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 affect 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 system. 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 worldwide.

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

CRFinduced 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 volunteer (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.