FYI
With permission from the UNC
Stress and the Gut
Dr. Howard Mertz
Associate Professor of Medicine and Radiology
Vanderbilt University
Stress is a ubiquitous condition that affects all people. Stress can be mental or physical, although in the context of this article the focus will be mental stress. Mental stress involves challenge, threat or worry about future adverse events. Such stress activates the brain's stress response systems, which in turn effect the body. Many of the body's major systems are altered by stress cardiovascular, muscular, urinary, gastrointestinal, sweat glands, etc often with adverse consequences. Gastrointestinal function is particularly influenced by stress. Common gastrointestinal symptoms due to stress are heartburn, indigestion, nausea and vomiting, diarrhea, constipation and associated lower abdominal pain. These symptoms and the alterations in intestinal function that cause them are becoming understood.
Gastrointestinal Stress Reactions in Animals and CRF
In animals such as rats, stress can be induced in experimental situations. When rats are wrap restrained, or placed on a small platform surrounded by water they become stressed. During these situations, alterations in motility of the gut occur. The upper gut, including the stomach and small intestine, exhibits markedly reduced transit. This may be a defense mechanism to promote vomiting and reduce oral intake. Conversely the large bowel motility increases with increased stool output and transit speed. This may be a defense mechanism to eliminate toxins. We have learned that a hormone called corticotropin releasing factor CRF influences these changes. CRF is released from nerve cells in the hypothalamus of the brain. These nerve cells release the hormone via long processes into other parts of the brain such as the locus ceruleus, where arousal and autonomic nervous system changes are mediated. In rats, injection of CRF blockers into the brain fluid diminishes the stress induced motility changes in the gut. CRF directly injected into the brain fluid mimics the stress response closely Figure 1. CRF also stimulates the gut directly via CRF-1 and CRF-2 receptors. CRF-1 receptors stimulate colonic contractions, while CRF-2 receptors reduce upper gut activity. Antagonists to CRF-1 receptors are currently being tested for treatment of depression, and may become available for testing in functional bowel disorders as well.
Brain Areas Involved in Stress Reaction
Two of the primary brain regions involved in stress reactivity are the hypothalamus and the locus ceruleus. Activation of the hypothalamus by stress is likely to be mediated in part by the limbic brain particularly the amygdala and hippocampus and partly by the locus ceruleus in the brainstem. The locus ceruleus and the hypothalamus actually stimulate each other, creating the potential for a vicious cycle, where a stress reaction in one region stimulates the other, which in turn stimulates the first to react even more. The limbic system is a group of connected and related brain regions that mediate emotions and flight or fight attitudes. The limbic or "emotional brain" is more primitive by evolutionary standards, and is not necessarily under control by the higher intellectual cortex. This system receives sensory and higher cortical inputs, calls upon memories and determines the threat level imposed by a stimulus. The amygdala for instance is a limbic structure in the base of the brain that is important in anger and rage. In cats, electrical stimulation of the amygdala causes hissing, back arching and the hair to stand on end, typical of anger and defense postures in cats. In animals that have damage to the amygdala a placid state results in which anger cannot be induced. Inputs to the amygdala are thought to originate from the hippocampus, the cingulate cortex and other parts of the limbic sytem. The locus ceruleus is located in the pontine portion of the brainstem. The locus ceruleus is the source of most of the stimulant neurotransmitter norepinephrine in the nervous system. Cells here project to other brain areas, releasing norepinephrine to activate other systems and increase arousal and alertness. Release of norepinephrine increases heart rate, blood pressure and primes the muscles and nervous system for fight or flight. This reaction is not helpful in routine stress of daily activities. If the stress reaction is excessive or the perceived threat too frequent, tachycardia racing heart, hypertension, muscle tension, bowel spasms and dyspepsia can result.
Hypothalamic-Pituitary-Adrenal Axis
CRF release is the first step in activation of the hypothalamic-pituitary-adrenal axis HPA axis involved in stress response. This is the major endocrine hormonal response system to stress. Release of CRF by the hypothalamus stimulates the pituitary gland immediately underneath it. The pituitary gland responds to CRF by release of adreno-corticotropic hormone ACTH to stimulate adrenal gland secretion of the stress hormone cortisol. Cortisol promotes fluid and salt retention and impairs inflammation, functions helpful in the short term during flight or fight situations or injury. Again, if the HPA system is activated too frequently adverse health outcomes such as hypertension from salt retention and impaired immune function from excess cortisol may result. The CRF system and the norepinephrine systems work together to respond to stress with resultant changes in bodily functions that prepare for flight or fight. Figure 2
Gastrointestinal Stress Response in Humans
Humans respond to stress in similar ways to animals. A variety of human studies indicate stress promotes decreased gastric emptying and accelerated colonic transit in normal volunteers. A pioneering study by Almy measured colonic contractions during flexible sigmoidoscopy. The volunteers were told that a cancer was found, leading to abrupt increases in colonic contractions, which resolved after the hoax was explained. Other stressors such as ball-sorting, driving in city traffic and mentally challenging listening tasks similarly increase colonic contractions and reduce gastric motility. Recent data also indicates that intestinal sensitivity increases with stress compared to relaxation. This effect may lower the threshold for sensing intestinal events. In gastroesophageal reflux for example, psychological stressors can increase heartburn symptoms. Analysis of the esophageal pH measurement of acid indicates that the amount of reflux doesn't increase during stress, but the probability of feeling a reflux as heartburn does increase. In one small study of normal controls, intravenous infusion of CRF induced greater rectal sensitivity to balloon distension. It may be that the sensitizing effects of stress on the gut are partly mediated by the stress hormone CRF.
Irritable Bowel Syndrome and Functional Dyspepsia
Two of the major causes of uncomfortable or painful intestinal symptoms are irritable bowel syndrome IBS and functional dyspepsia. IBS occurs in approximately 12% of people world-wide. Dyspepsia indigestion/upper abdominal discomfort is also very common. The majority of dyspepsia is functional, that is not associated with ulcers, gallstones, reflux esophagitis or cancer. In both of these common disorders, motility and sensory changes are present which mimic the stress state. Both disorders demonstrate hypersensitivity of the gut either stomach or intestine. Both disorders demonstrate alterations in motor function of the gut typical of stress and CRF-induced changes. In functional dyspepsia the stomach generally has mildly reduced emptying and reduced accommodation of meals. In IBS, colonic contractions are generally increased. Furthermore, IBS subjects appear to have increased stress responsiveness in the gut. In one study, IBS patients and healthy controls both underwent ambulatory motility recordings in the colon. Both groups were confronted on return to the lab "you're late", "you came to the wrong window", "now the study may need to be repeated". Colonic motility jumped up in the IBS patients during confrontation, but not in healthy volunteers. Figure 3 IBS patients may also have greater sensitivity to the stress hormone CRF. Infusion of CRF intravenously to IBS patients and controls in one study caused significantly greater colonic motor responses in IBS patients. Another study indicates that listening stress increases rectal sensitivity to balloon distension in IBS patients but not controls. It appears both intestinal motility and sensory responses to stress are heightened in IBS patients. These alterations are likely to cause symptoms such as diarrhea and intestinal cramps due to increased contractions of the gut and increased sensitivity of the gut during stress. The chemical mediators of these changes are not yet established, although alterations in CRF release or CRF receptors may be implicated to some extent in functional bowel diseases.
IBS and other functional bowel symptoms are generally worsened by stress. In fact recent research has indicated that IBS symptoms tend to resolve in those without major psychosocial stressors. Conversely, symptoms are persistent in subjects with ongoing "threatening" psychosocial stressors. The onset of IBS and functional dyspepsia often begin with bereavement, abuse or other major negative life events. Emotional distress is very common in IBS patients, particularly those who seek medical treatment for the condition. Anxiety and depression are significantly increased in IBS patient populations, present in nearly 40%. Psychosocial distress appears much less common in IBS sufferers who do not seek medical care. Population based surveys, however, do still suggest tendencies toward emotional reactivity in people with IBS. Accordingly, stress modification, psychotherapy and hypnosis appear helpful for IBS and functional dyspeptic symptoms. Tricyclic antidepressants also appear effective for IBS and other functional bowel symptoms, even in low doses. Recent evidence indicates the drugs may work by reducing the brain's response to intestinal pain during stress. Sedatives such as the benzodiazepine Librium can reduce the effect of stress on the gut. During ball sorting challenge, Librium blunts the colonic motor response to mental stress in IBS patients. This effect may explain the benefits of combined sedative-anti-spasmodic drugs for IBS.
Summary
There is much yet to learn about the effects of stress on the gastrointestinal tract. The exact neural and hormonal pathways that mediate excess gut sensitivity and altered contractility during stress are not defined. Where these pathways are excessive or dysfunctional in IBS, functional dyspepsia and other GI disorders is unclear. Specific neurotransmitters are likely to underlie the gastrointestinal stress reaction, and may be amenable to pharmacologic blockade. Psychological therapies are likely to blunt the stress response as well. New tools such as brain imaging to study brain responses to stressors and drugs, and molecular biology to study function of neurotransmitters and their receptors are likely to lead to better understanding of the stress response and its role in disease states. Based on this knowledge, advances in pharmacology may lead to better drug therapies to address these important health problems.
http://www.med.unc.edu/wrkunits/2depts/medicine/fgidc/welcome.htm
History of Functional Disorders
"PRESENT PATHOPHYSIOLOGICAL OBSERVATIONS
Despite differences among the functional gastrointestinal disorders, in location and symptom features, common characteristics are shared with regard to:
motor and sensory physiology,
central nervous system relationships,
approach to patient care.
What follows are the general observations and guidelines.
Motility
In healthy subjects, stress can increase motility in the esophagus, stomach, small and large intestine and colon. Abnormal motility can generate a variety of GI symptoms including vomiting, diarrhea, constipation, acute abdominal pain, and fecal incontinence. Functional GI patients have even greater increased motility in response to stressors in comparison to normal subjects. While abnormal motility plays a vital role in understanding many of the functional GI disorders and their symptoms, it is not sufficient to explain reports of chronic or recurrent abdominal pain.
Visceral Hypersensitivity
Visceral hypersensitivity helps to account for disorders associated with chronic or recurrent pain, which are not well correlated with changes in gastrointestinal motility, and in some cases, where motility disturbances do not exist. Patients suffering from visceral hypersensitivity have a lower pain threshold with balloon distension of the bowel or have increased sensitivity to even normal intestinal function. Additionally, there may be an increased or unusual area of somatic referral of visceral pain. Recently it has been concluded that visceral hypersensitivity may be induced in response to rectal or colonic distension in normal subjects, and to a greater degree, in persons with IBS. Therefore, it is possible that the pain of functional GI disorders may relate to sensitization resulting from chronic abnormal motor hyperactivity, GI infection, or trauma/injury to the viscera.
Brain-Gut Axis
The concept of brain-gut interactions brings together observations relating to motility and visceral hypersensitivity and their modulation by psychosocial factors. By integrating intestinal and CNS central nervous system activity, the brain-gut axis explains the symptoms relating to functional GI disorders. In other words, senses such as vision and smell, as well as enteroceptive information (i.e. emotion and thought) have the capability to affect gastrointestinal sensation, motility, secretion, and inflammation. Conversely, viscerotopic effects reciprocally affect central pain perception, mood, and behavior. For example, spontaneously induced contractions of the colon in rats leads to activation of the locus coeruleus in the pons, an area closely connected to pain and emotional centers in the brain. Jointly, the increased arousal or anxiety is associated with a decrease in the frequency of MMC activity of the small bowel possibly mediated by stress hormones in the brain. Based on these observations, it is no longer rational to try to discriminate whether physiological or psychological factors produce pain or other bowel symptoms. Instead, the Functional GI disorders are understood in terms of dysregulation of brain-gut function, and the task is to determine to what degree each is remediable. Therefore, a treatment approach consistent with the concept of brain-gut dysfunction may focus on the neuropeptides and receptors that are present in both enteric and central nervous systems. "
http://www.med.unc.edu/wrkunits/2depts/medicine/fgidc/historyfunctionaldisorders.htm
CME Diagnosis, Pathophysiology, and Treatment of Irritable Bowel Syndrome
Read this comprehensive update for primary care physicians on irritable bowel syndrome, by Kevin W. Olden, MD.
"Introduction
Definition
Irritable bowel syndrome IBS, in its essence, can be defined as a combination of abdominal pain or discomfort and altered bowel habit. The alteration in bowel habit can take the form of altered stool frequency ie, diarrhea or constipation or altered stool form in terms of thin, overly hard and firm, or soft and even liquid stools. Symptoms that are commonly associated with IBS include passage of clear or white mucus with a bowel movement, sensation of incomplete evacuation after having a bowel movement, and relief of abdominal pain or discomfort transiently after defecation and abdominal bloating. Patients with IBS have traditionally been described as being "constipation predominant," "diarrhea predominant," or as having an alternating pattern of constipation and diarrhea ie, so-called "alternators". Although the research on the exact epidemiology of these 3 variants of IBS is incomplete, our best understanding is that each type is represented approximately equally in the overall IBS population. Abdominal pain or discomfort is a sine qua non for the diagnosis of IBS. The pain or discomfort most commonly occurs in the left lower quadrant, but can be found anywhere in the abdomen; however, isolated pain or discomfort above the level of the umbilicus is uncommon in patients with pure IBS. This combination of altered bowel habits with abdominal pain or discomfort separates IBS from other functional bowel disorders, such as functional dyspepsia, functional constipation, functional diarrhea, or functional abdominal bloating, to name a few.
In addition to gastrointestinal symptoms, IBS has been associated with a number of extraintestinal conditions, such as fibromyalgia, sexual dysfunction, urinary symptoms, and certain psychiatric disorders in excess of non-IBS controls. These latter findings have implications both for further supporting the diagnosis of IBS, as well as for helping to define the level of disability of the patient who presents with IBS with extraintestinal manifestations."
"Pathophysiology of IBS
The pathophysiology of IBS is a work in progress. Roughly 200 years after its initial description by the English physician William Powell, our understanding of what causes IBS symptoms remains incompletely understood. For most of the second half of the 20th century, tremendous attention was paid to the concept of altered gut motility as a cause of IBS symptoms.20 However, several difficulties are apparent in this approach. First, although altered motility of the colon and small bowel can be demonstrated in patients with IBS, there is a very poor correlation between IBS symptomatology and the presence of alterations in gastrointestinal motility. 21 Likewise, drugs that alter gastrointestinal motility alone, such as antispasmodic 22,23 and prokinetic drugs like metoclopramide and cisapride, 24,25 have not been shown to be of any significant benefit in relieving IBS symptoms.
The third dilemma facing investigators in this area is that no pathognomonic pattern of gut dysmotility can be identified specifically with IBS, as opposed to other functional or organic disorders of the gut. 20 Altered motility, as occurs in IBS, is currently seen as one of many epiphenomena associated with the disorder, as opposed to being a cause of the disorder itself.
In the early 1980s, it was discovered that upon balloon distention in the rectum, individuals suffering from IBS were more sensitive to distention than were individuals who did not suffer from IBS. 26 This means that IBS patients feel discomfort at lower levels of balloon inflation in the rectum and lower bowel than do normal controls. This finding has been replicated in numerous studies, and the concept of "visceral" hypersensitivity has been established. 27 A second level of investigation in this area is the fascinating finding that individuals with IBS not only have a unique local response in the rectum to visceral stimulation, but they also tend to process signals in the brain differently from non-IBS controls. Mertz and others 27 have shown that IBS patients have differential responses in the anterior cingulate cortex and other areas of the brain when stimulated with rectal or sigmoid colon distention, compared with controls. These findings have been replicated by other investigators. 28 These data certainly suggest the possibility of a "brain-gut axis" where peripheral symptoms are processed in the end organ ie, the colon, and then neural signals are carried via visceral afferents to the spinal cord, and then to the brain, where they are subject to additional processing.29 It is this brain-gut axis that has received considerable attention recently in IBS research. The findings of enhanced visceral sensitivity in the colon and rectum, as well as altered processing of signals in the brain, have provided new insight. Regarding the pathophysiology of IBS, the altered processing of neural sensation in IBS patients logically raises the question as to which neurotransmitters play a role in this abnormal signal transmission.
A large number of neuropeptides are involved in the regulation of both gastrointestinal motility and sensation in the gut. These include motolin, gastrin, peptide Y, cholecystokinin, serotonin, and others.
Serotonin has received the most interest for a number of reasons. The first reason is the dramatic impact that modulation of serotonin has had on psychiatric disorders. The development of selective serotonin reuptake inhibitor SSRI medications in the late 1980s revolutionized the practice of psychiatry. The ability to treat depression with far fewer side effects than seen with earlier drugs made depression treatment more acceptable both to patients and physicians. The success of these medications led to increased interest in the role of serotonin in the nervous system. The second reason is that almost all ie, more than 90% of the serotonin contained in the body is found in the gut and not in the central nervous system.29 This fact raises the reasonable question of whether modulation of serotonin action in the gut could influence IBS and other functional bowel symptoms.
Serotonin 5-HT is an interesting molecule. There are at least 15 subtypes of the 5-HT molecule. 5-HT1 and 5-HT2 are contained almost exclusively in the central nervous system. These are the target neurotransmitters for the SSRIs. The subtypes of serotonin contained in the gut consist mainly of 5-HT3 and 5-HT4, which has led to the development of drugs designed specifically to act on these serotonin subtypes see detailed discussion in the Management section below. Identifying the role of serotonin in the pathophysiology of IBS symptomatology has led to the investigation of other neurotransmitters. Cholecystokinin antagonist and various neurokinin antagonists are all actively being investigated for their potential to influence IBS symptomatology. 30 This has led to a whole new era of gastrointestinal pharmacology based on a brain-gut axis. The opportunity to develop interventions at the level of the bowel, spinal cord, and brain based on this pathophysiologic conceptual model is considerable."
"Diet and Lifestyle Modification
IBS is not caused by stress. Likewise it is not caused by any particular dietary indiscretion. However, stress can clearly influence outcomes and severity of IBS, as it can in many other diseases. 31 Identifying stressors in a patient's life and urging the patient to develop coping strategies can be key in helping improve overall symptomatology and sense of well being. The patient who is working 60 hours per week in a job that he or she truly does not enjoy needs to have the courage to look at the situation and consider it as part of the overall clinical "problem." Likewise, pressure points in one's family relations, economic situation, or other psychosocial variables need to be evaluated as part of the overall treatment of IBS. Most patients can accomplish this simply by recognizing these stressors and promoting positive life changes. Some patients may benefit from counseling or psychotherapy to help them work through this process.32 Likewise, patients who have significant severe psychosocial issues, such as a history of being physically or sexually abused, or patients with diagnosable psychiatric disorders accompanying their IBS, such as depression or severe anxiety disorders like panic disorder may benefit from psychotherapy. 33 The literature supporting the efficacy of behavioral approaches in this setting is quite positive. 34 Cognitive behavioral therapy, hypnosis, and relaxation therapy have all been effectively applied to the treatment of IBS, particularly in patients with severe symptomatology. 35,36,37
The issue of diet is more convoluted. Recent studies suggest that although individual patients may have "food triggers," there is no definitive evidence that suggests that food allergies or food intolerance to large food groups, such as meats or grains, are associated with either the development or the exacerbation of IBS symptoms. Patients should be encouraged to eat a healthy diet and to avoid only foods that they know specifically can trigger symptoms. Extensive testing, such as radioallergosorbent RAST or immunoglobulin E IgE or IgA testing, for gut-based food allergies is usually nonproductive in IBS patients."
http://www.medscape.com/viewarticle/463481_4
There is a lot more to this article and a great section on diagnoses.
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My website on IBS is www.ibshealth.com
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