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Colonic Physiology
Ursula M. Szmulowicz and Tracy L. Hull
The human colon is a dynamic organ, involved in a vast array
of functions, including the absorption of water and electrolytes, the salvage of unabsorbed nutrients, and the transport
of luminal contents as feces. While not an organ essential for
life, the colon still plays a major role in maintaining the overall health of the human body. Understanding these physiologic principles is integral to the successful treatment – both
medical and surgical – of colonic disease.
Embryology
The embryology of the colon informs its anatomy. In the third
and fourth weeks of gestation, the primitive intestine arises
from the cephalocaudal and lateral folding of the dorsal surface of the endoderm-lined yolk sac, forming a straight tube
situated posteriorly in the embryo.1–3 Although the mucosa
originates from the endoderm of the yolk sac, the muscular
wall, connective tissue, and serosa have a mesodermal etiology.4 By the fourth week of gestation, the gut tube develops
into three distinct regions: the foregut, midgut, and hindgut.4
The midgut begins immediately distal to the confluence
of the common bile duct and the duodenum, extending to
include the proximal two-thirds of the transverse colon. At
the midgut, the primitive intestine maintains its connection
to the yolk sac via the vitelline duct; failure of the vitelline
duct to obliterate ultimately results in a Meckel’s diverticulum or a vitelline cyst or fistula.2,5 The hindgut reaches from
the distal third of the transverse colon to the anal canal proximal to the dentate line. The midgut receives its vascular
supply from the superior mesenteric artery and the hindgut
from the inferior mesenteric artery.6
The colon gains its ultimate position by means of a series
of rotations of the embryonic gut. During the fifth week of
gestation, the midgut, particularly the future ileum, rapidly
enlarges beyond the capacity of the abdominal cavity, culminating in its physiologic herniation through the umbilicus
in the sixth week.1 While exteriorized, this hairpin-shaped
primary intestinal loop rotates 90° counterclockwise around
an axis comprised of the superior mesenteric artery, as
viewed from the front. Although the cranial limb of the herniated primary intestinal loop – the future small intestine –
continues to elongate and organize into loops, the caudal
limb – the proximal colon – remains mainly unaltered, its
only adjustment involving the development of a cecal bud,
a bulge from its antimesenteric border.3 In the tenth week of
gestation, the herniated intestine commences its return to the
abdominal cavity, in the process completing an additional
180° counterclockwise rotation to finalize the disposition of
the embryonic proximal jejunum on the left and the primitive
colon on the right.2 The cecum – the last component to reenter the abdomen – initially is located in the right upper quadrant but then migrates inferiorly to the right iliac fossa as the
dorsal mesentery suspending the ascending colon shortens
and then recedes.4 As the cecal bud descends, the appendix
appears as a narrow diverticulum.2–7 The loss of the dorsal
mesentery of the ascending and descending colon produces
their retroperitoneal fixation, absent in the cecum, transverse
colon, and sigmoid colon.2
Innervation
Colonic innervation emanates from two sources: the extrinsic
and the intrinsic nerves. Extrinsic innervation involves the
sympathetic and parasympathetic nerves of the autonomic
nervous system, which are responsible for colonic motility
and sensation. Intrinsic innervation arises from the poorly
understood enteric nervous system.
The parasympathetic nerves primarily exert an excitatory
affect upon colonic motility. The main parasympathetic neurotransmitters include acetylcholine and tachykinins such
as substance P. The parasympathetic supply to the proximal
colon originates from the posterior division of the vagus
nerve – the tenth cranial nerve.8,9 These parasympathetic
fibers reach the colon by following the branches of the superior mesenteric artery: the ileocolic and middle colic arteries. The distal colon, however, receives its parasympathetic
D.E. Beck et al. (eds.), The ASCRS Textbook of Colon and Rectal Surgery: Second Edition,
DOI 10.1007/978-1-4419-1584-9_2, © Springer Science+Business Media, LLC 2011
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input from the second to fourth sacral nerves, with the third
sacral nerve the most dominant.8,9 These pelvic splanchnic
nerves – the nervi erigentes – emerge from the lateral horns
of S2–4.8,9 After exiting the spinal column, the preganglionic
parasympathetic fibers travel superiorly and laterally, deep
to the peritoneum, to join the inferior hypogastric plexus,
located on the anterolateral pelvic wall, adjacent to the lateral ligaments at the level of the lower third of the rectum.10
From the inferior hypogastric plexus, these parasympathetic
fibers are distributed to the pelvic organs and to the distal
colon as far proximal as the splenic flexure.11 The preganglionic parasympathetic fibers ultimately synapse in the bowel
wall at the ganglia within the myenteric plexus of Auerbach
and Meissner’s plexus.12
Unlike the parasympathetic nerves, the sympathetic system effects a tonic inhibition of the nonsphincteric colonic
muscle and, thus, of colonic peristalsis.11 Additionally,
sympathetic fibers prevent epithelial secretion and reduce
splanchnic blood flow.9 However, the sympathetic supply is
excitatory to sphincter muscles, particularly to the ileocecal
junction and the internal anal sphincter.9,11,13 The primary
sympathetic neurotransmitter is norepinephrine.8,11 The
inhibition of colonic tone, although not fully understood,
is believed to be mediated via a2 adrenergic receptors.14 In
one study in humans, the a2 agonist clonidine was determined to decrease fasting colonic tone, while the a2
antagonist yohimbine increased it.15 Stimulation of the a2
adrenoreceptor also blocked the release of acetylcholine
from the hyperpolarized parasympathetic neurons in the
myenteric and pelvic plexi, thus arresting parasympathetic
function.11,15 In contrast, the in vivo administration of the
a1 agonist phenylephrine and the b2 agonist ritodrine at the
highest acceptable dosages had no impact upon colonic
tone.15 Yet, in an in vitro study, agonists of the b1, b2, and
b3 colonic adrenoceptors relaxed the human taenia coli; the
circular muscular tone maximally diminished after treatment with the b1 agonist.16
The preganglionic sympathetic effector cells are derived
from the intermediolateral cell column (lateral horns) of the
thoracic (T1–12) and, in particular, the lumbar spine (L1–2
or 3–4). The sympathetic nerve fibers leave the spinal column via the ventral spinal nerve roots (rami). These myelinated preganglionic fibers then exit from the ventral spinal
nerve root as a white ramus communicans (“communicating branches”) to merge with the paired sympathetic trunks
(paravertebral ganglia), found along the entire length of the
vertebral column. Once it has joined a sympathetic trunk, the
preganglionic sympathetic nerve fiber either immediately
synapses at that ganglion or it ascends or descends along
the trunk before synapsing at another vertebral level, from
the first cervical vertebra to the first coccygeal vertebra,
along the sympathetic trunk.17 A single preganglionic fiber
synapses with 30 or more postganglionic fibers.8 After synapsing, the unmyelinated postganglionic fibers depart the
sympathetic trunk as a gray ramus communicans, reuniting
U.M. Szmulowicz and T.L. Hull
with the ventral spinal ramus, after which it is distributed to
the sweat glands and arrector pili muscles of the body wall
and to the smooth muscle of the blood vessels throughout
the body.18 Yet, most preganglionic fibers – those innervating the abdominopelvic viscera – pass through the sympathetic trunk without synapsing, instead proceeding to the
interconnected collateral (preaortic or prevertebral) ganglia
that lie anterior to the aorta at its junction with its main vascular branches as part of a specific splanchnic (“visceral”)
nerve: the greater (T5–T9 or 10), lesser (T10–T11), least
(T12), or lumbar (L1–2) splanchnic nerves.12,17,19 While
the midgut receives its sympathetic input from the lesser
splanchnic nerve, the hindgut is supplied by the lumbar
splanchnic nerve.18 Once these preganglionic fibers synapse
at a collateral ganglion, the postganglionic fibers follow the
vasculature to the intestine, concluding in the enteric ganglia.20 Some of the postganglionic fibers terminate instead
on intestinal epithelial cells, whereby intestinal secretion is
inhibited.20 The midgut derivatives are primarily innervated
by postganglionic fibers from the superior mesenteric ganglion and the hindgut structures, from the inferior mesenteric ganglion, although commingling between the ganglia
is common.8
The intrinsic innervation of the colon – the enteric
­nervous system – is uniquely able to mediate reflex behavior
independent of input from the brain or spinal cord.21 This
intrinsic network regulates the majority of colonic motility.9 However, the activity of the enteric nervous system is
impacted by the extrinsic nerves: the sympathetic, parasympathetic, and visceral afferent nerves.8,11 This “little brain”
employs the same modulators and neuro transmitters present in the central nervous system, including the excitatory
acetylcholine, substance P, and neurokinin A and the inhibitory nitric oxide, adenosine triphosphate (ATP), vasoactive
intestinal polypeptide (VIP), and pituitary adenyl cyclaseactivating peptide.9,13,21,22 The enteric nervous system acts
through many different types of neurons, with their cell bodies amassed within neuronal plexi positioned either between
the circular and longitudinal muscles (the myenteric plexus
of Auerbach) or in the submucosal layer.9 The submucosal
plexi are comprised of Meissner’s plexus, situated adjacent
to the mucosa, and Schabadasch’s plexus, which lies near
the circular muscle.9 Notably, the number of neurons in the
enteric nervous system greatly exceeds that of the entire
autonomic nervous system.9 The myenteric plexus directs
smooth muscle function while the submucosal plexus modulates mucosal ion transport and absorptive functions.11 Moreover, the enteric network influences blood flow to the colon.20
Control of colonic motor function via the enteric nervous
system remains poorly understood at this time. However, a
reflex arc is initiated by a mechanical (e.g., stretch), chemical, or other noxious stimulus, which activates an enteric
primary afferent neuron; the impulse is carried to an enteric
motor neuron – the effector cell – via an enteric interneuron,
producing an excitatory or inhibitory effect.9,20
2. Colonic Physiology
Colonic Function
Salvage, Metabolism, and Storage
Although digestion and absorption primarily take place in
the stomach and small intestine, the colon still plays a major
role in these operations. The colon processes various complex carbohydrates and, to a lesser extent, proteins that prove
resistant to digestion and absorption in the more proximal
intestine.23,24 Unlike the small intestine, the colon salvages
nutrients from these products via fermentation. Fermentation
occurs by means of the saccarolytic and proteolytic members
of the over 400 species of bacteria, the majority of which are
obligate anaerobes, present within the colon.25 Approximately
10% of ingested carbohydrates enter the cecum as undigested
material.11 Among the diverse end products of the bacterial
fermentation of complex carbohydrates – mainly the soluble
plant residues (fiber) – are the short-chain fatty acids, represented principally by butyrate (15%), propionate (25%), and
acetate (60%).26 Ingestion of a diet higher in complex carbohydrates, beans, resistant starches, and soluble fiber leads to
a greater output of short-chain fatty acids than that of insoluble fibers. The composition of the bacterial microenvironment also influences the amount of synthesized short-chain
fatty acids.11,27 The nondigestible carbohydrate inulin – an
extract of chicory – has been studied as a prebiotic, a food
that selectively alters the admixture of the colonic bacterial
flora; although its addition to the diet increased the proportion
of beneficial bifidobacteria in the feces in various studies, its
impact – whether healthful or harmful – upon other bacterial
species could not be well gauged.28 Bacterial fermentation of
the complex carbohydrates primarily transpires in the ascending and proximal transverse colon. In contrast, the undigested
dietary proteins that reach the colon, as well as proteins from
mucous and sloughed epithelial cells, are fermented in the
distal colon, primarily because the carbohydrates – the preferred nutrient of most bacteria – were previously exhausted in
the proximal colon; the concentration of the short-chain fatty
acids produced in the distal colon is 30% less than in the proximal colon.27,29,30 However, a diet that includes prebiotics such
as inulin results in a greater degree of saccarolytic fermentation in the distal colon due to the greater availability of these
slowly fermentable, highly polymerized carbohydrates.27 The
fermented proteins are converted into short-chain fatty acids,
branched chain fatty acids, and amines. In addition, the bacterial fermentation of undigested proteins generates ammonia,
phenols, indoles, and sulfurs; these possibly toxic substances
are considered potential etiologic agents for such diseases as
colon cancer and ulcerative colitis.27 Some of these proteolytic
metabolites become a nitrogen source for bacterial growth.29,31
The residual products of the bacterial fermentation of complex carbohydrates and proteins are absorbed or, like carbon
dioxide, hydrogen, and methane, passed with the feces.28 The
dietary fats that reach the colon likely are not recovered in the
colon but are expelled with the stool.25
25
The short-chain fatty acids occupy an integral position
in colonic health. More than 95% of the short-chain fatty
acids are created in and are immediately appropriated by the
colon, with very little excreted in the feces.25,27,32 An average of 400 mmol/day, with a range of 150–600 mmol/day,
of short-chain fatty acids are produced in the colon.33,34 This
reclamation of undigested matter in the colon as short-chain
fatty acids provides 5–15% of the total caloric needs of an
individual.27 These weak acids – the preeminent colonic
anions – mainly remain dissociated in the colonic lumen
until absorbed either in exchange for bicarbonate via a SCFA/
HCO3− transport channel; by an active transport mechanism
such as the sodium-coupled monocarboxylate transporter
(SMCT1) or the monocarboxylate transporter isoform 1
(MCT1); or by diffusion in their lipid soluble form.27 The
sodium-coupled monocarboxylate transporter facilitates the
conservation of sodium, chloride, and water in the colon.27
Furthermore, the short-chain fatty acids are incorporated as
the basic elements for mucin synthesis, lipogenesis, gluconeogenesis, and protein production. In particular, propionate
combines with other three-carbon compounds in the liver to
participate in gluconeogenesis. Acetate is used by the liver
as a component to fashion longer-chain fatty acids and by the
muscle as sustenance.23,24
Although the least abundant of the short-chain fatty acids,
butyrate has the greatest import in colonic homeostasis. This
short-chain fatty acid acts as the primary energy source for
the colonocyte, supplying 70–90% of its energy requirements; these epithelial cells receive their nourishment solely
from luminal substrates, not from the bloodstream.20,23,24
Of the short-chain fatty acids, butyrate best promotes the
absorption of water, sodium, and chloride from the colon,
acting as an antidiarrheal agent.27 This short-chain fatty acid
also advances colonic cell proliferation and differentiation,
repair, and immune function.11,27,35 Butyrate has been shown
to influence colon carcinogenesis: studies have revealed that
fewer butyrate transporters were present in human colonic
adenocarcinomas, resulting in a decrease in the utilization
of the trophic butyrate in the malignant cells.27 Moreover,
in vitro studies of cancer cell lines identified apoptosis, nonproliferation, and differentiation after the administration of
butyrate.27 One method by which butyrate modulates gene
expression and, thus, cancer growth likely arises from its
ability to suppress histone deacetylase, thus encouraging the
union of various transcription factors with nuclear DNA; to
modify intracellular kinase signaling; and to inhibit nuclear
factor-kB.27
In the colon, many metabolic processes are influenced
by functional food components. These foods – the pre- and
probiotics – alter the colonic microenvironment, adding
to the impact of environmental factors and genetics.33 As
previously discussed, prebiotics – primarily nondigestable
oligosaccharides (NDOs) – are slowly fermentable foods
that selectively propagate microbial proliferation and/or
­activity.36 These products are completely metabolized in the
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colon into short-chain fatty acids, energy, and lactic acid,
leaving no nondigestable oligosaccharides in the stool.33 In
contrast, probiotics represent active bacterial cultures that
benefit the host by replenishing the colonic microenvironment.37 Synbiotics combine the action of pre- and probiotics.33 Investigations of these functional foods have focused
on the lactobacilli and bifidobacteria, the growth of which
transforms the colonic milieu, augmenting the immune function of the gut-associated lymphoid tissue (GALT).31,33 The
effect of these supplements is thought to be attributable to an
increased production of butyrate, changes in mucin production, or interference in the binding of pathogenic bacteria to
the colonic mucosa.27,38 Prebiotics are particularly associated
with an elevation of the concentration of short-chain fatty
acids.33 To combat the rising incidence of antibiotic-resistant
bacteria in hospitals, the World Health Organization has
recommended the use of microbial interference therapies –
nonpathogenic bacteria that eradicate pathogens – such as
probiotics.34 Currently, probiotics are prescribed in cases of
disturbed microbial balance, such as antibiotic-associated
diarrhea. In the future, pre- and probiotics may become
important supplements regularly administered to patients to
promote health and to prevent illness. These functional foods
further present the possibility of reducing the potential of
carcinogens to form cancers.31,38
While the colon is one organ, it demonstrates regional
differences. As noted, the proximal and distal colon have
different embryological origins, derived from the mid- and
hindgut, respectively. In appearance, the proximal colon
is more saccular and the distal colon, more tubular.39 The
short-chain fatty acids are principally synthesized in the
more acidic environment of the proximal colon. The proximal colon serves as a reservoir, in contrast to the distal colon,
which mainly performs as a conduit.40 Yet, this truism is
­disputed by studies in which radiopaque markers were determined to have the same dwell time of approximately 11 h in
the proximal, distal, and middle colonic segments, suggesting that the proximal colon does not preferentially operate
as a receptacle for stool.9 Also, the character of the luminal contents impacts transit times. Large volumes of liquid
quickly pass through the ascending colon but remain within
the transverse colon for as long as 20–40 h; in contrast, a
solid meal is retained by the cecum and ascending colon for
longer periods than a liquid diet.9,41,42 The salvage of water
and electrolytes is primarily accorded to the proximal colon,
although the distal colon and rectum contribute to this task,
albeit to a lesser extent.43,44 In the event that a large amount of
chyme is delivered to the colon, the distal colon and rectum
may assist in the absorption of enough fluid to produce a
solid stool.41 The regional heterogeneity of the colon exhibits adaptability. After a right hemicolectomy, the transverse
colon adjusts to become a neo-proximal colon; 6 months
after the surgery, the progress of an ingested isotope from
the small intestine through the shortened colon returns to
the preoperative baseline.45 The assumption of this role may
U.M. Szmulowicz and T.L. Hull
ensue due to the greater concentrations of short-chain fatty
acids to which the transverse colon is exposed following a
right hemicolectomy, producing such changes as an increase
in water and sodium retention.30
Transport of Water and Electrolytes
Among its roles in preserving intestinal homeostasis, the
colon is also integral to water and electrolyte transport.
The colon maintains an appropriate hydration and electrolyte balance by means of the absorption and secretion of
intestinal water and electrolytes. The mucosal surface area
available for these processes amounts to approximately
2,000 cm2.30 While the surface epithelial cells in the colon
are primarily responsible for absorption, the crypt cells are
involved in fluid secretion; however, crypt cells have been
found to some degree to contribute to absorption.11,30,46 After
the liquid effluent from the small intestine has traversed
the colon, fluid and electrolyte absorption and secretion as
well as bacterial activity produce about 200 g of solid feces
per day.20
The colon is extremely efficient at conserving intestinal
water.13 Water is passively absorbed along an osmotic gradient, enabled by a luminal sodium concentration lower than
that of the epithelial cells; as such, the salvage of intestinal
water relies upon sodium conservation.11,30 Normally, the
colon is presented with 1.5–2 L of water daily, as compared
to the 9–10 L that pass through the small intestine; of this
amount, 1.5–2 L are ingested, with the remainder originating from salivary, biliary, pancreatic, and intestinal secretions.24,30 Approximately 90% of this water is reclaimed by
the colon, leaving 100–150 mL in the feces.20 The absorption
of water primarily follows a paracellular pathway, although
a transcellular route involves various protein channels: aquaporins 3, 4, 5, 8, and 9.20 The ascending colon demonstrates
the greatest absorptive capability, as the chyme resides within
this segment the longest, thus maximizing its contact with
the mucosa. As a consequence, diarrhea more consistently
ensues after a right, as opposed to a left, hemicolectomy.
Fluid retention is promoted by the antidiuretic hormone.43
When challenged, the proximal colon, with the additional
contribution of the sigmoid colon and rectosigmoid, is able
to save a further 5–6 L of intestinal water daily.47–49 Yet this
facility is contingent upon the composition, rate of flow (less
than 1–2 mL/min), and amount of the effluent. In the case
that the absorptive capacity of the colon is exceeded, diarrhea results. Fluid secretion in the colon only transpires in
the presence of diverse secretagogues, such as laxatives,
bacterial endotoxins, hormones (e.g., VIP), and endogenous
substances (e.g., bile acids).43
The colon is essential to the recovery of sodium. Under
normal conditions, the colon principally absorbs sodium and
chloride but secretes bicarbonate and potassium. The liquid
chyme delivered to the colon contains 130–140 mmol/L of
sodium whereas the concentration in stool is 40 mmol/L;
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2. Colonic Physiology
approximately 95% of the sodium transported into the colon
is conserved.29,43 If required, the colon is able to increase its
salvage of sodium to 800 mmol/L/day.43 The normal colon
can prevent hyponatremia even despite a diet containing as
little as 1 mEq of sodium daily; in contrast, the absence of
a colon encourages dehydration and hyponatremia.43 The
transport mechanisms for sodium absorption, located on
the luminal surface of the epithelial cells, vary throughout the
colon: a Na+/H+ exchange channel in the proximal colon and
an electrogenic sodium-specific channel (ENaC) in the distal
colon and rectum.20 The Na+/H+ exchange channels (NHE 2
and 3) are coupled to the Cl−-HCO3− exchange channels.20
The activity of the electrogenic sodium-specific channel in
the distal colon and rectum is requisite for the desiccation
of stool.20 These two types of transport channel allow for
the passive diffusion of sodium into the colonic epithelial
cells along an electrochemical gradient, consisting of a low
intracellular sodium concentration (<15 mM) and a negative
intracellular electrical potential difference as compared to
the lumen.30 This favorable electrochemical gradient is created by the active extrusion of sodium via the Na+/K+ ATPase
pump on the basolateral membrane of the epithelial cell:
three sodium ions are expelled in exchange for two potassium ions.20,30 Aldosterone, a mineralocorticoid secreted
by the adrenal gland in response to sodium depletion and
dehydration, enhances fluid and sodium absorption in the
colon.46,50 The absorption of sodium is further promoted by
somatostatin, a2-adrenergic agents (e.g., clonidine), and the
short-chain fatty acids.11,24
Like sodium, chloride is recovered from the colonic lumen.
In the proximal colon, chloride is traded for bicarbonate
via the Cl−-HCO3− exchange channel found on the luminal
surface of the epithelial cells; the activity of this channel is
linked to the Na+/H+ exchange protein.20,29 However, chloride
also is absorbed through a Cl−-HCO3− exchange channel that
is not associated with sodium.20 Chloride absorption is supported by an acidic luminal milieu; consequentially, the concomitant secretion of bicarbonate neutralizes organic acids
within the colonic lumen.24,43 The transport mechanism for
bicarbonate secretion is poorly understood. Yet, bicarbonate, responsible for the alkalinity of the feces, is the primary
electrolyte wasted in diarrhea.20
Potassium transport is primarily a passive process, following the movement of sodium across cell membranes. However,
active potassium secretion occurs in the proximal colon and
active absorption in the distal colon.11,20 The H+/K+ ATPase
actively conveys potassium into the epithelial cells of the distal colon and rectum.20 A potassium channel is believed to
facilitate active secretion in the proximal colon.20 Potassium
secretion, combined with potassium derived from bacteria
and colonic mucous, may explain the relatively high concentration of this electrolyte – 50–90 mmol/L – in stool.51,52
The colon contributes to the metabolism of urea.
Approximately 0.4–1 g of urea enters the colon in the small
bowel effluent daily.43 The urea is converted by the colonic
microorganisms into ammonia, which is then passively
absorbed by the surface epithelial cells.29,43 Ammonia is also
derived from dietary nitrogen, the sloughed mucosal lining,
and bacterial waste. Only 1–3 mmol of ammonia is excreted
with the feces. The majority of the ammonia that reaches
the colon is returned via the enterohepatic circulation to the
liver, where it is refashioned into urea.30
Colonic Motility
Methodology to Measure Colonic Transit
Although altered motility is thought to play a major role
in various gastrointestinal disorders, surprisingly little is
known about the subject. This lack of understanding arises
in part from the inaccessibility of the colon, particularly
the proximal colon, for direct study. Bowel questionnaires
have been used to gain insight into colonic motility; however, interestingly, stool frequency – or the recollection of
the patient of their stool frequency – and colorectal transit
time, which represents 75% of total intestinal transit time,
are poorly related.41,53,54 Early evaluations using barium were
also unable to achieve a precise measurement of colonic
motility.55 The initial techniques to determine colonic motility began with the calculation of colonic transit time.
Radiopaque Markers
One of the first methods to gauge colonic transit time
involves radiopaque markers. This study, proposed by Hinton and colleagues in 1969 to assess severe constipation, follows the passage of the markers over sequential abdominal
radiographs.11,56 Total and regional colonic transit times are
reflected by the number and the location of the markers.11
For men, the average total colonic transit is 30.7 h (SD 3.0)
and for women, 38.3 h (SD 2.9).55 Currently, the commercially available SitzmarksTM (Konsyl Pharmaceuticals, Easton, MD) are composed of a gelatin capsule containing 24
radioopaque PVC O-rings. Various protocols for the examination exist, all of which require the cessation of all laxatives
48 h prior to swallowing the markers. In one approach that
focuses on total colonic transit, 5 days after taking the capsule, an abdominal radiograph is obtained. A normal study
demonstrates evacuation of 80% of the markers. The retention of more than 20% of the markers suggests slow transit
constipation. Some physicians give a single capsule on Sunday evening and obtain abdominal X-rays on days 1, 3, and
5. The film on the first day provides evidence that gastric
and small motility are grossly normal if all the markers are
in the colon.
In order to localize the markers to specific segments of the
colon – right, left, and pelvis – another technique requires
that the patient consume one capsule, after which abdominal radiographs are performed every other day until all 24
markers have been expelled. As an alternative, patients
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ingest single capsules on three successive days, with only
one abdominal radiograph done on day 4 of the study so as
to minimize radiation exposure.57 The number of markers
present equals the colonic transit time in hours. To better
determine the distribution of the markers, some centers use
capsules holding markers of different shape on each of the
3 days. An accumulation of the markers in the rectosigmoid
indicates a dyssynergic defecation pattern.58 The reliability
of the technique is affected by patient compliance as well as
by differences in the interpretation of the results.59
Scintigraphy
Some centers favor the more expensive colonic scintigraphy over the radiopaque marker method to measure colonic
transit. As with the marker study, the protocols are not standardized among institutions. Although patients refrain from
taking laxatives or opiates 24 h before the test, a normal diet
is maintained throughout the study. The isotope is positioned
in the cecum by the ingestion of a delayed release capsule or
by orocecal intubation.11 The delayed release capsule, coated
with the pH-sensitive polymer methacrylate, is comprised of
activated charcoal or polystyrene pellets labeled with either
111
In or 99mTc. The coating dissolves at the pH of 7.2–7.4
found in the distal ileum, after which the radioactive material is delivered into the colon.40,60 Images are taken with a
gamma camera at specified intervals, usually at 4, 24, and
48 h after consumption of the isotope, although this can be
performed as frequently as twice daily.11,61 Segmental transit
is usually determined for the ascending, transverse, descending, and rectosigmoid regions of the colon. The proportion of
the counts is calculated in each section and then multiplied
by a weighing factor: 0 for the cecum, 1 for the ascending
colon, 2 for the transverse colon, 3 for the descending colon,
4 for the rectosigmoid colon, and 5 for stool.60 The results are
expressed as the geometric center of the isotope mass at any
given time point, with a low count indicating that the isotope
is close to the cecum and a higher count that it has progressed
more distally.11,61 For clinical use, the total percentage of
retained isotope as compared to normal data appears to be
the most convenient reporting system. Scintigraphy correlates well with the radiopaque technique in assessing colonic
transit, with a similar sensitivity in diagnosing patients with
slow transit constipation.60 The total exposure to radiation
is also equivalent.11 Due to its greater costs, in most cases
scintigraphy serves as a research instrument.
Wireless Motility Capsule
The wireless motility capsule has been proposed as an alternative method to determine colonic transit time. This technique, already proven for the study of gastroparesis, uses a
capsule containing miniature pressure, temperature, and pH
measurement devices. The capsule is ingested, after which
continuous recordings are obtained in an ambulatory setting,
with the data captured over 5 days via a wireless instrument.59
U.M. Szmulowicz and T.L. Hull
In one trial, the results from the capsule approach correlated
well with those acquired from the radiopaque markers, with a
similar sensitivity and specificity in detecting abnormal transit in those patients with constipation.59 The capsule is able
to gauge phasic colonic contractions but not colonic motor
patterns.62 This costly procedure is not widely employed but
is attractive in that radiation exposure is avoided and patient
compliance is facilitated.59
Techniques to Record Colonic Motility
Colonic motility remains a constantly evolving field of
study. The techniques by which colonic motility are gauged
rely upon the monitoring of electrical activity or of intraluminal pressure, using surface electrodes or a manometry
or barostat apparatus, respectively.11 This indirect assessment of colonic motility has been hindered by the instruments available for its measurement, the colonic anatomy,
and the need for prolonged readings. Recordings are usually obtained over 6 h in the laboratory and over 24 h in an
ambulatory setting due to the long colonic transit time, especially as compared to the small intestine.62 Also, the methods suffer from an absence of standardization. Although
evaluations of colonic motility had initially focused upon
the easily accessed distal colon, subsequent trials have indicated that this segment is not representative of the proximal
colon. Yet, placement of the intraluminal devices is difficult,
requiring either oral or nasal intubation or colonoscopy; furthermore, application of the surface electrodes demands surgery. Additionally, the necessity to purge the colon of stool
may impact the results, producing an increase in the number
of high amplitude propagated contractions, although these
findings are conflicting.63,64 Determinations of colonic pressure are further influenced by artifact from extrinsic forces
such as cough, straining, and sneezing.62 Thus, most of these
approaches rest in the researchers’ domain and have not
been assimilated into the standard clinical armamentarium.
However, significant progress is being gained with these
tools to understand the physiology and pathophysiology of
colonic motility.
Manometry
Colonic manometry has been the more frequently employed
method to measure phasic (brief) colonic contractions. However, few centers utilize this technique in regular practice.
In this procedure, a flexible catheter – either a solid-state or a
water-perfused catheter system – is inserted into the colon. It
is argued that the water-perfused system increases the amount
of fluid in the colon, thus altering the results. However, the
solid-state catheters are fragile, expensive, and sensitive to
corrosive damage from colonic irritants.65 However, this
nonperfused system is more convenient and portable, allowing for long-term and ambulatory recordings.66 The validity
of the readings depends upon the proper placement of the
catheter. As noted, the introduction of the catheter occurs
29
2. Colonic Physiology
via an oral or nasal route, confirmed with fluoroscopy, or by
colonoscopy. With endoscopy, the catheter is either carried
along with the colonoscope in a piggyback fashion, grasped
by biopsy forceps, or is threaded over a guidewire, deposited
via the colonoscope, under fluoroscopic guidance. The tip
of the catheter is stationed as far proximal as the transverse
colon; with direct colonoscopic deployment, the proximal
transverse colon is reached in all subjects, with the probe
remaining in position in greater than 80% of cases.65,67–69 To
adhere to more physiologic conditions, unprepared colons
are currently advocated, despite the impediment presented
by the retained stool to the retrograde placement of the
catheters; in some cases, enemas are instead used. Also,
to prevent data artifact, minimal air is insufflated via the
colonoscope and as much aspirated as possible during its
withdrawal. The patients are often asked to maintain a diary
to mark events such as bowel movements, flatus, and meals.
Manometry is well able to detect the changes in intraluminal
pressure after eating or the administration of a colonic stimulant (e.g., bisacodyl). However, these variations in pressure
do not consistently correspond to contractions: in a study
of colonic motility, the simultaneous use of manometry and
colonoscopy indicated that a majority of pressure fluctuations perceived by the catheter reflected colonic relaxation,
not contraction.70 Furthermore, manometry does not reliably
identify all contractions, some of which are not associated
with an appreciable pressure deflection.9,70 An investigation
comparing the barostat with manometry suggested that the
measurements obtained from manometry are also affected
by the luminal diameter in which the tip of the device lies.70
However, unlike the barostat, manometry recognizes patterns of motor activity due to the multiple recording sites
along the catheter.62
Barometry
The colonic barostat device addresses the inability of manometry to record colonic tone, i.e., sustained contractions. As
with manometry, it is utilized clinically in few centers. The
instrument includes a compressible polyethylene balloon,
placed within the colonic lumen, that is attached via tubing to a barostat – a cylinder containing a piston.11 The balloon is maintained at a low constant pressure such that it is
continuously in close contact with the colon wall in a single
location.71 Contraction of the colon constricts the balloon,
reducing its volume by forcing air into the barostat; in contrast, colonic relaxation produces an increase in the volume
of the balloon so as to sustain a constant pressure.11 Changes
in the volume of the balloon reflect colonic tone, although
phasic contractions are also assessed.72,73 However, patterns
of colonic activity cannot be distinguished as measurements
are obtained in only one site.62 Unlike the manometry technique, the barostat system is capable of detecting contractions that do not produce a significant pressure change, even
in colonic segments wider than 5.6 cm.11
Electrodes
Electrodes have also been applied for the study of colonic
motility. These devices record the myoelectrical signals
from the colon that result in muscular activity.74,75 The electrodes are placed on the serosal surface via surgery or on the
mucosa by colonoscopy. The technique is seldom used due
to ethical concerns.
Peristalsis
Peristalsis represents the alternating waves of contraction
and relaxation of the circular muscles of the colon wall.
Fecal material is propelled antegrade through the colon by
the contraction of the circular muscle proximal but the relaxation of the muscle distal to it, i.e., descending inhibition.11
During peristaltic activity, the saccular haustra – the product
of circular muscle contraction – recede and then reform, first
proximal to and subsequently at the level of the transferred
material, again giving rise to colonic segmentation.9,41,76 The
contribution of the longitudinal smooth muscle to colonic
activity is unknown.9 The average rate of antegrade colonic
transit is approximately 1 cm/h.9 The peristaltic reflex is
thought to be initiated by luminal distention and, possibly,
by chemical stimuli, which stimulate the enteric sensory
neurons; ultimately, the enteric motor neurons – the effector cells – are activated via the intermediary of the enteric
interneurons.11 The interneurons may also directly detect
changes in smooth muscle length.77 The primary neurotransmitters involved in the peristaltic reflex include the excitatory
acetylcholine and the inhibitory nitric oxide and adenosine
triphosphate (ATP).11 Although the enteric nervous network
primarily controls peristalsis, the extrinsic nervous system
modifies the reflex, with the sympathetic nerves suppressing
and the parasympathetic nerves promoting motility, especially during defecation. Interestingly, the parasympathetic
nerves also assist in the synchronization of descending inhibition. The antegrade movement of the fecal bolus is further
dependent upon the radius of the colonic segment, the consistency of the feces, and the pressure differential between
segments.
Colonic motility adheres to several patterns. Generally,
contractions vary between tonic and phasic. The poorly
understood tonic contractions are sustained events of slow
onset, not necessarily inciting an elevation of the intraluminal pressure.76 Bassotti et al. further classify the briefer
phasic contractile episodes as high and low amplitude propagated contractions and as segmental contractions.71,78
High amplitude propagated contractions – also known
as migrating long spike bursts, large bowel peristalsis, and
giant migrating contractions – function to transport large
volumes of feces over long distances.71,78,79 These contractions are believed to be the manometric equivalent
of mass movement – first identified on radiographic studies
of the colon – whereby colonic contents are projected
30
distally in seconds.40,67,80,81 The high amplitude propagated
contractions transpire between 2 and 24 times a day, with an
average of approximately five to six times a day.62,71 These
contractions, with an amplitude of 100–200 mmHg (average
of 100 mmHg), persist for 20–30 s.62,71 The contraction usually begins in the proximal colon and is transmitted distally
for 15 cm or longer, with the velocity gradually increasing to
as fast as 1 cm/s as the impulse moves caudad.11 A contraction that starts in the proximal colon is conveyed farther than
that commencing in the distal colon: 50 cm from the cecum
and 20 cm from the sigmoid colon.9 More than 95% of these
contractions proceed antegrade; however, only one-third of
these contractions result in the transit of fecal material.11,71,78
Moreover, not all instances of defecation, particularly those
involving liquid stool, are incited by a high amplitude
propagated contraction.78 High amplitude propagated contractions are considered the probable origin of the pressure
spikes that occur upon morning waking (35%) and after
meals (50%).71 The urge to defecate is likely attributable
to these contractions.71 Borborigmy is thought also to arise
from high amplitude propagated contractions.78 The impetus for these contractions is incompletely comprehended.
These contractions are elicited by cholinergic medications
(e.g., neostigmine), eating, colonic distention, short-chain
fatty acids, and laxatives (e.g., bisacodyl).11 However, only
in 50% of cases does colonic distention produce propagating activity.78 In patients with constipation, high amplitude
propagated contractions are decreased in number, amplitude, extent, and speed.
The low amplitude propagated contractions are still
less understood. These contractions (5–40 mmHg) – also
referred to as long spike bursts – last for 3 s.71 As with the
high amplitude propagated contractions, these contractions
are strongly related to meals and the sleep-wake cycle. There
may be an association with the passage of flatus and, in particular, liquid stool.82,83 Similar to the high amplitude propagated contractions, these contractions are likely provoked by
colonic distention.71 The mechanisms by which these two
propagated contractions are regulated remain unclear. However, propulsive activity depends upon a functional enteric
nervous system.71
Segmental contractions, presenting singly or in rhythmic
or arrhythmic bursts, account for the majority of colonic
activity, particularly at rest.78 These contractions appear
with an amplitude of 5–50 mmHg.71 Found primarily in the
ascending and transverse colon, this activity produces localized contractions of the circular and longitudinal muscles, in
effect segregating the haustrae.71 These segmental contractions, the correlate of myoelectical short spike bursts, result
in the slow, sequential antegrade or retrograde movement of
colonic contents among the haustra, allowing for mixing of
the material.13 Additionally, contact with the mucosal surface is maximized, which permits the absorption of intestinal
water and electrolytes.71 Only 6% of segmental contractions
are rhythmic, with a frequency of 2–8 cycles per minute;
U.M. Szmulowicz and T.L. Hull
however, in the rectosigmoid region, a slower interval of 3
cycles per minute is preeminent, possibly giving rise to a
physiologic sphincter to aid in continence.9,78,83
Unlike other mammals, humans possess a colon in which
cyclic motility is absent.78 The human rectum, however, does
display such cyclic activity, the rectal motor complex. The
rectal motor complex is comprised of phasic contractions
with amplitude of more than 5 mmHg. These phasic contractions appear at a cycle of 2–3 per minute, with each persisting for approximately 3 min. Yet, the interlude between
these contractions ranges from 10 to 260 min. This phasic
activity in the rectum and, potentially, the rectosigmoid may
contribute to fecal continence, as it is correlated with an elevated anal canal pressure; this role is further suggested by
the greater prominence of this activity at night.
Cellular Basis of Motility
Colonic motor activity is driven and coordinated by the
interstitial cells of Cajal, the intestinal pacemaker cells.84 In
the absence of these cells, the intestinal smooth muscle is
inactive.85 The interstitial cells of Cajal arise from smooth
muscle precursor cells; that is, the cells are of mesenchymal, not neuronal, origin.86 These cells are classified by their
location as ICCMY – in the myenteric plexus, between the
muscular layers; ICCSM – in the submucosal surface of the
circular muscle; and ICCIM – within the circular and longitudinal muscles.87 The interstitial cells of Cajal are linked
to the individual smooth muscle cells via intracellular gap
junctions; the similarly coupled smooth muscle cells function as a single unit, a syncytium.9 The gap junctions allow
for the passage of current – predominantly slow waves –
from the interstitial cells of Cajal to the smooth muscle
syncytium, leading to its depolarization.86 The interstitial
cells of Cajal are believed to be mechanosensitive, able to
transduce stretch stimulus from the distended colonic lumen
into electrical activity.88 The ICCSM – the primary pacemaker
cells – ­continuously generate high amplitude slow waves, at
a frequency of 2–4 per minute, within the circular muscle
layer.9 Unlike the other types of interstitial cells of Cajal, the
ICCSM are present only within the colon, solely in its proximal portion.86 A slow wave of sufficient charge produces a
smooth muscle action potential, allowing for an influx of
calcium into the smooth muscle cells via the L-type calcium
channels and, thus, a brief contraction.76 The amplitude of the
slow waves is greatest at the submucosal surface of the circular muscle, diminishing while traveling through the muscular
wall.89 Slow waves migrate antegrade and retrograde along
short segments of the colon, rapidly in the circumferential
and slowly in the longitudinal axis; as waves of different
inception meet, their propagation ceases, giving rise to nonpropulsive mixing activity.9,85 A second pacemaker site may
involve the ICCMY. In addition to the slow waves, the ICCMY
may initiate low amplitude myenteric potential oscillations
(MPOs) at a frequency of 12–20 per minute, which are
31
2. Colonic Physiology
conveyed to the circular and longitudinal smooth muscle.9
The MPOs possibly are the source of propagating contractions.9 Moreover, the ICCMY synchronize the activity of the
circular and longitudinal layers of the smooth muscle.86 As
opposed to the ICCSM, the ICCMY are widespread throughout
the colon.86 The etiology of the intrinsic electrical activity of
the ICCMY and ICCSM is uncertain but may involve calcium
regulated nonselective cation channels or large-conductance
chloride channels; the oscillations from the interstitial cells
of Cajal remain even the absence of extrinsic neural input.9
The ICCIM are thought to mediate such extrinsic input – from
the enteric and autonomic neural networks – upon smooth
muscle function; the release of acetylcholine and nitric oxide
from excitatory and inhibitory neurons, respectively, results
in alterations in the activity of the ICCIM.9,88 Furthermore, the
ICCIM appear to augment the slow waves and MPOs from
the ICCSM and ICCMY , respectively, as they are transmitted
along the smooth muscle syncytium.9 Much still remains to
be elucidated about the cellular basis of colonic motility.
Characteristics of Colonic Motility in Health
Manometry studies have demonstrated a noncyclical pattern
of colonic activity.11 The variations in colonic activity are
mirrored by changes in colonic tone.83 The human colon follows a circadian rhythm in which sleep is associated with its
relaxation and, thus, with a marked diminution of its pressure
activity.65,90 However, as previously noted, the rectum and
rectosigmoid display continued phasic activity during the
night. Immediately after morning waking, a two- to threefold increase in colonic pressure activity – likely due to high
amplitude propagated contractions – occurs, inciting an urge
to defecate in some cases. A similar rise in colonic activity
transpires during brief night-time arousals or during REM
sleep.71 The mechanism by which the colon rapidly responds
to these alterations in wakefulness is unknown. During the
day, the transverse and descending colon reveal more pressure activity than the rectosigmoid colon. Moreover, less
activity is seen in the transverse and descending colon of
women, as compared to men.65
Oral intake also impacts colonic activity. Within 1–3 min
of the initial bites of a meal, long before the food reaches
the colon, segmental contractions begin in the proximal and
distal colon, persisting for 2–3 h.65,91 This colonic motor
response to eating, or gastrocolic reflex, also features a
concomitant increase in the colonic smooth muscle tone,
especially in the proximal colon, often affiliated with high
amplitude propagated contractions.39,41,71 The colon exhibits
regional differences in its response to a meal: the proximal
colon evinces a swifter but briefer duration of contractile
activity than the distal colon.71 Although infrequently identified during scintigraphic studies, retrograde propulsion most
commonly appears after meals as well as during morning
waking.65 Colonic motility is instigated by a higher calorie
meal (more than 500 kcal), fat, and, to a lesser degree,
carbohydrates; in contrast, proteins inhibit motor function.71
The colonic response to eating includes two phases: an initial stimulation of the gastro-duodenal wall mechano- and
chemoreceptors and a subsequent activation of receptors
in the colonic wall.71 The means by which the gastrocolic
reflex arises is unclear but may involve cholecystokinin,
gastrin, serotoninergic input, or cholinergic stimuli. However, cholecystokinin antagonists do not block the reflex;
also, infusions of high dose cholecystokinin have no effect
upon colonic activity although pancreatic exocrine secretion and gallbladder contraction are maximally stimulated.92
Interestingly, the colonic motor response to eating persists
following a gastrectomy or spinal injury; yet, the colon must
be in continuity for the reflex to take place.71
Stress, both physical and emotional, also influences
colonic function. One study found that psychological stress
induced a significant increase in propagating contractions,
both in their frequency and amplitude, throughout the colon,
even in the absence of an appreciable autonomic response.93
Despite the withdrawal of the stressor, the augmented motor
activity endured.93 In contrast, physical stress, consisting of
exposures to extremes of temperature, precipitated a significant elevation in the frequency and amplitude of simultaneous contractions, which ceased immediately after the activity
stopped.93 In some trials, low and high amplitude propagated
contractions are stimulated by acute physical exercise.71,94
Defecation
The process of defecation involves the entire colon, not
solely the anus and rectum. As already described, the
majority of colonic activity – the segmental contractions –
serve to retain fecal material so as to promote the salvage
of intestinal water and electrolytes. However, periodically,
colonic activity shifts in order to foster the expulsion of
stool. Approximately 1 h prior to the act of defecation, an
involuntary preexpulsive phase is initiated, in which the
frequency and amplitude of antegrade nonpropagating and,
particularly, propagating contractions steadily increase
throughout the whole colon.95 The early component of the
preexpulsive phase – the first 15–60 min – is characterized
by propagating contractions that initially arise from the
proximal colon but subsequently from the distal colon; this
initial sequence is thought to transport stool into the distal
colon, thus stimulating distal colonic afferent nerves, which
in turn provoke further propagating sequences.9,95 During
the late phase, consisting of the last 15 min, the point of
origin of these contractions reverses from the distal to the
proximal colon.9,95 Scintigraphic studies reveal that, in one
bowel movement, 20% of the ascending colon can be emptied; other evaluations indicate that nearly the entire colon
may be evacuated of stool in a single defecatory action.9,96
A number of investigations identified antegrade high amplitude propagated contractions in close temporal relation to
32
defecation; yet, not all of these contractions necessarily
­precede or end in ­defecation.78,97,98 However, at least one
high amplitude propagated contraction of very high amplitude usually coincides with the urge to defecate.95 While the
early activity is unnoticed, the late phase is often associated
with the urge to defecate that occurs prior to the voluntary
act of fecal evacuation.95
Colonic Sensation
Colonic sensation has proved a complicated, poorly understood topic. The normal physiologic processes of the healthy
colon are largely unnoticed, with only fullness and an urge
to defecate consciously perceptible.11 The colon itself contains no specialized sensory end organs.41 However, naked
nerve endings lie within the serosa, muscularis propria, and
mucosa of the colon while Pacinian corpuscles are found
in the mesentery.9 Afferent nerve fibers reach the central
nervous system via parasympathetic pathways and spinal
afferent nerves, both of which display mechano- and chemosensitivity.99 The parasympathetic fibers convey sensory
information from the proximal colon via the vagus nerve
to cell bodies in the nodose and jugular ganglia and, from
the distal colon, by the pelvic splanchnic nerves.13,41,99 The
precise role of the parasympathetic afferent fibers remains
unknown but likely involves unconscious reflex sensation,
not painful stimuli.9 Sensory input from the colon is chiefly
detected by spinal afferent neurons, primarily by those with
their cell bodies within the lumbar dorsal root ganglia.8,9,99
These lumbar spinal afferent nerves travel with the sympathetic fibers within the lumbar splanchnic nerves from
the colon by way of the inferior mesenteric ganglia.9 The
lumbar spinal afferent fibers conclude in sensory endings
throughout the entire large intestine, whereby pain, colorectal distention, mesenteric traction, and noxious mucosal
stimuli are discerned.9 In contrast, the sacral spinal afferents, with their cell bodies in the sacral dorsal root ganglia
of S2–4, are thought to be concerned with a sensation of
rectal fullness and an urge to defecate.9 These sacral spinal afferent fibers are borne along with the parasympathetic
pelvic splanchnic nerves.8
Visceral pain sensation is carried by rapidly conducting
Ad fibers or by unmyelinated C fibers.11 The Ad fibers are
associated with the more localized “discriminative” pain,
which persists for as long as the stimulus, and the C fibers
in the diffuse “affective-motivational” pain, which continues beyond the duration of the catalyst.11 Sensory information is transported to the brain along the spinothalamic and
spinoreticular tracts as well as by the dorsal column of the
spinal cord.11 The spinothalamic tracts specifically transmit
sensation from the Ad and C fibers to the somatosensory cortex via the lateral thalamic nuclei or to the frontal, parietal,
and limbic regions by means of the medial thalamic nuclei,
respectively.11
U.M. Szmulowicz and T.L. Hull
The modulation of visceral sensation occurs through
s­ everal methods. Enteroenteric reflexes mediated by the
spinal cord produce variations in the smooth muscle tone,
leading to changes in the activation of the nerve endings
in the intestine or mesentery.100 The perception of visceral
pain is influenced by descending noradrenergic and serotonergic pathways that emanate from the reticular formation,
hypothalamus, and frontal cortex. These fibers project to the
dorsal horn of the spinal cord, where they modify noxious
input from the visceral afferent nerves.13 This mechanism
likely explains the experience of wounded soldiers who feel
no pain in the midst of battle.101 The intersection of visceral
spinal afferent nerves with somatic afferent nerves in the
dorsal horn of the spinal cord produces the phenomenon
of referred pain, in which visceral sensation is consciously
recognized as somatic pain, located in a dermatome of the
same embryologic origin as the visceral structure: T8–T12
for the midgut and T12–L2 for the hindgut.8,13,101 In addition,
visceral afferent nerves from the colon relay information via
collaterals to the reticular formation and thalamus, which
induce alterations in affect, appetite, pulse, and blood pressure through autonomic, hypothalamic, and limbic system
connections.13,102
Disturbances in Colonic Physiology
Physiology of Constipation
Constipation is a common complaint, with a prevalence of
2–28% among Western populations.103 This disorder refers
to infrequent bowel movements (fewer than three per week);
hard or lumpy stools; incomplete evacuation; a sensation
of anorectal obstruction; the need for manual maneuvers
to facilitate defecation; and/or excessive straining.104 Individuals with constipation are an incredibly heterogeneous
group. Distinct subtypes of constipation exist, each requiring different treatment modalities; however, even within
these subtypes, there may be wide variability in the clinical
presentation and pathophysiologic etiology. The causes for
constipation range from dietary, pharmacologic, structural,
to systemic.
Many people become constipated due to dietary and lifestyle neglect. In the USA, fiber intake is overall low. Two
primary roles of the colon, solidifying liquid chyme into
stool and defecation, are dependent upon adequate dietary
fiber: dietary fiber “normalizes” large bowel function.105,106 In
particular, the bulkier stool produced by fiber supplementation
stimulates propulsive activity, thus decreasing colonic transit
time.103 The recommendation for adequate fiber intake ranges
from 20 to 35 g/day for adults.107 For an individual on a
1,500–2,000 kcal/day diet, in order to include 15 g of fiber,
11 servings of refined grains and 5 servings of fruits and
vegetables must be consumed.105 Fiber is classified as either
soluble or insoluble, acting by differing mechanisms to
33
2. Colonic Physiology
increase stool weight. Soluble fibers such as oat bran provide
rapidly fermentable material to the proximal colon, which
allows for sustained bacterial growth.108 The consequent
higher bacterial content of the stool results in the greater
fecal mass.108 In an average bowel movement, 50% of the
stool weight consists of bacteria.103 Also, soluble fibers cause
a rise in the excretion of lipid and fat, further boosting stool
weight.108 In contrast, poorly fermentable insoluble fibers such
as wheat bran, cellulose, and lignin augment stool weight by
providing more undigested plant material for evacuation.108
One gram of wheat bran generates 2.7 g of stool.103 Wheat
bran also promotes fat excretion, but not to the extent of oat
bran.108 The outcomes of fiber supplementation as a treatment
for constipation have yielded conflicting data.
Constipation may be seen more commonly in sedentary
individuals. The Nurses Health Study suggested that those
women who engaged in daily strenuous activity were 44%
less likely to experience constipation than those who exercised less than once a week.109 During exercise, phasic and
propagating motor activity is diminished in the colon, with the
effect more pronounced with more vigorous effort; however,
after the physical exertion is completed, an increase in the
frequency and amplitude of the propagating pressure waves
is demonstrated, possibly due to the restoration of parasympathetic input.68 This postexercise pattern may precipitate
the propulsion of feces.68 During or after exercise, individuals often report an urge to defecate or defecation itself.109 In
fact, abdominal cramps and diarrhea are frequently related
by runners.110,111 However, in a small study of the impact of
regular exercise – 1 h a day, 5 days a week – upon chronic
idiopathic constipation, there was no symptomatic improvement in the eight subjects after 4 weeks of increased activity.112 Moreover, a small study examining colonic transit in
otherwise sedentary men after mild exercise, consisting of
1 h of walking on a treadmill for 3 days/week, showed no
significant difference in the passage of radiopaque markers
as compared to baseline.113
Idiopathic slow transit constipation involves ineffectual
colonic propulsion, resulting in a measurable delay in the
movement of fecal material through the colon. The severity of the presentation is variable, with the most intractable
cases referred to as colonic inertia. These patients with slow
transit constipation, usually women, have fewer than one
bowel movement per week, often in association with abdominal pain, a lack of an urge to defecate, malaise, fatigue, or
bloating.103 Little benefit is gained from dietary fiber supplementation, which, conversely, may cause worsened constipation, or from laxatives.103 The symptoms often arise
during puberty and steadily deteriorate over time.103 Retarded
colonic transit in these individuals is either pan-colonic or
segmental.60 Slow transit constipation is consistently affiliated with a blunted colonic motor response to eating (i.e.,
gastrocolic reflex), including both propulsive and segmental
contractions.60,64,83 In contrast, in patients with colonic inertia, there is no colonic response to a meal.103 A significant
decrease in the frequency as well as the amplitude of high
amplitude propagated contractions is demonstrated in slow
transit constipation, leading to reduced colonic propulsive
activity.41,64,71,114,115 Furthermore, the preexpulsive phase of
the defecatory process is depressed.103 Conflicting results
have been obtained from investigations into excessive, disorganized rectosigmoid phasic activity – a “brake” to antegrade propulsion – as a factor in slow transit constipation.60,64
Histological evaluations reveal a marked decrease in the population of myenteric plexus neurons; however, of the neurons present in the myenteric plexus, those that produce the
potent inhibitory neurotransmitter nitric oxide are vastly predominant, especially as compared to controls.116 Slow transit constipation also features a significant reduction in the
interstitial cells of Cajal either throughout the colon or solely
in the sigmoid colon.84,117,118 Moreover, the morphology of
the existing cells is seen to be strikingly abnormal, demonstrating few dendrites and an irregular surface.103 Colonic
transit studies of slow transit constipation reveal retention of
more than 20% of the radiopaque markers 5 days after their
­ingestion.103
Obstructed Defecation
Obstructed defecation usually results from abnormalities in
pelvic as opposed to colonic function. Typically, this disorder is associated with failure of the puborectalis muscle to
relax during defecation, producing a functional – not a physical – obstruction.11 Anatomic abnormalities also causing
obstructed defecation include rectocele, enterocele, excessive
perineal descent, and rectal intussusception. These patients
report inordinate straining, incomplete evacuation, painful
defecation, infrequent bowel movements, and digital anal
disimpaction.103 Among the diagnostic tests for obstructed
defecation are anorectal manometry or electromyelography,
balloon expulsion, barium defecography, and dynamic MRI.
A defecogram may identify retention of 50–100% of the
instilled barium in the rectum of patients with obstructive
defecation.58 Colonic transit studies in these patients demonstrate collection of six or more radiopaque markers in the
distal colon, indicating partial evacuation of the rectum.58,119
Two-thirds of patients with obstructive defecation may display a concurrent pattern of slow transit constipation.58
Obstructed defecation rarely arises from a colonic
source – a sigmoidocele. In this variant, a redundant sigmoid
colon descends into the rectovaginal pouch (of Douglas)
during defecation, impinging upon the rectum during
attempted evacuation.120 In one study of 463 patients with
constipation, fecal incontinence, or chronic idiopathic
rectal pain, a sigmoidocele was diagnosed on defecography
in 5.2%.120 Defecography is the primary method of diagnosis
of a sigmoidocele. The severity of a sigmoidocele is
determined by the extent of its decline into the pelvis, as
­compared to the pubococcygeal and ischiococcygeal lines.120
34
While third degree sigmoidoceles likely benefit from a
s­ igmoid ­colectomy, the significance and optimal management of first and second degree sigmoidoceles are not fully
understood.120 The clinician should also be cognizant of concomitant pelvic floor disorders in these patients.
Irritable Bowel Syndrome
Irritable bowel syndrome (IBS) is a functional disorder with
multiple manifestations: constipation-predominant (IBS-C),
diarrhea-predominant (IBS-D), and mixed (IBS-A). Irritable
bowel syndrome is characterized by altered bowel habits and
chronic, recurring abdominal pain directly related to defecation, in the absence of an anatomic abnormality.54 Extracolonic complaints include lower back pain, lethargy, nausea,
urinary symptoms, dyspareunia, and dysmenorrhea.121 The
etiology of irritable bowel syndrome is unclear but is believed
to involve visceral hypersensitivity to intraluminal stimuli.54
Aberrant motility, inflammation, anomalies in extrinsic autonomic innervation, abnormal brain–gut interaction, and the
role of psychosocial factors have also been extensively investigated. Hormonal factors may be involved, as symptoms are
often increased perimenstrually; however, the complaints
persist even in the absence of menses.122 The treatment of IBS
is based on the nature and severity of symptoms. ­Education,
reassurance, and the elimination of foods that incite the typical complaints are the initial interventions. In some patients,
fiber supplementation exacerbates the IBS.121 For those who
do not respond to conservative measures, medication is considered. However, the pharmacologic therapy of IBS-A has
not been well studied.
In approximately one-third of patients with irritable
bowel syndrome, constipation is the main feature (IBS-C).
Women are primarily affected by IBS-C. The majority of
these patients demonstrate normal colonic transit and motility patterns, although there is a possible overlap with slow
transit constipation.123 Tegaserod, an agonist of the 5-HT4
receptor that is involved in the metabolism of serotonin,
showed promise as a treatment of IBS-C but was withdrawn
by the Food and Drug Administration in 2007 due to a high
incidence of myocardial infarction, stroke, and unstable
angina.124,125 In some studies, probiotics such as Lactobacillus and Bifidobacterium produce variable degrees of
alleviation of IBS symptoms such as pain.126 Lubiprostone
(Amitiza®, Sucampo Pharmaceuticals, Inc., Bethesda, MD),
a prostaglandin E1 analog, activates type 2 chloride channels on the apical membrane of colonic epithelial cells.127,128
This medication promotes intestinal fluid secretion and,
indirectly, colonic motility in patients with IBS-C.128 Studies of lubiprostone revealed significant improvement in stool
frequency and consistency, abdominal discomfort and pain,
straining, and bloating.128 Cholecystokinin, found in elevated
levels in the plasma and sigmoid colon of IBS-C patients,
U.M. Szmulowicz and T.L. Hull
has been ­implicated in the pathogenesis of IBS: infusion of
cholecystokinin induces typical symptoms of irritable bowel
syndrome.129,130 However, in a randomized trial, the CCK-1
receptor antagonist dexloxiglumide led to no amelioration
in IBS symptomology; moreover, overall colonic transit was
unchanged, although emptying of the ascending colon was
delayed.130 However, a pilot study of a similar CCK-1 receptor
antagonist, loxiglumide, yielded some improvement in IBS
symptoms.131 A randomized trial of neurotrophin-3, a protein
growth factor integral to the development of the enteric nervous system, in constipated patients revealed more frequent
spontaneous bowel movements, a more rapid colonic transit
time, and a reduction in associated symptoms.132 Approximately one-third of subjects experienced transient injection
site reactions after subcutaneous administration.132
Diarrhea-predominant irritable bowel syndrome is
encountered in approximately one-third of patients with IBS.
The majority of men with irritable bowel syndrome experience the diarrhea-predominant type. This subtype is often
affiliated with urgency and fecal incontinence.121 IBS-D may
follow an episode of acute gastroenteritis, pelvic surgery, or
emotional stress.11 Some patients with IBS-D display accelerated proximal colonic transit, with an increased frequency
of high and low amplitude propagated contractions.11,78 Additionally, the colonic motor response to eating is enhanced in
a proportion of these patients, resulting in an intense urge
to defecate and abdominal pain immediately after meals.11
Rectal hypersensitivity is also a feature in some of these
patients.11 Antispasmodics such as hyoscine are prescribed
for those with abdominal pain and bloating, especially after
meals. Low-dose tricyclic antidepressants (e.g., amitriptyline) are added when the pain is more constant and even
disabling; these medications function not as mood stabilizers but instead act directly on the gut and central pain processing.121,124,133 Loperamide is an antidiarrheal agent safe for
long-term use.121 Diarrhea is effectively addressed by selective serotonin 5-HT3 antagonists such as Alosetron. This
drug was initially FDA approved in March 2000, only to be
retracted due to reports of ischemic colitis, severe constipation, and even death.134 In June 2002, it was adopted solely
for women with chronic, severe IBS-D.135 However, the
medication may only be supplied by physicians participating in the Prometheus Prescribing Program, after the patient
signs a patient–physician agreement.135 Further investigation
into these novel pharmaceuticals for IBS is required.
Ogilvie’s Syndrome
Ogilvie’s syndrome, initially described in 1948, is also
known as acute colonic pseudo-obstruction. This disorder
is characterized by an imbalance of autonomic innervation
to the colon: the inhibitory sympathetic input exceeds that
of the excitatory parasympathetic nerves.136 A massively
35
2. Colonic Physiology
dilated colon – particularly the proximal colon – results
from the consequent suppression of peristaltic activity.136
The ­specific source for the initial motor disturbance that
allows for this scenario is unknown.136 One hypothesis
ascribes this functional obstruction to impairment of the
pelvic (parasympathetic) splanchnic nerves supplying the
distal colon, ­giving rise to an atonic segment, lacking peristaltic function.136 Acute colonic pseudo-obstruction has
been reported ­concurrent with infectious or inflammatory
(e.g., acute pancreatitis), cardiovascular (e.g., myocardial
infarction), metabolic (e.g., hypokalemia), postoperative
(e.g., spinal or pelvic surgery), posttraumatic, neurologic
(e.g., Alzheimer’s disease), respiratory (e.g., pneumonia),
and neoplastic causes (e.g., metastatic disease); drugs (e.g.,
antidepressants); and old age.136 As indicated by the law
of LaPlace (wall stress = [(transmural pressure) × (radius)]/
wall thickness), the cecum is at greatest risk of perforation
in light of its thin wall and large diameter.137 Despite symptoms and signs consistent with a large bowel obstruction, no
mechanical blockade is present. The management of Ogilvie’s syndrome begins with eliminating the presence of a
physical obstruction with a water-soluble contrast enema.
In the majority of cases, colonic dilatation responds to conservative therapy, including nasogastric decompression,
­correction of fluid and electrolyte abnormalities, cessation
of antimotility medications such as opiates, and remedy of
the underlying illness.138 In the absence of peritoneal signs
or a cecal diameter greater than 12 cm on radiographic studies, conservative measures may be continued for 48–72 h.
This approach is associated with a 14% mortality rate.136
The colon may also be mechanically decompressed via
colonoscopy, although, in one study, this difficult procedure
in an unprepared colon was affiliated with a 1.7% morbidity and a 3.4% mortality rate; yet, colonoscopic decompression was successful in 79.3% of cases, albeit with a
recurrence in 20% of patients.139 Pharmacologic treatment
has become the mainstay of management for acute colonic
pseudo-obstruction if conservative measures fail. Neostigmine (2–2.5 mg IV over 1–60 min), an acetylcholinesterase
inhibitor, provides a surfeit of acetylcholine to the enteric
neurons and the neuromuscular junctions, thus inducing
propagating contractions, specifically high amplitude propagating contractions, and the prompt evacuation of stool
and flatus.62,138,140 In a double-blind randomized trial, the
initial clinical response to neostigmine was 91%, as compared to 0% among those receiving a placebo; colonic distention recurred in two patients (18%) given neostigmine,
ultimately requiring a subtotal colectomy in one patient.138
Administration of neostigmine may produce bradycardia,
abdominal pain, vomiting, and excessive salivation.138 Alternative, less-studied pharmacologic treatments are comprised
of 5-HT4 receptor agonists (e.g., cisapride), motilin receptor
agonists (e.g., erythromycin), muscarinic receptor agonists
(e.g., bethanechol), neurotrophins (e.g., NT-3), nitric oxide
synthase inhibitors (e.g., nitro-l-arginine methyl ester), and
somatostatin analogs (e.g., octreotide).136 Surgical treatment – a cecostomy tube or a subtotal colectomy – is a final
option if less invasive techniques are unsuccessful. Even in
a nonemergent setting, surgery has a 30% mortality rate.136
However, failure to decompress the colon may yield cecal
ischemia and/or perforation in 14–40% of cases; the mortality
of these patients increases to 40–50%.136
Implications of Colonic Physiology
for the Surgeon
Why is an understanding of colonic physiology important for
the surgeon? Knowledge of the embryologic development of
the colon is essential when considering nerve preservation,
vascular supply, and resection margins during colectomies.
The poorly understood topic of colonic motility impacts
surgeons, particularly in the phenomenon of postoperative
ileus. In a murine model of postoperative ileus, a reduction
in the number of interstitial cells of Cajal was evident on
both sides of the colonic anastomosis within hours of the surgery; as a consequence, fewer slow waves were identified in
that particular segment, possibly giving rise to postoperative
ileus.88 Various disorders of colonic motility may stem from
abnormalities of the interstitial cells of Cajal. These cells are
significantly depleted in the colons of patients with diverticulosis and with slow transit constipation.141 As basic science research advances, the surgeon ultimately will be called
upon to evaluate and apply novel pharmaceuticals to reduce
the impact of postoperative ileus as well as to treat other disorders of colonic motility. Surgeons also will invariably be
consulted to assess the suitability of surgical management
for abnormalities of colonic motility such as colonic inertia
and intractable constipation.
The resection of a portion or the entirety of the colon can
have profound functional ramifications for the patient. Prior
to a colectomy, the surgeon optimally should discuss these
possible outcomes with the patient. Postoperatively, the physiologic consequences of a colectomy must be managed. For
instance, a patient with a new ileostomy requires counseling
regarding adequate fluid and salt intake to compensate for
the loss of the colon. Furthermore, defecatory ­dysfunction –
frequent bowel movements, urgency, or soiling – may occur
after a low anterior resection. Subsequent to the procedure,
injury of the parasympathetic pelvic splanchnic nerves due
to dissection around the inferior mesenteric artery may produce a denervated colonic segment with an increased colonic
transit time and a greater proportion of nonpropagating contractions.142 The neorectum demonstrates a decline in compliance postoperatively, although the maximum tolerated
volume returns to normal 6 months later.143 Yet, the volume
needed to elicit the recto-anal inhibitory reflex is persistently
reduced even 1 year after surgery.143
36
Conclusion
The colon has proven an enigmatic organ. Its major roles –
the salvage of intestinal water and electrolytes, the storage of
fecal material, and the production of short-chain fatty acids –
seem unambiguous. However, the mechanisms underlying
its physiologic and pathophysiologic processes remain difficult to define. Although not essential for life, its normal
function is integral to our well-being.
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