The Pathophysiology of Irritable
Bowel Syndrome CME
Michael Camilleri, MD
Supported by an independent educational grant from Sucampo Pharmaceuticals and Takeda Pharmaceuticals International, Inc.
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The Pathophysiology of Irritable Bowel Syndrome CME
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Target Audience
This activity is intended for gastroenterologists, primary care physicians, and obstetricians/gynecologists.
Goal
The goal of this activity is to provide clinicians with a better understanding of the modulation of intestinal barrier function as a
rationale for available emerging therapies for irritable bowel syndrome (IBS) and with a better understanding of how to
appropriately use novel treatments for IBS as they become available.
Learning Objectives
Upon completion of this activity, participants will be able to:
1. Assess the current research results regarding possible causes of IBS, including the role of mucosal permeability
2. Discuss mechanisms of action regarding available and emerging therapies
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The Pathophysiology of Irritable Bowel Syndrome CME
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Author
Michael Camilleri, MD
Professor of Medicine, Pharmacology, and Physiology, Mayo Clinic, Rochester, Minnesota
Disclosure: Michael Camilleri, MD, has disclosed the following relevant financial relationships:
Served as a speaker or a member of a speakers bureau for: Shire
Received grants for clinical research from: Salix Pharmaceuticals, Sk Life Science, and Tsumura & Co.
Dr Camilleri does not intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA
for use in the United States.
Dr Camilleri does not intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the
FDA for use in the United States.
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Scientific Director, Medscape, LLC
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Kristen L. Dascoli
Clinical Editor, Medscape, LLC
Disclosure: Kristen L. Dascoli has disclosed no relevant financial relationships.
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Nafeez Zawahir, MD
CME Clinical Director, Medscape, LLC
Disclosure: Nafeez Zawahir, MD, has disclosed no relevant financial relationships.
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www.medscape.org/lecture/ibs/pathophysiology
Slide 1.
Dr Michael Camilleri: Hello. I am Michael Camilleri, professor of medicine, pharmacology, and physiology at the Mayo Clinic in
Rochester, Minnesota. I would like to welcome you to this program titled “Pathophysiology of Irritable Bowel Syndrome.”
Slide 2.
Irritable bowel syndrome (IBS) affects 10% to 20% of the population in developed countries.[1] The diagnosis of IBS is traditionally
based on the presence of symptoms of recurrent abdominal pain or discomfort at least 3 days per month in the previous 3 months
in association with 2 or more of the following: an improvement with defecation, an onset that is associated with a change in the
frequency of bowel movements, or an onset associated with a change in the form or appearance of stool.[2]
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The Pathophysiology of Irritable Bowel Syndrome CME
Slide 3.
In the past, the predominant pathophysiologic mechanisms in IBS were thought to be abnormalities in the gut smooth
muscle function, visceral hypersensitivity, and central nervous system (CNS) hypervigilance. However, hypersensitivity and CNS dysfunction are not ubiquitous. In many respects, IBS is not always all in the patient’s head. We now recognize that symptoms of
IBS are manifestations of several peripheral mechanisms that perturb the motor and sensory functions of the gut. During the past
10 years, there has been a renaissance in our understanding of IBS.
The mechanisms underlying IBS include the traditionally recognized CNS hypervigilance, altered sensitivity, altered motility, as
well as psychosocial factors. We now recognize, however, the existence of peripheral mechanisms that initiate perturbation of
gastrointestinal (GI) motor and sensory functions that lead to IBS symptoms. These irritants include the products of digestion,
neurotransmitters, transporters, a history of gastroenteritis, changes in the microbiome, mucosal immune activation, and
increased mucosal permeability. In addition, it is recognized that disorders of rectal evacuation mimic the symptoms of
constipation-predominant irritable bowel syndrome (IBS-C).
The relevance of these advances in our understanding is that the identification of these peripheral irritants provides an
opportunity to prevent or reverse the symptoms of IBS.
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Slide 4.
The symptoms of evacuation disorder -- constipation, straining, a sense of incomplete evacuation, bloating, left-sided abdominal
pain that are relieved by bowel movements -- are very similar to those of IBS-C.[3] In clinical practice, we recognize spastic
disorders of the pelvic floor or the anal sphincter that prevent evacuation. Women who have had multiple vaginal deliveries,
forceps delivery, or injury to the perineum can have descending perineum syndrome, in which the pelvic floor does not function
normally; in contrast to spastic disorders, it results in a flaccid pelvic floor.
During normal evacuation, the puborectalis muscle relaxes and the rectoanal angle opens up in order to facilitate defecation. In
the spastic disorders, the anal sphincter and puborectalis contract spastically, preventing the opening of the rectoanal angle. In
descending perineum syndrome, the entire perineum balloons out with straining, but the angle between the rectum and the anal
canal remains acute, preventing expulsion of stool.
Prokinetic and stimulant agents will have limited or no benefit in evacuation disorders mimicking IBS-C, and can worsen pain
without overcoming the problem of rectal evacuation. The diagnosis of an evacuation disorder requires history, examination,
evaluation of perineal descent, anorectal manometry, and balloon expulsion test.
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The Pathophysiology of Irritable Bowel Syndrome CME
Slide 5.
Among the peripheral mechanisms associated with IBS is disturbance of colonic motility, which may be accelerated or delayed,
and may be secondary to an abnormality in secretion in the intestine or colon.
Several factors may be involved, including neuromuscular dysfunction, products of the enteroendocrine cells, production of
organic acids within the lumen, and sometimes even genetic predisposition, as has been described in patients who have a
disturbance in either bile acid synthesis or a rare mutation involving the guanylate cyclase C receptor.[4] As a result of this
abnormality of motility or transit, approximately 45% of patients with diarrhea-predominant IBS (IBS-D) have accelerated transit,
and about 25% of those with IBS-C have delayed transit.
Slide 6.
Studies using scintigraphy have demonstrated that 32% of IBS patients had abnormal transit.[5] It has also been demonstrated in
the much more easily available radiopaque marker transit through studies that were done by Sadik and colleagues in Gothenburg,
Sweden. Approximately 35% of the patients with IBS-D had accelerated transit and the same proportion of patients who had IBS-C
had delayed transit.[6]
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Slide 7.
What might be the cause of this underlying change in transit through the colon? Recent research suggests that excess hepatic
synthesis and excretion of bile acids may contribute to IBS-D; and that decreased production and excretion may contribute to
IBS-C.[7]
We know that certain types of bile acids have at least 2 α-hydroxy groups at the 3, 7, and 12 positions are natural secretory agents;
they are natural laxatives that facilitate movement of contents through the colon. There is now evidence that a deficiency in these
secretory bile acids contributes to the slow transit in patients who have constipation or IBS-C. This is relevant as it may provide a
rationale for new approaches to treatment of both diarrhea and constipation in IBS.
Slide 8.
A second major peripheral mechanism pertains to the sensing of the small bowel and colon, and responses to those sensations.[4]
Activation of local secretory and motor reflexes and sensory mechanisms may result from ingestion of foods that stimulate
enteroendocrine cells or the organic acids, such as short-chain fatty acids (SCFAs) that are produced by the breakdown of complex
carbohydrates in the colon by the resident microflora. As mentioned earlier, it may also be related to the presence of bile acids
that bypass the ileal reabsorptive mechanism and reach the colon, causing symptoms such as diarrhea, bloating, and
abdominal pain.
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The Pathophysiology of Irritable Bowel Syndrome CME
Important cellular mechanisms present in the small intestine and colon -- goblet cells, enterocytes, and enteroendocrine cells -- work
in unison to change fluid and electrolyte movement through the epithelium. For example, goblet cells produce not only mucins,
but also secrete guanylin, and uroguanylin which activate the guanylate cyclase C receptor to induce chloride secretion from the
enterocytes. Similarly, enteroendocrine cells produce transmitters, such as 5-hydroxytryptamine, which then stimulate either the
submucosal neuron to evoke secretion, or directly stimulate the enterocytes to produce chloride secretion and thereby drag water
and sodium into the lumen.
Different mechanisms may be involved in the pathophysiology of IBS, but more importantly, perhaps, is that these mechanisms
provide a means to treat IBS-C. For example, drugs that activate the chloride channel directly, and drugs that bind to the
guanylate cyclase C receptor to induce chloride secretion, help to manage constipation in IBS-C.
Rectal hypersensitivity had previously been thought to be associated with IBS, but it is now apparent that not all patients with
IBS have evidence of hypersensitivity of the rectum or the intestines. IBS is not all about sensation, and we need to consider other
mechanisms for IBS.
Slide 9.
One of those mechanisms is a change in the barrier function in the small intestine and in the colon, which we term mucosal
permeability.[4] Increased permeability with alteration of the expression of the tight junction proteins may occur as the result of
prior gastroenteritis, atopy, or food intolerance. These may occur, for example, with gluten intake or ingestion of fermentable
oligosaccharides, disaccharides, monosaccharides and polyols (FODMAPs), the sugar entities that alter barrier function of the
intestine. Stress also is known to make the mucosa leaky (more permeable) and allow antigens or other chemicals in the lumen
access to the surface epithelial cells and to nerve cells below that level. Typically, changes in permeability results in IBS-D, with
fluid secretion or activation of those sensory mechanisms that ultimately become expressed as pain.
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Slide 10.
It is not only the epithelial cells that constitute the barrier. Within the lumen, there is degradation of bacteria and antigens by
bile, gastric acid, and pancreatic juice. There are commensal bacteria that inhibit the colonization of pathogens by producing
antimicrobial substances. The microclimate provides an unstirred water layer, the glycocalyces from the epithelial cells, and the
mucus layer, which, along with secretion of immunoglobulin-A (IgA) within the intestine, prevents bacterial adhesion.[8]
Those 3 layers prevent entry of antigens, or attack by microorganisms, even before we get to the epithelial cells, which are
connected by junctional complexes that have the ability to transport luminal content and react to noxious stimuli by secretion
of chloride and antimicrobial peptides. This secretion can wash away those antigens so that they cannot gain ground within the
lining of the intestine.
Below the epithelial cells, we have a number of other mechanisms. Within the lamina propria, we have immune cells that bring
innate and acquired immunity, secretion of immunoglobulin cytokines to protect the intestine from attack. We also have other
endocrine and enteric nervous systems that induce intestinal propulsion and move that attacking organism or antigen,
preventing it from gaining ground within the intestinal wall.
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The Pathophysiology of Irritable Bowel Syndrome CME
Slide 11.
Just as there is a mucosal barrier in the small intestine, there is also a low permeability in the normal state in the colon.[4] The
barrier in the colon may be broken, however, when malabsorption of either carbohydrates or fat results in the production of
SCFAs, when there is bile acid malabsorption or immune activation, in the presence of genetic predisposition to inflammation or
immune activation or bile acid synthesis. Typically, this is going to be associated with IBS-D, increased fluid secretion and
activation of sensory mechanisms.
Research has documented an increased intestinal permeability in IBS[9]; this is relevant because 1 of the agents used in the
treatment of IBS, lubiprostone, has been shown in a porcine ischemia model to restore tight junction function and normalize
permeability of the intestine.[10] This may be advantageous if permeability is indeed a significant mechanism causing the patient’s
diarrhea.
The cumulative excretion of a sugar molecule such as mannitol has been shown to be a fairly good noninvasive marker of
permeability, as has been demonstrated in patients who have IBS-D.[9] Although the increase in permeability is lower than that
which is observed in patients with inactive or microscopic or ulcerative colitis, changes in permeability and tight junction
proteins appear to be quite relevant in IBS. There is a relationship among duration of disease, body mass index, and, importantly,
the expression of the tight junction protein occludin and pain in IBS.
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Slide 12.
Another mechanism relevant in IBS is the activation of mucosal immune mechanisms.[4] This activation has a secondary effect
of increasing permeability as well as switching on reflexes and sensory mechanisms that result in manifestations of IBS. The
factors involved in mucosal immune activation are a history of gastroenteritis, and inflammatory cells such as mast cells and T
lymphocytes. Increased circulating cytokines can also result from mucosal immune activation. The T lymphocytes and mast cells
appear to be activated among patients who have IBS-D, rather than IBS-C.
This leads to the question of whether IBS-D may be an inflammatory disease, and if so, what is its cause? At the present time 2
of the mechanisms thought to be causally related to this mucosal inflammation or immune activation are the bile acid
malabsorption and the presence of dietary antigens, such as gluten, to which some patients may be sensitive, even in the
absence of overt celiac disease.
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The Pathophysiology of Irritable Bowel Syndrome CME
Slide 13.
The last mechanism to be discussed is the colonic microbiome and production of SCFAs.[4] Even people without IBS pass about
10% of those complex carbohydrates from the ileum to the colon. Because of the interaction between the microbes in the colon
and the complex carbohydrates that reach the colon, the production of SCFAs results in the stimulation of motor, secretory, and
sensory mechanisms.
This is identified primarily by an increase in Firmicutes spp, or the ratio of Firmicutes spp to Bacteroidetes spp.[11] Clearly, the
microbiome in the colon can be modified by antibiotics and probably also by probiotics. Bile acids influence the microbial species
in the colon. The consequences of these changes in the microbiome are abdominal bloating, pain, and diarrhea.
Studies have examined the microbiota and the feces from patients with IBS. The most straightforward summary of those findings
is that, in general, the number of Firmicutes spp is increased and the number of Bacteroidetes spp is decreased. As examples,
Clostridia spp and Veillonella spp are increased, whereas Bacteroides spp and Prevotella spp are decreased in patients with IBS.[11]
More work is being done in this area.
In summary, there are a number of pathophysiologic mechanisms that result in the symptoms of IBS. It is also important to
recognize there is a potential role of genetics in altered sensing and stimulation of secretion and motility, permeability, immune
activation, colonic transit. These include changes in serotonergic control, inflammation, bile acid synthesis, and the guanylate
cyclase C receptor on the enterocytes.
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Slide 14.
How has this information about pathophysiology changed the management of IBS? At present, management is guided by the
symptom criteria, such as the Rome III criteria. Commonly used treatments for IBS-C include fiber, osmotic laxatives, bisacodyl,
lubiprostone, and linaclotide; loperamide and alosetron are available for patients with functional diarrhea or IBS-D. We also use
antispasmodics for colic, and antidepressants for pain.
As we think about the different mechanisms I’ve just described, however, we may be moving toward an approach guided less
by symptoms than by pathophysiology. We recognize that constipation and bloating may arise in the presence of pelvic floor
dysfunction, or normal transit constipation, or slow transit constipation. We recognize that diarrhea may be the result of altered
motility and secretion. Beyond that, we know that factors such as increased permeability, mucosal inflammation, and activation
of sensory fibers that induce those changes in motility and secretion may have a role and may, in part, explain the pain associated
with IBS.
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The Pathophysiology of Irritable Bowel Syndrome CME
Slide 15.
What is the cause of the increased permeability and mucosal inflammation? Could it be a change in the bacterial ecology, or
irritants taken by mouth such as gluten or FODMAP, or endogenously produced by the body such as bile acids which activate
permeability mechanisms to produce inflammation and activation of sensation? We know that the activation of sensation in the
presence of psychosocial dysfunction or hypervigilance in the brain may also result in pain. One can see how knowledge of the
mechanism that may be contributing to a patient’s constipation, bloating, diarrhea, or pain-evoking factors can lead to more targeted and potentially, more effective treatment of symptoms.
Slide 16.
A number of treatments for IBS are under development. While they focus on central pain perception, altered sensation, and
altered motility and secretion, novel approaches appear very promising as they will be directed at specific mechanisms that
can be identified through tests that are either available or will be in future. For example, in patients who have mucosal immune
activation or evidence of inflammation, these treatments may include probiotics, antibiotics, mast-cell stabilizers, or
5-aminosalicylic acid compounds. Similarly, alterations of motility and secretion may be targeted with new classes of medications
that include serotonin synthesis inhibitors, chloride channel openers, guanylate cyclase C agonists, and ileal bile acid transporter
inhibitors, as well as other agents directed at the specific mechanisms occurring in the GI tract.
In addition, novel approaches are being directed at central pain perception, which is beyond the scope of this lecture.
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Slide 17.
IBS is not an idiopathic bowel dysfunction that originates exclusively from psychological stress or brain dysfunction. I believe
that fecal tests, such as the measurements of fecal calprotectin and lactoferrin levels or colonic imaging, including colonoscopy,
may be indicated to rule out inflammatory bowel disease or neoplastic disease. A patient whose symptoms do not respond to
lifestyle, dietary, or symptomatic remedies should undergo tests to identify the causative factors. For patients with IBS-C, these
tests include colonic transit or rectal evacuation; for patients with IBS-D, tests for carbohydrate or fat digestion, increased bile acid
synthesis, fecal excretion, and dietary intolerance.
Slide 18.
In the future, we may have more information about the roles of diet, the microbiome, endogenous irritants (such as barrier
function, immune activation, and genetic factors) in the motor, sensory, secretory, and psychologic dysfunctions in IBS.
An overall hypothesis appears to be that, as in inflammatory bowel disease, IBS may result from an interaction between
intraluminal and host genetic factors. This has been well documented and proposed for such entities as Crohn’s disease and celiac
disease, in which intraluminal factors such as nutrition, antibiotics, and bacteria, and changes in the barrier can alter the way in
which the intestines respond -- related, in part, to the underlying host genetics.
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The Pathophysiology of Irritable Bowel Syndrome CME
Slide 19.
I believe that the other aspect of future research will be the development of more specific individualized treatments based on the
underlying peripheral pathophysiological mechanisms. These might be dietary recommendations, for instance, the exclusion of
gluten or FODMAPs, biofeedback-based treatments for defecation disorders, bile acid sequestrants, or 5-HT-3 antagonists for IBS-D
and urgency; prokinetics or secretagogues for IBS-C; and possibly probiotics, nonabsorbable antibiotics, anti-inflammatory agents,
tight-junction modulators, and even lubiprostone, as shown from the porcine ischemia model to restore normal barrier function,
reduction of immune activation, and restoration of intestinal functions.
Slide 20.
Thank you for participating in this activity. You may now take the CME posttest by clicking on the “Earn CME Credit” link. Please
also take a moment to complete the program evaluation that follows.
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Abbreviations
References
5-ASA = 5-aminosalicylic acid
1. Longstreth GF, Thompson WG, Chey WD, Houghton LA, Mearin F, Spiller RC. Functional bowel disorders. Gastroenterology. 2006;130:1480-1491.
2. Saito YA, Schoenfeld P, Locke GR 3rd. Epidemiology of irritable bowel syndrome in North America: a systematic review. Am J Gastroenterol. 2002;97:1910-1915.
3. Lembo A, Camilleri M. Chronic constipation. N Engl J Med.
2003;349:1360-1368.
4. Camilleri M. Peripheral mechanisms in irritable bowel syndrome.
N Engl J Med. 2012;367:1626-1635.
5. Camilleri M, McKinzie S, Busciglio I, et al. Prospective study of motor,
sensory, psychologic, and autonomic functions in patients with irritable
bowel syndrome. Clin Gastroenterol Hepatol. 2008;6:772-781.
6. Sadik R, Stotzer PO, Simrén M, Abrahamsson H. Gastrointestinal transit
abnormalities are frequently detected in patients with unexplained GI
symptoms at a tertiary centre. Neurogastroenterol Motil. 2008;20:197-205.
7. Wong BS, Camilleri M, Carlson P, et al. Increased bile acid biosynthesis is
associated with irritable bowel syndrome with diarrhea. Clin Gastroenterol
Hepatol. 2012;10:1009-1015.
8. Keita AV, Söderholm JD. The intestinal barrier and its regulation by neuro
immune factors. Neurogastroenterol Motil. 2010;22:718-733.
9. Rao AS, Camilleri M, Eckert DJ, et al. Urine sugars for in vivo gut perme
ability: validation and comparisons in irritable bowel syndrome-diarrhea
and controls. Am J Physiol Gastrointest Liver Physiol. 2011;301:G919-G298.
10.Cuppoletti J, Blikslager AT, Chakrabarti J, Nighot PK, Malinowska DH.
Contrasting effects of linaclotide and lubiprostone on restitution of
epithelial cell barrier properties and cellular homeostasis after exposure to cell stressors. BMC Pharmacology. 2012;12:3.
11.Rajilić-Stojanović M, Biagi E, Heilig HG, et al. Global and deep molecular
analysis of microbiota signatures in fecal samples from patients with
irritable bowel syndrome. Gastroenterology. 2011;141:1792-1801.
12.Camilleri M. Pharmacology of the new treatments for lower
gastrointestinal motility disorders and irritable bowel syndrome. Clin Pharmacol Ther. 2012;91:44-59.
5-HT = 5-hydroxytryptamine
BA = bile acid
CNS = central nervous system
CRF = corticotropin-releasing factor
FODMAP = fermentable oligosaccharides, disaccharides,
monosaccharides and polyol
GC-C = guanyl cyclase C
GI = gastrointestinal
HV = healthy volunteers
IBAT = ileal bile acid transporter
IBS = irritable bowel syndrome
IBS-C = constipation-predominant irritable bowel syndrome
IBS-D = diarrhea-predominant irritable bowel syndrome
IgA = immunoglobulin-A
NTC = normal transit constipation
SCFA = short-chain fatty acid
SNP = single nucleotide polymorphism
STC = slow transit constipation
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