Stress and the Gut: Mind Over Matter Part 2

STRESS AND THE GUT: MIND OVER MATTER? (Part 2)
(PART 2 OF 2 – Continued)

In another experiment, GERD patients were stressed by being forced to do mental arithmetic tasks and compete in a difficult computer video game under time pressure. Although participants reported increased subjective ratings of anxiety and heartburn symptoms during these stressful challenges, there was no corresponding change in esophageal acid concentrations. To evaluate the effect of stress reduction, patients were taught a progressive muscular relaxation technique during which they alternately tensed and relaxed 16 muscle groups in sequence. Those who practiced this regularly reported lower subjective ratings of anxiety and acid reflux symptoms. It was noted that during relaxation there was also a reduction in the concentration of acid in the esophagus. So what’s going on? How does this help to explain the relationship between stress, heartburn and GERD?

The authors of the study believe that stress causes an increase in esophageal sensitivity to smaller amounts of acid in certain patients. Support for this comes from studies in their laboratory in symptoms when acid is infused into the esophagus of GERD patients who were simultaneously subjected to psychological stress. Preliminary results confirm that the threshold for experiencing symptoms is markedly lowered during stress and that this increased sensitivity to acid occurs regardless of whether or not there is any evidence of esophageal inflammation. The mechanism by which stress causes this hypersensitivity to acid is not clear. Most of the GERD patients that were studied seemed to be psychologically similar to controls without evidence of esophageal inflammation. However, those who tended to be anxious and were exposed to sustained periods of stress during their daily activities, were much more likely to notice a worsening of their symptoms at such times. Heartburn patients who did not have significant esophageal inflammation also had a greater tendency to exhibit symptoms of anxiety and hysteria. What may be equally important is that both groups had less social support from family and friends and were deprived of the powerful stress reduction benefits that this provides.

There has been heightened interest in reflux disease because of a study showing that GERD workers cost their employers an annual average of $3,355 due to medical care, prescription drugs and other expenses such as a 10 percent reduction in productivity. Decreased productivity alone is estimated to cost U.S. employers up to $75 billion a year. As indicated previously, you might have GERD if you have heartburn two or more days a week for at least three months. However, the diagnosis can only be confirmed by endoscopic examination of the esophagus and a biopsy of the affected area to rule out other pathology. Many patients in whom the diagnosis is established have no heartburn symptoms but are arbitrarily put on proton pump inhibitors for a year to treat or prevent Barrett’s esophagus, a precancerous but asymptomatic lesion. Unfortunately, no drugs have been shown to reduce the likelihood of cancer and this complication is uncommon, if not rare. One report indicated ”a physician would have to follow almost 50 patients with Barrett’s esophagus for 10 years to have a chance of finding a single cancer.” Surgery can eradicate Barrett’s, the most popular being a procedure that involves taking the top of the stomach and wrapping it around the bottom of the esophagus. This creates a one-way valve so that food can go down but acid can’t back up. Since there are adverse side effects as well as complications that occur with all abdominal surgery, this is likely to be replaced by the new outpatient ”Halo 360” procedure. It consists of inserting an expandable balloon device into the esophagus and inflating it at the site of the lesion. Short bursts of radiofrequency energy are then delivered that burn away the top diseased layer of the esophagus, allowing healthy tissue to grow back. The procedure takes 15 to 25 minutes, is effective in eradicating Barrett’s in 90 percent of cases with minimal discomfort, and patients can return home within two hours.

Gastritis refers to inflammation of the lining of the stomach that is usually manifested by a burning sensation in the upper abdomen and occasionally bloating, belching or nausea. It can be caused by the regular use of aspirin and other pain relief medications that reduce levels of prostaglandin, a chemical that normally preserves the protective lining of the stomach. Gastritis can also result from infection with H. Pylori, the bacterium associated with stomach and duodenal ulcers. The important role of stress was emphasized by Hans Selye over 70 years ago, in his initial description of what he called ”The Alarm Reaction”. He had observed that when experimental animals were subjected to severe stress, the first evidence of changes in the body were inflammation of the lining of the stomach, atrophy of the thymus and lymphatic tissues, and enlargement of the adrenal glands. These three responses occurred whether the animals were exposed to frigid temperatures, excessive heat, shining bright lights in their eyes while the eyelids were sewn back, prolonged exercise by being forced to keep swimming to stay alive, unbearable frustration, painful stimuli and other forms of torture that researchers previously used that would not be permitted today. While excesses of temperature might cause specific damage such as frostbite or a burn, these and other potent stressors all produced the same pathological triad of superficial stomach inflammation with tiny ulcerations, thymus and lymphoid tissue atrophy and enlarged adrenals.

This led to Selye’s definition of stress as ”the nonspecific response of the body to any demand for change”. This was in sharp contrast to the prevailing concept that every disease had a specific cause. Tuberculosis was caused by the tubercle bacillus, anthrax by the anthrax bacillus, scurvy by a lack of vitamin C, rickets by a lack of vitamin D, etc., etc. What Selye was proposing was the opposite, namely that the identical pathology could have many different causes due to the nonspecific effects of stress. In addition to the immediate responses seen in the ”Alarm Reaction”, which Selye viewed as a call to arms of the body’s defenses, he found that when animals continued to be subjected to stress, they entered a ”Stage of Resistance”, during which defense mechanisms were maximized, and subsequently a ”Stage of Exhaustion”, characterized by dwindling or disappearance of defenses and eventually death. He called this three-phased response to stress ”The General Adaptation Syndrome”. During the course of this syndrome he noted pathological changes in the gastrointestinal tract, heart, blood vessels, kidneys and other organs similar to those seen in patients with peptic ulcers, ulcerative colitis, heart attacks, hypertension, kidney damage and other diseases. He suggested that nonspecific stress could also cause these disorders in humans and referred to them as ”Diseases of Adaptation”.

The significance of the pathological changes seen in the ”Alarm Reaction” and why they only involved the stomach, lymphatic system and adrenals was not clear at the time. Decades before, Walter Cannon previously described his ”fight or flight” responses to acute stress as being due to a stimulation of sympathetic nervous system activity and an outpouring of adrenaline from the adrenal medulla. Unlike Cannon, Selye was an accomplished pathologist, and noted that the enlargement of the adrenal was due to an increase in its outer shell or cortex, rather than the medulla it surrounded. Being a superb biochemist, he knew that this is where steroid hormones were manufactured. Some of these, like cortisone, had anti-inflammatory effects while others, such as desoxycorticosterone, caused sodium and fluid retention and there were some with weak androgenic actions. Symptoms related to all of these hormones are seen in patients where there is hyperactivity of the adrenal cortex due to stimulation from a benign pituitary tumor. This is known as Cushing’s disease, since it was first described by Harvey Cushing, the father of brain surgery, who demonstrated that everything returned to normal after the tumor was removed.

Cushing also noted that increased intracranial pressure from any cause was often associated with ulcerations in the stomach, and occasionally the esophagus and duodenum, that are still referred to as Cushing ulcers. This is sometimes confused with Curling’s ulcer, an acute ulcer of the duodenum that results from the stress of severe burns and is named after Thomas Curling, the physician who described ten such patients in 1842. Both of these disorders are likely due to increased production of anti-inflammatory hormones like cortisone. When cortisone became available for the treatment of rheumatoid arthritis in 1948, the immediate response was often dramatic. However, it soon became apparent that patients on long term treatment often had GI complications, including bleeding from severe peptic ulceration, activation of previously quiescent tuberculosis, decreased resistance to other infections as well as delayed wound healing. Not much was known about the immune system when Selye described the ”Alarm Reaction”, although it is now evident that atrophy of the thymus and lymphoid tissues markedly reduces the production of the T and B cells they manufacture that allow us to resist bacteria, viruses or any perceived foreign intruder. This also helps to explain the role of stress in autoimmune disorders like rheumatoid arthritis, lupus and multiple sclerosis, in which the immune system attacks normal tissue, because it is somehow interpreted as being foreign.

As emphasized in a prior Newsletter, it is not generally recognized that in addition to the brain in our skull, we have a ”second brain” in the gut, and that the two are in constant communication. The reason for this is that during early fetal development, both the brain and the gut (esophagus, stomach, small intestine and colon) developed from the same clump of embryonic tissue. This subsequently divided with one section growing into the central nervous system (brain and cranial nerves) and the other into an enteric nervous system that contains a ”gut brain”. Later on, these two brains then became connected via the massive vagus nerve. Nearly every brain-regulating hormone and neurotransmitter found in the brain has also been found in this ”gut brain”, which also has more nerve cells than the total of all nerves connecting the rest of your body to the brain. Because of this, the state of your gut has a profound influence on your brain, as well as vice versa. That’s why you have ”gut feelings” about something that may differ from rational appraisal and why you feel ”butterflies in the stomach” if you are very anxious or nervous. This two way conversation helps to explain why the feeling of a full stomach stops your appetite and why stress can cause GI symptoms ranging from diarrhea and constipation as well as its role in functional disorders like irritable bowel syndrome, as well as ulcerative colitis, terminal ileitis and other inflammatory bowel diseases.

This is also why many drugs used to treat gastrointestinal diseases were originally designed to act on the brain, like Imitrex for migraine and clonidine, which is prescribed for various psychiatric disorders. Antidepressants like Prozac that increase brain serotonin to relieve depression can cause abdominal cramps due to gut spasms. Both Lotronex, which is derived from an anti-anxiety medication, and Zelnorm, another drug used to treat irritable bowel syndrome, work by effects on serotonin in the gut. Scientists have discovered that some Alzheimer’s and Parkinson’s patients accumulate the same type of tissue damage in their bowels as they do in their skulls, raising the possibility that these disorders might someday be diagnosed by routine rectal biopsy.

The ability of stress to produce peptic ulcers was unequivocally demonstrated by Stewart Wolf in his study of Tom, which was featured in a 1943 Time magazine cover story. Tom was a patient with an esophagogastric fistula that allowed direct visualization of the stomach, so that it was possible to see and photograph changes in secretory and motility patterns that correlated with his emotional status. On one occasion, when Tom was extremely upset, Stewart painstakingly documented the progressive development of a peptic ulcer due to increased gastric secretions and diminished blood flow to the stomach that also damaged its lining. As Walter Cannon commented, ”The functions of the stomach have never been investigated with the detailed care, the skill and ingenuity displayed in the research on Tom’s stomach”. However, this and other supportive studies confirming the relationship between stress and ulcers seemed to go out the window when it was discovered that the vast majority of ulcer patients had an H. pylori infection and that antibiotics effectively eradicated the ulcer. Although this seemed to be solid proof that ulcers were due to H. pylori infection, as emphasized in a previous Newsletter devoted to this, at least half the world’s population harbors H. pylori by the age of 10. The organism lives only in the gut, where it lies dormant and usually causes no symptoms, since only a tiny fraction of those that have it develop ulcers.

What seems most likely is that stress induced anti-inflammatory hormones like cortisone impair defense mechanisms that normally prevent ulcers. As noted previously, peptic ulcers and activation of asymptomatic tuberculosis is not uncommon in patients who take cortisone to treat chronic conditions like rheumatoid arthritis. A similar situation is seen with other quiescent microorganisms like herpes simplex virus, which causes recurrent cold sores during periods of stress. Finally, those who are dubious about the effect of stress on the gut, should be aware that the stomach might be a more sensitive barometer than the heart in some instances. Standard lie detector polygraph tests utilize changes in the electrocardiogram (ECG) and blood pressure to help in reaching an evaluation. However, a recent comparison study revealed that an electrogastrogram (EGG), which records changes in stomach motility and contractions, might be a superior indicator to detect lying. As the senior author noted, ”We concluded that the addition of the EGG to standard polygraph methods has clear value in improving the accuracy of current lie detectors. The communication between the big brain and the little brain in the stomach can be complex and merits further study.”

Stress, Irritable Bowel Syndrome And Inflammatory Bowel Disease

Irritable Bowel Syndrome (IBS) is characterized by chronic abdominal pain, discomfort, and irregular bowel movements. Researchers believe that this is due to the fact that nerves in the intestinal wall do not react normally to food and gas passing by, causing muscles in the colon contract erratically. As a result, food travels too slowly or too rapidly, causing constipation or diarrhea. IBS patients often experience both these symptoms regularly, in addition to abdominal pain, gas and bloating. The diagnosis requires a year’s history of at least 12 weeks (not necessarily consecutive) of pain or abdominal discomfort that is relieved with defecation and/or is associated with a change in stool frequency or form. However, the diagnosis is difficult to make since unlike other gastrointestinal diseases, there are no structural changes. This, as well as the fact that symptoms are usually related to stress, has led many doctors to dismiss complaints as being psychosomatic in origin. In addition, up to 40 percent of patients have increased anxiety levels similar to those reported in other presumed ”functional” disorders like fibromyalgia and chronic fatigue syndrome. IBS has also become a wastebasket diagnosis for anyone with unexplained abdominal distress or significant change in bowel habit, which is why it is the most common disorder reported by gastroenterologists.

IBS is estimated to affect one in five Americans, including 2.5 million children. The disorder tends to run in families since three out of four kids with IBS have at least one parent or sibling with gastrointestinal problems. Symptoms can start as early as five years of age but more often begin around the age of 10. Although they may temporarily disappear during early adolescence, there is usually a recurrence a few years later and the condition becomes chronic with intermittent periods of relief that vary in duration. IBS may follow an infection, suggesting that the immune system may play a role. The disorder can be managed but not cured by adding fiber to the diet and avoiding certain triggers. Lotronex was hailed as a breakthrough drug when it was released in 1999 but had to be withdrawn less than a year later because of severe side effects and several possible deaths. Zelnorm, another IBS drug introduced in 2002 with a massive publicity blitz, was also banned earlier this year for similar reasons. Because of numerous complaints, the FDA reversed itself and both drugs have since been reapproved for severe diarrhea or constipation not responsive to other medications, but with strict warnings and restrictions. Unfortunately, Lotronex worsens constipation and Zelnorm causes diarrhea. Most IBS patients suffer from both complaints, so that these drugs are two-edged swords with limited benefits and significant risks. Since there is no effective treatment, the most effective way to manage IBS is to prevent attacks. Various risk factors, triggers and influences shown below emphasize the important role of stress.

How stress can affect the development and modulation of IBS symptoms. Different stressors may trigger the onset of symptoms as well as contribute to their persistence depending on genetics and other factors. (From Mayer et al. Am J Physiol Gastrointest Liver Physiol 280: G519-G524, 2001)

For all these reasons, stress reduction approaches should be instituted in the management of all IBS patients. Options include various meditative and progressive muscular relaxation procedures, regular exercise (walking, jogging, yoga), insuring regular sleep, providing counseling and support and avoiding foods and stressful situations that have been found to trigger attacks. It is believed that the basic problem is that the brain and autonomic nervous system respond excessively or erratically to normal gastrointestinal sensations. A large NIH study is currently in progress to test this hypothesis in IBS patients with similar disease severity. Those in the first group are taught progressive muscle relaxation techniques to reduce tension and stress. A second group focuses on identifying situations and thought processes that aggravate their symptoms so they can learn not to overreact to challenges or ”castastrophize” perceived threats. They can learn not to react overly anxiously to events in their lives–or ”catastrophize”. The third group is given educational materials on the physiology of IBS to determine if an understanding of this might reduce attacks. Volunteers in all three groups receive 10 weekly sessions with a psychologist and a follow-up meeting after six months. Researchers will also use sophisticated brain imaging and other techniques to investigate feedback mechanisms between the GI tract and the brain, since some studies suggest that activation of the limbic system is associated with flare-ups.

Inflammatory bowel disease (IBD) refers to a group of disorders that include ulcerative colitis, Crohn’s disease, and bacterial infections. More then 600,000 Americans a year suffer from IBD symptoms such as abdominal pain, severe cramps, nausea, diarrhea or loose stools containing blood, pus and excess mucus. Ulcerative colitis causes ulcers in the lower part of the large intestine, often starting at the rectum, that frequently bleed. Crohn’s disease patients have similar ulcerations throughout the small intestine, especially the ileum, and although the colon can be involved, the rectum is usually spared. What causes these disorders has not been determined but it is believed that both result from exaggerated immune system responses to normal bacteria and food in the gut that are mistakenly perceived as being foreign. In an attempt to attack and destroy these presumed invaders, white blood cells accumulate in the lining of the bowel wall producing chronic inflammation, ulcerations and tissue damage.

There is little doubt that stress can aggravate and precipitate attacks of IBD. One study found a significant relationship between exacerbation of ulcerative colitis and long-term stress as rated on the Perceived Stress Questionnaire. In another, researchers studied patients with inactive ulcerative colitis and healthy controls. Both groups were told they were participating in a study to assess the relationship between their intelligence and their responses to stress. They were then given an IQ test to complete in 50 minutes that should have taken an hour or more while contrasting types of music were played into each ear. They were also reminded, at increasingly frequent intervals, to increase their effort to finish the test. Blood pressure, heart rate, and blood- and mucus-levels of inflammatory markers were measured before, during and after completing the test. While the cardiovascular responses were similar, systemic and mucosal inflammation were greater in the ulcerative colitis group as assessed by interleukin-6, tumor necrosis factor, natural killer cells, platelet activation, and other markers of increased immune system activity. Lifetime psychiatric diagnoses are associated with an increased incidence of Crohn’s disease. Further proof of the influence of the brain comes from the observation that if the spinal cord is severed above the level of T4, where nerves to the gut begin, ulcerative colitis patients have a complete remission. Similarly, large studies show that patients with spinal cord transection at this level, but not below, never develop ulcerative colitis. All of the above confirm Ren? Dubos’ assertion,

”What happens in the mind of man is always reflected in the diseases of his body.”

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Be sure and read Part 1 of this article in last week’s
Youthful Aging Health Newsletter by guest author:
Paul Rosch, M.D. , American Institute of Stress.