Why Zebras Don't Get Ulcers: The Acclaimed Guide to Stress, Stress-Related Diseases, and Coping

by Robert M. Sapolsky

(It is not clear why lots of stress-induced contractions of the colon can lead to constipation. As a possible explanation, the stress-induced contractions in the colon are directional, which is to say, they push the contents of the colon from the small intestinal end to the anus. And if they do that a lot, things get accelerated, resulting in diarrhea. However, in one plausible scenario, with long enough periods of stress, the contractions begin to get disorganized, lose their directionality, so that not much of anything moves toward the anus).

So people with IBS are disproportionately likely to be experiencing a lot of stressors. But in addition, IBS can be a disorder of too much ...

stress can blunt the sort of pain you feel in your skin and skeletal muscles while increasing the sensitivity of internal organs like the intestines to pain (something called “visceral” pain).

As we saw earlier, the sympathetic nervous system is responsible for the increased large intestinal contractions during stress. And as would be expected, people with IBS have overactive sympathetic nervous systems

And just to make the whole process worse, the pain of that gassy, distended, hypersensitive gut can stimulate sympathetic activation even further, making for a vicious circle.

So ongoing stress can be closely associated with IBS. Interestingly, traumatic stress early in life (abuse, for example) greatly in...

most studies are retrospective (they look at people who already have IBS and ask them to identify stressors in their past) rather than prospective (in which people who do not have a disease are followed to see if stress predicts who is going to get it). The problem here is that people are terribly inaccurate at recalling information about stressors and symptoms that are more than a few months old,

Moreover, as was mentioned above, the sorts of stressors that can increase the risk of IBS can occur many years prior to the emergence of symptoms, making the link hard to detect even in prospective studies.

An ulcer is a hole in the wall of an organ, and ulcers originating in the stomach or in the organs immediately bordering it are termed peptic ulcers. The ones within the stomach are called gastric ulcers; those a bit higher up than the stomach are esophageal, and those at the border of the stomach and the intestine are duodenal (the most common of peptic ulcers).

stomach ulcers have emerged as the disorder most recognized by the lay public as a stress-related disease:

Helicobacter pylori turns out to be able to live in the acidic stomach environment, protecting itself by having a structure that is particularly acid-resistant and by wrapping itself in a coat of protective bicarbonate. And this bacterium probably has a lot to do with 85 to 100 percent of ulcers in Western populations (as well as with stomach cancer).

Nearly 100 percent of people in the developing world are infected with Helicobacter—it is probably the most common chronic bacterial infection in humans. The bacteria infect cells in the lining of the stomach, causing gastritis, which somehow compromises the ability of those cells lining the duodenum to defend themselves against stomach acids. Boom, under the right conditions, you’ve got a hole in that duodenal wall.

up to 15 percent of duodenal ulcers form in people who aren’t infected with Helicobacter, or with any other known bacterium related to it. More damning, only about 10 percent of the people infected with the bacteria get ulcers.

It’s got to be Helicobacter pylori plus something else. Sometimes, the something else is a lifestyle risk factor—alcohol, smoking, skipping breakfast habitually, taking a lot of nonsteroidal anti-inflammatory drugs like aspirin. Maybe the something else is a genetic tendency to secrete a lot of acid or to make only minimal amounts of mucus to protect stomach linings from the acid.

But one of the additional factor...

duodenal ulceration is more likely to occur in people who are anxious, depressed, or undergoing severe life stressors (imp...

An analysis of the entire literature shows that somewhere between 30 and 65 percent of peptic ulcers have psychosocial factors (i.e., stress) involved. The problem is that stress causes people to drink and smoke more. So maybe stress increases the risk of an ulcer merely by increasing the incidence of those lifestyle risk factors. But no—after you control for th...

Helicobacter is relevant to ulcers, but it is only in the context of its interactions with these oth...

Along comes a stressful period that lasts months. Your body cuts down on its acid secretion—there are now frequent times when digestion is being inhibited. During this period, your stomach essentially decides to save itself some energy by cutting corners. It cuts back a bit on the constant thickening of the stomach walls, undersecretes mucus and bicarbonate, and pockets the difference. Why not? There isn’t much acid around during this stressful period anyway.

End of stressful period; you decide to celebrate by eating a large chocolate cake inscribed for the occasion, stimulate your parasympathetic nervous system, start secreting hydrochloric acid, and…your defenses are down. The walls have thinned, there isn’t as thick a protective mucous layer as there used to be, the bicarbonate is overwhelmed. A couple of repeated cycles of stress and rebound with a bacterial infection that is already compromising the defenses and you’ve got an ulcer.

ulcers are not formed so much during the stressor as during the recovery. This idea predicts that several periods of transient stress should be more ulcerative than one long, continuous period, and animal experiments have generally shown this to be the case.

Note how similar this scenario is to the acid-rebound mechanism: in both cases, the damage occurs not during the period of stress but in its aftermath, and not so much because stress increases the size of an insult (for example, the amount of acid secreted or the amount of oxygen radicals produced), but because, during the stressful emergency, the gut scrimps on defenses against such insults.

Immune Suppression Helicobacter as a bacterium triggers your immune system into trying to defend against it.* As you will soon learn in sickening detail (chapter 8), chronic stress suppresses immunity, and in this scenario, lowered immune defenses equals more Helicobacters reproducing happily.

In this scenario, stress does not so much cause ulcers to form as impair your body’s ability to catch them early and repair them.

Calcium must be obtained to build bones, amino acids are needed for all that protein synthesis, fatty acids build cell walls—and it’s glucose that pays for the building costs.

A large part of what various hormones do is to mobilize the energy and the material needed for all these civic expansion projects. Growth hormone dominates the process. Sometimes it works directly on cells in the body—for example, growth hormone helps to break down fat stores, flushing them into the circulation so they can be diverted to the growing cells.

different aspects of metabolism and physiology get programmed at different points of fetal development. If you were a first-trimester fetus during the famine, that programs you for a greater risk of heart disease, obesity, and an unhealthy cholesterol profile, whereas if you were a second- or third-trimester fetus, that programs you for a greater diabetes risk.

Fetal Origins of Adult Disease (FOAD).

do non-nutritional stressors during pregnancy also induce FOAD-like effects? The answer is, yes.

stressing a female rat in any number of ways while she is pregnant will cause lifelong changes in the physiology of her offspring.

think of the fetal body “learning” about the outside world, this time along the lines of, “How stressful is it out there?” Fetuses can monitor signals of stress from the mother, insofar as glucocorticoids readily pass through to the fetal circulation, and lots of glucocorticoids “teach” the fetus that it is indeed a stressful world out there. The result? Be ...

Prenatally stressed rats grow into adults with elevated glucocorticoid levels—depending on the study, elevated basal levels, a larger stress-response, and/or a...

Is it the glucocorticoid secretion by the stressed pregnant female that gives rise to these permanent changes in the offspring? Seemingly yes—the effect can be replicated in a number of species, including nonhuman primates, by injecting the pregnant female with high glucocorticoid levels, instead of stressing her.

A smaller but fairly solid literature shows that prenatal stress programs humans for higher glucocorticoid secretion in adulthood as well.

How about the reproductive system? An extensive literature shows that if you stress pregnant rats, you “demasculinize” the male fetuses. They are less sexually active as adults, and have less developed genitals. As we will see in the next chapter, stress decreases testosterone secretion, and it seems to do so in male fetuses as well.

Seriously stress a pregnant rat and her offspring will grow up to be anxious. Now, how do you tell if a rat is anxious? You put it in a new (and thus, by definition, scary) environment; how long does it take for it to explore? Or take advantage of the fact that rats, being nocturnal, don’t like bright lights. Take a hungry rat and put some food in the middle of a brightly lit cage; how long until the rat goes for the food? How readily can the rat learn in a novel setting, or socially interact with new rats? How much does the rat defecate in a novel setting?* Prenatally stressed rats, as adults, freeze up when around bright lights, can’t learn in novel settings, defecate like crazy.

anxiety revolves around a part of the brain called the amygdala, and prenatal stress programs the amygdala into a lifelong profile that has anxiety written all over it. The amygdala winds up with more receptors for (that is, more sensitivity to) glucocorticoids, more of a neurotransmitter that mediates anxiety, and fewer receptors for a brain chemical that reduces anxiety.

Does prenatal stress in humans make for anxious adults? It’s difficult to study this in humans, in that it is hard to find mothers who are anxious during pregnancy, or anxious while their child is growing up, but not both. So there...

Prenatally stressed rodents grow up to have fewer connections between the neurons in a key area of the brain involved in learning and memory,

Suppose you have a fetus exposed to lots of stress, say, malnutrition, and who thus programs a thrifty metabolism. Later, as an adult, she gets pregnant. She consumes normal amounts of food. Because she has that thrifty metabolism, is so good at storing away nutrients in case that fetal famine ever comes back again, her body grabs a disproportionate share of the nutrients in her bloodstream for herself. In other words, amid consuming an average amount of food, her fetus gets a less than average share of it, producing mild malnutrition. And thus programs a milder version of a thrifty metabolism. And when that fetus eventually becomes pregnant….

In other words, these FOADish tendencies can be transmitted across generations, without the benefit of genes. It’s not due to shared genes, but to shared environment, namely, the intimately shared blood supply during gestation.

So expose a fetus to lots of glucocorticoids and you are increasing its risk for obesity, hypertension, cardiovascular disease, insulin-resistant diabetes, maybe reproductive impairments, maybe anxiety, and impaired brain development.

does postnatal stress have lifelong adverse effects on development as well? Of course it can. To begin, what’s the most stressful thing that could happen to an infant rat? Being deprived of its mother (while still receiving adequate nutrition).

How about something more subtle? What if your rat mom is around but is simply inattentive? Michael Meaney of McGill University has looked at the lifelong consequences for rats of having had a highly attentive or highly inattentive mother. What counts as attentiveness? Grooming and licking. Infants whose mothers groomed and licked the least produced kids who were milder versions of rats who were maternally deprived as infants, with elevated glucocorticoid levels.

What are the consequences of childhood stress for disease vulnerability during adulthood in humans? This has been studied only minimally, which is not surprising, given how difficult such studies are. A number of studies, mentioned earlier, show that loss of a parent to death during childhood increases the lifelong risk of depression.

early trauma increases the risk of irritable bowel syndrome in adulthood, and similar animal studies show that early stress produces large intestines that contract to abnormal extents in response to stress.

the longer the child spent in the orphanage, the higher the resting glucocorticoid levels.

Similarly, children who have been abused have elevated glucocorticoid levels, and decreased size and activity in the most highly evolved part of the brain, the frontal cortex.

Growth hormone is secreted by the pituitary gland, which in turn is regulated by the hypothalamus in the brain (see chapter 2). The hypothalamus controls the release of growth hormone through the secretion of a stimulatory hormone and an inhibitory one, and it looks as if stress dwarfism involves too much release of the inhibitory hormone. Stress-induced overactivity of the sympathetic nervous system may play some role in this. Furthermore, the body becomes less responsive to what little growth hormone is actually secreted. Therefore, even administering synthetic growth hormone doesn’t necessarily solve the growth problem.

Kids with stress dwarfism also have gastrointestinal problems, in that they’re impaired at absorbing nutrients from their intestines. This is probably because of the enhanced activity of their sympathetic nervous systems.