by reduced capacitance in the ascending colon and an exaggerated colonic motor response to eating, causing rapid proximal colonic emptying.96 5-HT3 antagonists, such as ondansetron and aldosterone, reduce the colonic tonic response to eating and the rate of emptying, respectively, suggesting that 5-HT3 receptors may partly mediate the motor dysfunction in these patients.45 Disturbances in motility and NaCl absorption have been described in patients with ulcerative colitis. Patients with active proctitis have a stiff, noncompliant rectum, which may explain the enhanced sensation of urgency prior to defecation.97 Diarrhea after ileal resection of less than 100 cm is induced by the secretory effects of bile acids, associated with mild steatorrhoea (<20 g/day) and responsive to cholestyramine (4 to 6 g/day).98 After more extensive ileal resection (>100 cm) steatorrhea is severe (>20 g fat/day) and attributable to fat maldigestion and malabsorption secondary to low jejunal concentrations of bile acids. Cholestyramine will not ameliorate and may aggravate diarrhea in these patients. Clonidine ameliorates the diarrhea related to diabetic neuropathy by restoring the α2-mediated sympathetic “brake” (i.e., promoting intestinal and colonic absorption of NaCl, and inhibiting motility).99

DIVERTICULOSIS Considerations relevant to the pathophysiology of diverticulosis include the orientation of taenia coli, the course taken by perforating arteries supplying the colonic wall, and changes in the biomechanical properties of the colon that accompany diverticulosis. Colonic diverticula are mucosal pouches that are pushed out between arcs of circular muscle at weak points (i.e., where arteries pierce

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the muscularis propria in the spaces between the mesenteric taenia and the two antimesenteric taeniae). Thus diverticula do not occur where the taeniae fuse to form a longitudinal muscle layer surrounding the rectum.100 Thickening of the colonic circular and longitudinal muscle layers, partly due to elastin deposition with shortening of taenia coli, may narrow the colonic lumen in diverticulosis. Studies also reveal colonic motor disturbances (i.e., more propulsive activity, more 2 to 3 cycles/ minute regular, phasic, nonpropagated activity) and heightened perception of colonic distention in patients with uncomplicated, symptomatic diverticulosis.101 Thus it is conceivable that increased motor activity, particularly rhythmic contractions, may lead to mucosal outpouching and formation of diverticula, particularly when the colon is less compliant and/or narrower (e.g., in the sigmoid colon or in the presence of long-standing disorders of defecation). These motor disturbances may be partly attributable to cholinergic hypersensitivity.102 It has been speculated that a low residue diet with diminished fecal bulk predisposes to colonic luminal narrowing and ultimately diverticulosis. However, there is no direct evidence to corroborate a cause and effect relationship between lack of dietary fiber and luminal narrowing or elastin deposition in the taenia coli.

IMPLICATIONS OF COLONIC PHYSIOLOGY FOR SURGICAL PRACTICE It is crucial to treat pelvic floor dysfunction in patients with severe constipation prior to considering colectomy in those with delayed colonic transit. A colectomy with ileorectostomy is the preferred procedure for patients with intractable constipation and adequate anal sphincter function.103 Assessment of gastric and small intestinal transit or motor activity may permit recognition of patients with generalized gut dysmotility disorders in whom longterm success rates after a colectomy for constipation are lower than in patients with selective colonic dysmotility. Left-sided colectomy may result in postoperative colonic transit delays in the unresected segment; this likely represents parasympathetic denervation because ascending intramural fibers travel in retrograde manner from the pelvis to the ascending colon. The sigmoid colon and rectum are also supplied by descending fibers that run along the inferior mesenteric artery. These nerves may be disrupted during a low anterior resection, leaving a denervated segment that may be short or long, depending on whether the dissection line includes the origin of the inferior mesenteric artery.104 A long denervated segment is more likely to be associated with nonpropagated colonic pressure waves and delayed colonic transit than a short denervated segment. In addition to colonic denervation, a low anterior resection may also damage the anal sphincter and reduce rectal compliance 105; in contrast to anal sphincter injury, rectal compliance may recover with time.106 Physiologic assessments confirm clinical observations suggesting that colonic motor function recovers more rapidly after laparoscopic-assisted compared with open sigmoid colectomy.107 Surgeons should also be aware of the fluid absorptive capacity of the colon and its importance in fluid and electrolyte homeostasis. The retention of a segment of

colon can make an enormous difference to the postoperative management of short bowel syndrome after massive resection for mesenteric vascular thrombosis or Crohn disease. Motor disorders of the colon may be manifest with colonic dilatation; not all dilatation is secondary to obstruction and, in the presence of comorbidity or electrolyte imbalance, megacolon should be considered early, particularly because it can be treated medically or endoscopically without resorting to resection. Finally, the colorectal surgeon, like the gastroenterologist, will encounter many patients in his or her practice in whom the diagnosis is functional diarrhea, constipation, or fecal retention. These patients deserve a compassionate, careful appraisal and advice on how to restore normal colonic physiology. Avoidance of unnecessary colonic or other surgery is the best course of management—primum non nocere.

ACKNOWLEDGMENTS This study was supported in part by USPHS NIH Grants R01 DK78924 (AEB) and RO1 DK92179 (MC) from National Institutes of Health.

REFERENCES 1. Christensen J. Colonic Motility. Bethesda: American Physiological Society; 1989. 2. Fraser ID, Condon RE, Schulte WJ, DeCosse JJ, Cowles VE. Longitudinal muscle of muscularis externa in human and nonhuman primate colon. Arch Surg. 1981;116:61-63. 3. Pace J. The anatomy of the haustra of the human colon. Proc R Soc Med. 1968;61:934-935. 4. Whiteway J, Morson BC. Pathology of the ageing—diverticular disease. Clin Gastroenterol. 1985;14:829-846. 5. von der Ohe M, Camilleri M. Measurement of small bowel and colonic transit: indications and methods. Mayo Clin Proc. 1992;67: 1169-1179. 6. Metcalf AM, Phillips SF, Zinsmeister AR, MacCarty RL, Beart RW, Wolff BG. Simplified assessment of segmental colonic transit. Gastroenterology. 1987;92:40-47. 7. Rao SS, Kuo B, McCallum RW, et al. Investigation of colonic and whole gut transit with wireless motility capsule and radioopaque markers in constipation. Clin Gastroenterol Hepatol. 2009;7:537-544. 8. Camilleri M, Thorne NK, Ringel R, et al. Wireless pH-motility capsule for colonic transit: prospective comparison with radiopaque markers in chronic constipation. Neurogastroenterol Motil. 2010; 22:874-882, e233. 9. Kuo B, McCallum RW, Koch KL, et al. Comparison of gastric emptying of a nondigestible capsule to a radio-labelled meal in healthy and gastroparetic subjects. Aliment Pharmacol Ther. 2008;27: 186-196. 10. Rae MG, Fleming N, McGregor DB, Sanders KM, Keef KD. Control of motility patterns in the human colonic circular muscle layer by pacemaker activity. J Physiol. 1998;510:309-320. 11. Sadik R, Abrahamsson H, Ung KA, Stotzer PO. Accelerated regional bowel transit and overweight shown in idiopathic bile acid malabsorption. Am J Gastroenterol. 2004;99:711-718. 12. Bharucha AE, Camilleri M, Zinsmeister AR, Hanson RB. Adrenergic modulation of human colonic motor and sensory function. Am J Physiol. 1997;273:G997-G1006. 13. Proano M, Camilleri M, Phillips SF, Thomforde GM, Brown ML, Tucker RL. Unprepared human colon does not discriminate between solids and liquids. Am J Physiol. 1991;260:G13-G16. 14. Fich A, Steadman CJ, Phillips SF, et al. Ileocolonic transit does not change after right hemicolectomy. Gastroenterology. 1992;103: 794-799. 15. Phillips SF, Giller J. The contribution of the colon to electrolyte and water conservation in man. J Lab Clin Med. 1973;81:733-746.

Physiology of the Colon and Its Measurement  CHAPTER 144  16. Hammer J, Phillips SF. Fluid loading of the human colon: effects on segmental transit and stool composition. Gastroenterology. 1993; 105:988-998. 17. Singh SK, Binder HJ, Boron WF, Geibel J. Fluid absorption in isolated perfused colonic crypts. J Clin Invest. 1995;96:2373-2379. 18. Sandle GI. Salt and water absorption in the human colon: a modern appraisal. Gut. 1998;43:294-299. 19. Binder HJ, McGlone F, Sandle GI. Effects of corticosteroid hormones on the electrophysiology of rat distal colon: implications for Na+ and K+ transport. J Physiol. 1989;410:425-441. 20. Cho JH, Musch MW, Bookstein CM, McSwine RL, Rabenau K, Chang EB. Aldosterone stimulates intestinal Na+ absorption in rats by increasing NHE3 expression of the proximal colon. Am J Physiol. 1998;274:C586-C594. 21. Binder H, Sandle G. Electrolyte Transport in the Mammalian Colon. 3rd ed. New York: Raven Press; 1994. 22. Cook SI, Sellin JH. Review article: short chain fatty acids in health and disease. Aliment Pharmacol Ther. 1998;12:499-507. 23. Dethlefsen L, McFall-Ngai M, Relman DA. An ecological and evolutionary perspective on human-microbe mutualism and disease. Nature. 2007;449:811-818. 24. Sender R, Fuchs S, Milo R. Revised estimates for the number of human and bacteria cells in the body. PLoS Biol. 2016;14:e1002533. http://dx.doi.org/10.1101/036103. Accessed 14 October 2016. 25. Barbara G, Stanghellini V, Brandi G, et al. Interactions between commensal bacteria and gut sensorimotor function in health and disease. Am J Gastroenterol. 2005;100:2560-2568. 26. Vandeputte D, Falony G, Vieira-Silva S, Tito RY, Joossens M, Raes J. Stool consistency is strongly associated with gut microbiota richness and composition, enterotypes and bacterial growth rates. Gut. 2016;65:57-62. 27. Parthasarathy G, Chen J, Chen X, et al. Relationship between microbiota of the colonic mucosa vs feces and symptoms, colonic transit, and methane production in female patients with chronic constipation. Gastroenterology. 2016;150:367-379, e361. 28. Islam KB, Fukiya S, Hagio M, et al. Bile acid is a host factor that regulates the composition of the cecal microbiota in rats. Gastroenterology. 2011;141:1773-1781. 29. Pimentel M. An evidence-based treatment algorithm for IBS based on a bacterial/SIBO hypothesis: part 2. Am J Gastroenterol. 2010;105: 1227-1230. 30. Pimentel M. Evaluating a bacterial hypothesis in IBS using a modification of Koch’s postulates: part 1. Am J Gastroenterol. 2010; 105:718-721. 31. Posserud I, Stotzer PO, Björnsson ES, Abrahamsson H, Simrén M. Small intestinal bacterial overgrowth in patients with irritable bowel syndrome. Gut. 2007;56:802-808. 32. Sellin JH. A breath of fresh air. Clin Gastroenterol Hepatol. 2016;14: 209-211. 33. Bassotti G, Iantorno G, Fiorella S, Bustos-Fernandez L, Bilder CR. Colonic motility in man: features in normal subjects and in patients with chronic idiopathic constipation. Am J Gastroenterol. 1999;94: 1760-1770. 34. Camilleri M, Ford M. Review article: colonic sensorimotor physiology in health, and its alteration in constipation and diarrhoeal disorders. Aliment Pharmacol Ther. 1998;12:287-302. 35. Lemann M, Flourié B, Picon L, Coffin B, Jian R, Rambaud JC. Motor activity recorded in the unprepared colon of healthy humans. Gut. 1995;37:649-653. 36. Dinning PG, Wiklendt L, Maslen L, et al. Colonic motor abnormalities in slow transit constipation defined by high resolution, fibre-optic manometry. Neurogastroenterol Motil. 2015;27:379-388. 37. von der Ohe M, Hanson R, Camilleri M. Comparison of simultaneous recordings of human colonic contractions by manometry and a barostat. Neurogastroenterol Motil. 1994;6:213-222. 38. O’Dwyer RH, Acosta A, Camilleri M, Burton D, Busciglio I, Bharucha AE. Clinical features and colonic motor disturbances in chronic megacolon in adults. Dig Dis Sci. 2015;60:2398-2407. 39. Cook I, Furukawa Y, Panagopoulos V, Collins PJ, Dent J. Relationships between spatial patterns of colonic pressure and individual movements of content. Am J Physiol. 2000;278:G329-G341. 40. Ford MJ, Camilleri M, Wiste JA, Hanson RB. Differences in colonic tone and phasic response to a meal in the transverse and sigmoid human colon. Gut. 1995;37:264-269. 41. Narducci F, Bassotti G, Granata MT, et al. Colonic motility and gastric emptying in patients with irritable bowel syndrome. Effect

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of pretreatment with octylonium bromide. Dig Dis Sci. 1986;31: 241-246. 42. Wiley J, Tatum D, Keinath R, Chung OY. Participation of gastric mechanoreceptors and intestinal chemoreceptors in the gastrocolonic response. Gastroenterology. 1988;94:1144-1149. 43. Snape WJ Jr, Wright SH, Battle WM, Cohen S. The gastrocolic response: evidence for a neural mechanism. Gastroenterology. 1979;77: 1235-1240. 44. Coffin B, Fossati S, Flourié B, et al. Regional effects of cholecystokinin octapeptide on colonic phasic and tonic motility in healthy humans. Am J Physiol. 1999;276:G767-G772. 45. von der Ohe MR, Camilleri M, Kvols LK. A 5HT3 antagonist corrects the postprandial colonic hypertonic response in carcinoid diarrhea. Gastroenterology. 1994;106:1184-1189. 46. Dapoigny M, Cowles VE, Zhu YR, Condon RE. Vagal influence on colonic motor activity in conscious nonhuman primates. Am J Physiol. 1992;262:G231-G236. 47. Steadman CJ, Phillips SF, Camilleri M, Talley NJ, Haddad A, Hanson R. Control of muscle tone in the human colon. Gut. 1992;33:541-546. 48. Coulie B, Tack J, Gevers A, et al. Influence of the sumatriptaninduced colonic relaxation on the perception of colonic distention in man. Gastroenterology. 1997;112:A715. 49. Coulie B, Tack J, Vos R, et al. Influence of the 5-HT1A agonist buspirone on rectal tone and the perception of rectal distention in man. Gastroenterology. 1998;114:G3046. 50. Law N-M, Bharucha A. Phasic rectal distention induces colonic relaxation in humans. Gastroenterology. 1998;114:G3233. 51. Kreulen DL, Szurszewski JH. Reflex pathways in the abdominal prevertebral ganglia: evidence for a colo-colonic inhibitory reflex. J Physiol. 1979;295:21-32. 52. Phillips S. Megacolon. 1st ed. New York: Raven Press; 1991. 53. Mollen RM, Salvioli B, Camilleri M, et al. The effects of biofeedback on rectal sensation and distal colonic motility in patients with disorders of rectal evacuation: evidence of an inhibitory rectocolonic reflex in humans? Am J Gastroenterol. 1999;94:751-756. 54. Bharucha AE. High amplitude propagated contractions. Neurogastroenterol Motil. 2012;24:977-982. 55. Mertz H, Naliboff B, Munakata J, Niazi N, Mayer EA. Altered rectal perception is a biological marker of patients with irritable bowel syndrome. Gastroenterology. 1995;109:40-52. [Erratum appears in Gastroenterology. 1997;113(3):1054.] 56. Camilleri M, Saslow SB, Bharucha AE. Gastrointestinal sensation. Mechanisms and relation to functional gastrointestinal disorders. Gastroenterol Clin North Am. 1996;25:247-258. 57. Bharucha AE, Hubmayr RD, Ferber IJ, Zinsmeister AR. Viscoelastic properties of the human colon. Am J Physiol Gastrointest Liver Physiol. 2001;281:G459-G466. 58. Corsetti M, Cesana B, Bhoori S, et al. Rectal hypersensitivity to distention in patients with irritable bowel syndrome: role of distention rate. Clin Gastroenterol Hepatol. 2004;2:49-56. 59. Ford MJ, Camilleri M, Zinsmeister AR, Hanson RB. Psychosensory modulation of colonic sensation in the human transverse and sigmoid colon. Gastroenterology. 1995;109:1772-1780. 60. Posserud I, Agerforz P, Ekman R, Björnsson ES, Abrahamsson H, Simrén M. Altered visceral perceptual and neuroendocrine response in patients with irritable bowel syndrome during mental stress. Gut. 2004;53:1102-1108. 61. Simrén M, Abrahamsson H, Björnsson ES. Lipid-induced colonic hypersensitivity in the irritable bowel syndrome: the role of bowel habit, sex, and psychologic factors. Clin Gastroenterol Hepatol. 2007;5:201-208. 62. Törnblom H, Van Oudenhove L, Tack J, Simrén M. Interaction between preprandial and postprandial rectal sensory and motor abnormalities in IBS. Gut. 2014;63:1441-1449. 63. Bharucha AE, Pemberton JH, Locke GR 3rd. American Gastroenterological Association technical review on constipation. Gastroenterology. 2013;144:218-238. 64. Bharucha AE, Locke GR, Pemberton JH. AGA practice guideline on constipation: technical review. Gastroenterology. 2013;144:218238. 65. Voderholzer WA, Schatke W, Mühldorfer BE, Klauser AG, Birkner B, Müller-Lissner SA. Clinical response to dietary fiber treatment of chronic constipation. Am J Gastroenterol. 1997;92:95-98. 66. O’Brien MD, Camilleri M, von der Ohe MR, et al. Motility and tone of the left colon in constipation: a role in clinical practice? Am J Gastroenterol. 1996;91:2532-2538.

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SECTION IV  Colon, Rectum, and Anus

67. Ravi K, Bharucha AE, Camilleri M, Rhoten D, Bakken T, Zinsmeister AR. Phenotypic variation of colonic motor functions in chronic constipation. Gastroenterology. 2010;138:89-97. 68. Hasler WL, Saad RJ, Rao SS, et al. Heightened colon motor activity measured by a wireless capsule in patients with constipation: relation to colon transit and IBS. Am J Physiol Gastrointest Liver Physiol. 2009;297:G1107-G1114. 69. Chaudhary NA, Truelove SC. Human colonic motility: a comparative study of normal subjects, patients with ulcerative colitis, and patients with the irritable colon syndrome: I. Resting patterns of motility. Gastroenterology. 1961;40:1-17. 70. Connell AM. The motility of the pelvic colon. Part II. Paradoxical motility in diarrhea and constipation. Gut. 1962;3:342-348. 71. Lyford GL, He CL, Soffer E, et al. Pan-colonic decrease in interstitial cells of Cajal in patients with slow transit constipation. Gut. 2002;51:496-501. 72. Jun S, Dimyan M, Jones KD, Ladabaum U. Obstipation as a paraneoplastic presentation of small cell lung cancer: case report and literature review. Neurogastroenterol Motil. 2005;17:16-22. 73. Bharucha AE. Obstructed defecation: don’t strain in vain. Am J Gastroenterol. 1998;93:1019-1020. 74. Ratuapli S, Bharucha AE, Noelting J, et al. Phenotypic identification and classification of functional defecatory disorders using high resolution anorectal manometry. Gastroenterology. 2013;144: 314-322. 75. Grossi U, Carrington EV, Bharucha AE, Horrocks EJ, Scott SM, Knowles CH. Diagnostic accuracy study of anorectal manometry for diagnosis of dyssynergic defecation. Gut. 2016;65:447-455. 76. Lee TH, Bharucha AE. How to perform and interpret a highresolution anorectal manometry test. J Neurogastroenterol Motil. 2016; 22:46-59. 77. Minguez M, Herreros B, Sanchiz V, et al. Predictive value of the balloon expulsion test for excluding the diagnosis of pelvic floor dyssynergia in constipation. Gastroenterology. 2004;126:57-62. 78. Ratuapli S, Bharucha AE, Harvey D, Zinsmeister AR. Comparison of rectal balloon expulsion test in seated and left lateral positions. Neurogastroenterol Motil. 2013;25:e813-e820. 79. Rao SS, Mudipalli RS, Stessman M, Zimmerman B. Investigation of the utility of colorectal function tests and Rome II criteria in dyssynergic defecation (Anismus). Neurogastroenterol Motil. 2004;16: 589-596. 80. Ekberg O, Mahiew PHG, Bartram CI, Piloni V. Defecography: dynamic radiological imaging in proctology. Gastroenterol Int. 1990;3:93-99. 81. Shorvon PJ, McHugh S, Diamant NE, Somers S, Stevenson GW. Defecography in normal volunteers: results and implications. Gut. 1989;30:1737-1749. 82. Bharucha AE, Fletcher JG, Seide B, Riederer SJ, Zinsmeister AR. Phenotypic variation in functional disorders of defecation. Gastroenterology. 2005;128:1199-1210. 83. Karlbom U, Påhlman L, Nilsson S, Graf W. Relationships between defecographic findings, rectal emptying, and colonic transit time in constipated patients. Gut. 1995;36:907-912. 84. Ponec RJ, Saunders MD, Kimmey MB. Neostigmine for the treatment of acute colonic pseudo-obstruction. N Engl J Med. 1999;341:137141. 85. Gibbons D, Camilleri M, Nelson AD, Eckert D. Characteristics of chronic megacolon among patients diagnosed with multiple endocrine neoplasia type 2B. United European Gastroenterol J. 2016; 4:449-454. 86. Camilleri M. Peripheral mechanisms in irritable bowel syndrome. N Engl J Med. 2013;368:578-579. 87. Spiller RC. Postinfectious irritable bowel syndrome. Gastroenterology. 2003;124:1662-1671. 88. Vassallo M, Camilleri M, Phillips SF, Brown ML, Chapman NJ, Thomforde GM. Transit through the proximal colon influences stool weight in the irritable bowel syndrome. Gastroenterology. 1992;102:102-108.

89. McKee DP, Quigley EM. Intestinal motility in irritable bowel syndrome: is IBS a motility disorder? Part 1. Definition of IBS and colonic motility. Dig Dis Sci. 1993;38:1761-1772. 90. Whitehead WE, Palsson OS. Is rectal pain sensitivity a biological marker for irritable bowel syndrome: psychological influences on pain perception. Gastroenterology. 1998;115:1263-1271. 91. Posserud I, Syrous A, Lindström L, Tack J, Abrahamsson H, Simrén M. Altered rectal perception in irritable bowel syndrome is associated with symptom severity. Gastroenterology. 2007;133:1113-1123. 92. Odunsi-Shiyanbade ST, Camilleri M, McKinzie S, et al. Effects of chenodeoxycholate and a bile acid sequestrant, colesevelam, on intestinal transit and bowel function. Clin Gastroenterol Hepatol. 2010;8:159-165. 93. Wedlake L, A’Hern R, Russell D, Thomas K, Walters JRF, Andreyev HJN. Systematic review: the prevalence of idiopathic bile acid malabsorption as diagnosed by SeHCAT scanning in patients with diarrhoea-predominant irritable bowel syndrome. Aliment Pharmacol Ther. 2009;30:707-717. 94. Pimentel M, Park S, Mirocha J, Kane SV, Kong Y. The effect of a nonabsorbed oral antibiotic (rifaximin) on the symptoms of the irritable bowel syndrome: a randomized trial. Ann Intern Med. 2006;145:557-563. [Summary for patients in Ann Intern Med. 2006;145(8):I24; PMID: 17043334]. 95. Pimentel M, Lembo A, Chey WD, et al. Rifaximin treatment for 2 weeks provides acute and sustained relief over 12 weeks of IBS symptoms in non-constipated irritable bowel syndrome: results from 2 North American phase 3 trials (target 1 and target 2). Gastroenterology. 2010;138:S64-S65. 96. von der Ohe MR, Camilleri M, Kvols LK, Thomforde GM. Motor dysfunction of the small bowel and colon in patients with the carcinoid syndrome and diarrhea. N Engl J Med. 1993;329:1073-1078. [Erratum appears in N Engl J Med. 1993;329(21):1592.] 97. Farthing MJ. Lennard-jones JE. Sensibility of the rectum to distension and the anorectal distension reflex in ulcerative colitis. Gut. 1978;19:64-69. 98. Hofmann AF, Poley JR. Role of bile acid malabsorption in pathogenesis of diarrhea and steatorrhea in patients with ileal resection. I. Response to cholestyramine or replacement of dietary long chain triglyceride by medium chain triglyceride. Gastroenterology. 1972;62:918-934. 99. Fedorak RN, Field M, Chang EB. Treatment of diabetic diarrhea with clonidine. Ann Intern Med. 1985;102:197-199. 100. Painter N, Truelove S, Ardran E, Tuckey M. Segmentation and the localisation of intraluminal pressures in the human colon with special reference to the pathogenesis of colonic diverticula. Gastroenterology. 1965;49:169-177. 101. Bassotti G, Battaglia E, De Roberto G, Morelli A, Tonini M, Villanacci V. Alteration in colonic motility and relationship to pain in colonic diverticulosis. Clin Gastroenterol Hepatol. 2005;3:248-253. 102. Golder M, Burleigh DE, Belai A, et al. Smooth muscle cholinergic denervation hypersensitivity in diverticular disease. Lancet. 2003;361: 1945-1951. 103. Nyam DC, Pemberton JH, Ilstrup DM, Rath DM. Long-term results of surgery for chronic constipation. Dis Colon Rectum. 1997;40:273-279. [Erratum appears in Dis Colon Rectum. 1997;40(5):529.] 104. Koda K, Saito N, Seike K, Shimzu K, Kosugi C, Miyazaki M. Denervation of the neorectum as a potential cause of defecatory disorder following low anterior resection for rectal cancer. Dis Colon Rectum. 2005;48:210-217. 105. Batignani G, Monaci I, Ficari F, Tonelli F. What affects continence after anterior resection of the rectum? Dis Colon Rectum. 1991;34: 329-335. 106. Williamson ME, Lewis WG, Finan PJ, et al. Recovery of physiologic and clinical function after low anterior resection of the rectum for carcinoma: myth or reality? Dis Colon Rectum. 1995;38:411-418. 107. Kasparek MS, Muller MH, Glatzle J, et al. Postoperative colonic motility in patients following laparoscopic-assisted and open sigmoid colectomy. J Gastrointest Surg. 2003;7:1073-1081.