The Pathophysiology of Irritable Bowel Syndrome CMEimg.medscape.com/images/779/326/779326_Web_Reprint.pdf · The Pathophysiology of Irritable Bowel Syndrome CME ... The Pathophysiology

The Pathophysiology of Irritable Bowel Syndrome CMEMichael 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

This article is a CME-certified activity.To earn credit for this activity visit:

http://www.medscape.org/viewarticle/779326

CME Released: 02/21/2013 Valid for credit through 02/21/2014

Target AudienceThis activity is intended for gastroenterologists, primary care physicians, and obstetricians/gynecologists.

GoalThe 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 ObjectivesUpon 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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Faculty and DisclosuresAs an organization accredited by the ACCME, Medscape, LLC, requires everyone who is in a position to control the content of an education activity to disclose all relevant financial relationships with any commercial interest. The ACCME defines “relevant financial relationships” as financial relationships in any amount, occurring within the past 12 months, including financial relationships of a spouse or life partner, that could create a conflict of interest.

Medscape, LLC, encourages Authors to identify investigational products or off-label uses of products regulated by the US Food and Drug Administration, at first mention and where appropriate in the content.

AuthorMichael Camilleri, MDProfessor 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: ShireReceived 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.

EditorsJulia MuinoScientific Director, Medscape, LLC

Disclosure: Julia Muino has disclosed no relevant financial relationships.

Kristen L. DascoliClinical Editor, Medscape, LLC

Disclosure: Kristen L. Dascoli has disclosed no relevant financial relationships.

CME ReviewerNafeez Zawahir, MDCME Clinical Director, Medscape, LLC

Disclosure: Nafeez Zawahir, MD, has disclosed no relevant financial relationships.


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Slide 1.Dr Michael Camilleri: Hello.IamMichaelCamilleri,professorofmedicine,pharmacology,andphysiologyattheMayoClinicinRochester, 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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Slide 3.In the past, the predominant pathophysiologic mechanisms in IBS were thought to be abnormalities in the gut smooth musclefunction,visceralhypersensitivity,andcentralnervoussystem(CNS)hypervigilance.However,hypersensitivityandCNSdysfunctionarenotubiquitous.Inmanyrespects,IBSisnotalwaysallinthepatient’shead.WenowrecognizethatsymptomsofIBS 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 wellaspsychosocialfactors.Wenowrecognize,however,theexistenceofperipheralmechanismsthatinitiateperturbationofgastrointestinal (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 disordersofthepelvicfloorortheanalsphincterthatpreventevacuation.Womenwhohavehadmultiplevaginaldeliveries,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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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 abnormalityofmotilityortransit,approximately45%ofpatientswithdiarrhea-predominantIBS(IBS-D)haveacceleratedtransit,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.Whatmightbethecauseofthisunderlyingchangeintransitthroughthecolon?Recentresearchsuggeststhatexcesshepaticsynthesis and excretion of bile acids may contribute to IBS-D; and that decreased production and excretion may contribute to IBS-C.[7]

Weknowthatcertaintypesofbileacidshaveatleast2α-hydroxygroupsatthe3,7,and12positionsarenaturalsecretoryagents;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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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.

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.


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Slide 10.Itisnotonlytheepithelialcellsthatconstitutethebarrier.Withinthelumen,thereisdegradationofbacteriaandantigensbybile, 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.

Belowtheepithelialcells,wehaveanumberofothermechanisms.Withinthelaminapropria,wehaveimmunecellsthatbringinnateandacquiredimmunity,secretionofimmunoglobulincytokinestoprotecttheintestinefromattack.Wealsohaveotherendocrine 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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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.

ThisleadstothequestionofwhetherIBS-Dmaybeaninflammatorydisease,andifso,whatisitscause?Atthepresenttime2of 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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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.HowhasthisinformationaboutpathophysiologychangedthemanagementofIBS?Atpresent,managementisguidedbythesymptom criteria, such as the Rome III criteria. Commonly used treatments for IBS-C include fiber, osmotic laxatives, bisacodyl, lubiprostone,andlinaclotide;loperamideandalosetronareavailableforpatientswithfunctionaldiarrheaorIBS-D.Wealsouseantispasmodics 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 bysymptomsthanbypathophysiology.Werecognizethatconstipationandbloatingmayariseinthepresenceofpelvicfloordysfunction,ornormaltransitconstipation,orslowtransitconstipation.Werecognizethatdiarrheamaybetheresultofalteredmotility 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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Slide 15.Whatisthecauseoftheincreasedpermeabilityandmucosalinflammation?Coulditbeachangeinthebacterialecology,orirritants taken by mouth such as gluten or FODMAP, or endogenously produced by the body such as bile acids which activate permeabilitymechanismstoproduceinflammationandactivationofsensation?Weknowthattheactivationofsensationinthepresence 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 tar-geted and potentially, more effective treatment of symptoms.

Slide 16.AnumberoftreatmentsforIBSareunderdevelopment.Whiletheyfocusoncentralpainperception,alteredsensation,andaltered 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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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 glutenorFODMAPs,biofeedback-basedtreatmentsfordefecationdisorders,bileacidsequestrants,or5-HT-3antagonistsforIBS-Dand 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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Disclaimer The educational activity presented above may involve simulated case-based scenarios. The patients depicted in these scenarios are fictitious and no association with any actual patient is intended or should be inferred.

The material presented here does not necessarily reflect the views of Medscape, LLC, or companies that support educational programming on medscape.org. These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or employing any therapies described in this educational activity.

Medscape Education © 2013 Medscape, LLC

This article is a CME certified activity. To earn credit for this activity visit: http://www.medscape.org/viewarticle/779326

Abbreviations5-ASA = 5-aminosalicylic acid

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=healthyvolunteers

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

References 1. LongstrethGF,ThompsonWG,CheyWD,HoughtonLA,MearinF,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. CamilleriM.Peripheralmechanismsinirritablebowelsyndrome. 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. SadikR,StotzerPO,SimrénM,AbrahamssonH.Gastrointestinaltransit abnormalities are frequently detected in patients with unexplained GI symptoms at a tertiary centre. Neurogastroenterol Motil. 2008;20:197-205.7. WongBS,CamilleriM,CarlsonP,etal.Increasedbileacidbiosynthesisis 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.CuppolettiJ,BlikslagerAT,ChakrabartiJ,NighotPK,MalinowskaDH. 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-StojanovićM,BiagiE,HeiligHG,etal.Globalanddeepmolecular 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.

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The Pathophysiology of Irritable Bowel Syndrome CMEimg.medscape.com/images/779/326/779326_Web_Reprint.pdf · The Pathophysiology of Irritable Bowel Syndrome CME ... The Pathophysiology