# Stress and Irritable Bowel Syndrome: Unraveling the Code



## eric (Jul 8, 1999)

FYIStress and Irritable Bowel Syndrome: Unraveling the Codehttp://www.giresearch.org/Tache.html


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## eric (Jul 8, 1999)

with permissionStress and Irritable Bowel Syndrome: Unraveling the CodeBy: Yvette Taché, Ph.D., Center for Neurovisceral Sciences and Women Health, Digestive Diseases Center, Department of Medicine,Digestive Diseases Division, University of California at Los Angeles and VA Greater Los Angeles Health Care System, CaliforniaDr. Taché was the recipient of the IFFGD 2005 ResearchAward to Senior Investigator, Basic Science. Her earlypublications put the "brain-gut axis" on the map. Since then,she has been one of the pioneers in this field. In many ways,it has been her energy and enthusiasm that has ensured thecontinued vibrancy of the field. Her identification of the roleof corticotrophin-releasing factor (CRF) signaling pathwaysin stress-related alterations of gut motor function andvisceral pain are of major and lasting importance.At a Glance"Stress" is a term doctors use to describe normal responses inthe body that are needed for health and survival.Our bodies regularly respond to the constant flow of changesthat happen around and within us.CRF is the brain's "stress hormone." When stimulated, itinteracts with many systems within the body.These interactions include those between the brain and thedigestive tract. They effect whether or not we feel discomfort orpain, and the way our bowels move.In some people, the stress response is overactive. When thestress response is out of balance, unwanted symptoms canresult.Understanding how this works will help find new and betterways to treat an illness like IBS."No one can live without experiencing some degree of stressall the time. You may think that only serious disease orintensive physical or mental injury can cause stress. This isfalse. Crossing a busy intersection, exposure to a draft, oreven sheer joy are enough to activate the body's stressmechanisms to some extent."- Hans Selye. The Stress of Life.Revised Edition, McGraw-Hill, New York.Hans Selye, M.D. (1907-1983) is credited to have introducedthe term "stress" in the medical field. He defined it as the"stereotyped body response to any demand." In his pioneerstudies reported 70 years ago, he identified key targetsaltered by a variety of physical and chemical stressors. Theseincluded the gut (intestines or bowel), endocrine (glands thatcontrol metabolism), and immune (protects the body againstforeign substances) systems. His studies are importantbecause some common medical conditions such as irritablebowel syndrome (IBS), inflammatory bowel disease (IBD),fibromyalgia, and migraine headaches may be stress-related.IBS can affect 1 in 10 or more people in North Americaand has a significant worldwide prevalence. It ischaracterized by chronic or recurrent abdominal pain and/ordiscomfort associated with changes in bowel habits. Theseare the key symptoms in the absence of traditionallyidentifiable structural diseases (e.g., colon cancer,inflammatory bowel disease, etc). The expression ofsymptoms in IBS reflects a disorder where various factorsinteract. Among them, psychosocial trauma and high rate ofstressful life events (alone or combined with previousepisodes of bowel infection/inflammation) have beenidentified as important risk factors in the onset, severity,and/or persistence of IBS symptoms.The question is often asked, are psychological conditions acause or effect of IBS? While not all persons with IBSexhibit psychological distress, it may be present in somepatients with IBS, particularly in those with more severesymptoms and who seek health care in highly specialized(tertiary) referral centers. On the other hand, the symptoms ofIBS can sometimes be so bothersome and affect dailyactivities so much that the patient understandably developsemotional distress. Because various forms of emotional stressare important in the development and management of IBS,the understanding of the mind and body's responses calledupon during stress may provide insight on the underlyingcause of IBS and open the door to new and more effectivetreatment.The Stress ResponseA person's stress response involves a network of brainregions that interact as they receive information from insideor outside the body. When stress actives this network, ittriggers two main pathways. One is called the pituitaryadrenalaxis, which acts to increase circulating hormones(glucocorticoids - particularly cortisol) involved withregulating the body's response to stress. The other is theautonomic nervous system, which regulates involuntarybodily functions such as our blood pressure, heart rate, andbowel function. Both of these pathways directly or indirectlyaffect gut function through the unique system of nerveswithin the bowel wall (enteric nervous system). Thesepathways, along with the brain and enteric nervous system,are collectively referred to as the "brain-gut axis."Within the last decade, milestone progress has beenachieved in identifying the substances that drive the stressresponse. One of the most important discoveries is a familyof peptides (small proteins made of amino acids) namedcorticotropin-releasing factor (CRF), urocortin 1, urocortin 2,and urocortin 3. These peptides act as messengers andinteract with CRF receptors named CRF1 and CRF2. Thereceptors are structures on cells that receive a stimulus ormessage. In turn, they induce a physiological response in thebody. These CRF peptides and receptors are located, amongother sites, both in the brain and the gut. In the brain, they arelocated in regions linked with digestive function, emotionalbehavior, and autonomic nervous system activity. It isincreasingly recognized that CRF1 receptors are activatedduring stress by CRF and urocortin 1. They play a key role inthe endocrine, behavioral (mood), and gut responses tostress.The Role of CRF1 Receptors in IBS SymptomsRecently, growing evidence indicates that the activation ofCRF1 receptors also plays a key role in mediating stressrelatedchanges in colon function, such as musclecontractions or motility, and pain sensitivity. For instance,studies showed that CRF or urocortin 1 acts in the brainstress network to increase anxiety-like behavior, abdominalpain, colon secretions, and muscle contractions (motility).These lead to the development of watery stool/diarrhea, andincreased permeability within the lining of the bowel. (Themore permeable the bowel lining, the easier it is forsubstances to pass through, which could allow the passage ofbacteria within the intestine into the bowel wall.) The actionof CRF in the brain-gut axis brings about changes that occurthrough the spinal cord and enteric nerve activity.In addition, studies showed that CRF and urocortin 1 canact directly within the colon where they stimulate secretionand motor activity. In particular, CRF increases mucus andwater secretion into the colon from cells lining the colonwall, and activates the enteric nervous system. Theseresponses promote colonic motility, bowel movements, anddiarrhea. CRF also stimulates a type of immune cell, calledmast cells, to release substances that play a role in increasingpermeability, bacterial uptake from inside the colon to thecolonic tissue, and pain response. Similarly, when givenCRF, muscle contractions in the colon and pain reportsincrease in IBS patients compared to healthy individuals.When examined under a microscope tissue specimens of thecolon from patients with IBS support a possible role of mastcells in affecting abdominal pain. Administration of CRF orurocortin 1 results in many of the features already observedin the symptoms experienced by IBS patients.Another aspect consistent with a role of CRF pathways inIBS symptoms are findings related to an amplification ofinformation - like turning up the volume of signals - fromthe gut to the brain. They are increasingly perceived asbothersome gut sensations. Animal studies have shown thatpainful stimulation of the colon activates brain nerve cellsthrough CRF/CRF1 mechanisms associated with thedevelopment of increased vigilance and anxiousness.Therefore, it is conceivable that the increased sensitivity toabdominal pain in IBS patients may cause, in turn, a morepronounced, sustained, and/or frequent activation ofCRF/CRF1 pathways. This may lead to increased vigilance,tension, and gut reactivity, which is then, associated withincreased IBS symptoms.Another key piece of evidence supporting the role of CRFpathways in the gut response to stress arises from medicationinterventions. Here blockade of CRF1 receptors prevented thedevelopment of the CRF or stress-related effects describedabove. For instance, a drug that selectively blocked the CRF1receptors (CRF1 antagonist) abolished or reduced emotionaldistress, colonic motility, mucus secretion, mast cellactivation, diarrhea, and pain brought on by CRFadministration or stress. Blocking CRF receptors in IBSpatients has reportedly reduced the increased abdominaldiscomfort induced by rectal stimulation compared withhealthy individuals. In addition, a clinical trial of CRF1antagonists in people already supports the improvement ofmood without side effects. Tricyclic antidepressants (e.g.,amitriptyline, desipramine) used in the treatment of IBS mayalleviate abdominal pain and bowel symptoms. Interestingly,they also reduce CRF effects in brain regions involved instimulating anxiety and colon function in animals.SummaryIn summary, these investigational studies reported to dateindicate that the activation of CRF1 pathways may result in acombination of effects that are key features of symptoms insome IBS patients. These include stimulation of colonicmotility, defecation/watery diarrhea, gut hypersensitivity thatincreases the perception of stimuli within the bowel (e.g.,food, gas, motor contractions), focused attention(hypervigilance) toward gut sensations, and mast cellactivation. Blocking the CRF1 receptors may alleviate allthese effects. Thus, the conceptual framework emergingsupports that sustained activation of the CRF1 system at sitesin the brain and/or in the gut may be one componentunderlying IBS symptoms. Targeting these mechanisms bydrugs that block the action of CRF on selected CRF1 receptorsites may lead to treatment that is more effective to reduceIBS symptoms.Further ReadingMartinez V, Taché Y. CRF1 receptors as a therapeutic targetfor irritable bowel syndrome. Current PharmaceuticalDesign, 2006, 12, 4071-4088.Opinions expressed are an author's own and not necessarily those ofthe International Foundation for Functional Gastrointestinal Disorders(IFFGD). IFFGD does not guarantee or endorse any product in thispublication nor any claim made by an author and disclaims all liabilityrelating thereto.This article is in no way intended to replace the knowledge ordiagnosis of your doctor. We advise seeing a physician whenever ahealth problem arises requiring an expert's care.IFFGD is a nonprofit education and research organization. Ourmission is to inform, assist, and support people affected bygastrointestinal disorders. For more information, or permission toreprint this article, write to IFFGD, PO Box 170864, Milwaukee, WI53217-8076. Toll free: 888-964-2001. Visit our websites at:www.iffgd.org or www.aboutibs.org.


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