The role of stress in negatively impacting the gastrointestinal system has long been recognized. It doesn’t take an Einstein to note a strong correlation between acute psychological stress and the onset of gut feelings that are anything but pleasant.
I’ve written about how gut dysbiosis is capable of initiating psychological states like depression and anxiety. However, the gut-brain axis is by no means a one-way street.
Until recently, direct evidence for the effect of psychological stress on increased intestinal permeability and endotoxemia in humans has been spotty at best. Most studies testing this hypothesis have been done in animals. While it’s tempting to assume that lab rodents are nothing more than little furry human beings, there are many physiological responses that we just don’t share.
The study I’m going to cover today sought to determine whether humans also experience increased gut leakiness when under stress. To answer this, researchers evaluated gut function in a group of thirty-nine male Singaporean army recruits undergoing intense combat training. (1)
For as long as there has been armed conflict, there has been a strong association between combat and gastrointestinal distress. It can get so bad as to negatively impact the effectiveness of entire armies. Irritable bowel syndrome, ulcerative colitis and other GI disorders are very common complaints among active-duty troops, as well as many veterans who leave the service sporting an active case of gut dysbiosis.
The soldiers in today’s study underwent six weeks of combat medical response training (MRT). MRT involves learning the necessary skills to effectively stabilize and evacuate injured soldiers from the field of combat while all hell is breaking loose around you.
Training involved not only a relatively stress-free two-week classroom course, but also a highly charged combat-simulated training period lasting four weeks. This simulation involved exercises that included wearing protective gear for chemical, biological, radiological and nuclear situations. This all took place in temperatures hovering around 86 degrees Fahrenheit (30 degrees Celsius), and with an average humidity of 80%.
If you haven’t been to tropical Singapore, just think of Florida during the month of August. That gives you some idea of how miserably hot it would be donning these protective outfits for any length of time.
Now, let me just say at the outset that these extreme temperatures are a bit of a confounder. As I discussed in this post, high heat combined with physical exertion is more than capable of increasing intestinal permeability, endotoxemia, cortisol secretion and gastrointestinal distress in the absence of overt psychological stress. While I don’t believe heat alone can entirely account for the observed phenomenon in these soldiers, it does muddy the conclusions reached by this study.
With that caveat out of the way, all recruits had to be physically and psychologically healthy before inclusion in this trial. No soldier was chosen who had a medical history of significant illness, including gastrointestinal symptoms or disease. Also excluded were any participants taking any type of prescribed medication or who had previously undergone abdominal surgery.
At the conclusion of training, blood and urine samples measuring for stress, inflammatory immune markers and intestinal permeability were taken. A second set of samples was taken after a 12-day, post-combat rest period.
Questionnaires assessing anxiety, depression, stress and bowel function were also utilized. To quantify stress, the Perceived Stress Scale-10 item (PSS-10) questionnaire was used. The Hospital Anxiety and Depression (HAD) questionnaire was administered to measure these two mental states. Finally, the IBS-Symptoms Severity Score (IBS-SSS) was utilized to track changes in bowel function and intestinal symptoms.
To measure stress markers, fasting blood levels of corticotropin-releasing hormone (CRH) and serum cortisol (aka the stress hormone) were taken from each subject after an overnight fast. As you may remember from my post on endotoxemia and the hypothalamic-pituitary-adrenal (HPA) axis, CRH is released by the hypothalamus and sets in motion the hormonal cascade that results in cortisol release from the adrenals.
Levels of two inflammatory cytokines—interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-a)—were also measured. Interleukin 10 (IL-10), an anti-inflammatory cytokine, was also sampled.
Intestinal permeability was measured by the urinary excretion of various sugars after ingesting them in a prepared drink. Sucrose, aka table sugar, was used to assess permeability in the duodenum. Recall that the duodenum comprises the first 10 to 15 inches (25-38 cm) of the small intestine.
Urinary lactulose and mannitol were used to determine permeability elsewhere in the small intestine. Finally, sucralose was used to assess permeability in both the small intestine and colon. Urine samples were collected at 5 and 24 hours after sugar intake.
OK, let’s get to the results.
Of the original thirty-nine soldiers asked to participate, two were ultimately excluded because they developed a fever during the days when samples were to be drawn.
In the remaining soldiers, all showed higher anxiety, depression and stress during combat training in contrast to the twelve-day rest period:
Morning serum cortisol levels were significantly increased in the soldiers during training. Curiously, corticotropin-releasing hormone was similar during both periods. I’ll return to this anomaly in a minute.
As mentioned, none of these soldiers reported any gastrointestinal illness or symptoms at the beginning of the study. Sadly, that all changed for the worse after four weeks in the field. Twenty-six or 70% reported significant GI symptoms at the end of combat training:
Of the 70% (pie chart on the right), 13% experienced abdominal pain/discomfort, 35% suffered from abnormal bowel habits that involved constipation, diarrhea or alternations in both and 22% experienced both abdominal discomfort and altered bowel habits.
At the end of the rest period, 70% were no longer experiencing gastrointestinal distress. Unfortunately, 30% were still reporting symptoms. Whether these soldiers eventually recovered is not reported. I suspect that for some of them training may have precipitated a case of gut dysbiosis that they are dealing with to this day.
As for small bowel intestinal permeability, there was a non-significant increase in both urinary mannitol and lactulose excretion during combat training. However, in those scoring highest on the IBS symptom questionnaire, lactulose excretion was greater suggesting a higher level of small bowel intestinal permeability in this group.
There was a significant increase in urinary sucrose and sucralose excretion during combat training in all soldiers. This suggests that stress increased intestinal permeability in the duodenum and colon far more than in the jejunum and ileum of the small intestine.
The finding of increased permeability in both these areas is especially alarming. In the duodenum, site of most food digestion, the increase in intestinal permeability would be expected to elevate the risk of allergic reactions to food as the immune system responds to food molecules that should never cross the gut wall intact.
Increased gut leakiness in the duodenum also raises the risk of auto-immune disorders via molecular mimicry. Large food molecules that escape digestion, yet enter circulation, induce an antibody response. Once formed, these antibodies can attack various sites throughout the body if the amino acid structure of these tissues closely resembles the original dietary antigen.
In the colon, gut leakiness here will also precipitate an inflammatory response as bacteria from this part of the digestive tract enters the portal vein to the liver. This immune activation is especially robust in response to lipopolysaccharides derived from gram-negative gut bacteria.
Levels of both inflammatory interleukin 6 and tumor necrosis factor alpha were significantly higher during training. No surprise here as these cytokines would be raised in response to the translocation of gut bacteria to the liver and beyond. No difference in the anti-inflammatory interleukin 10 cytokine was observed for either time period.
Finally, high irritable bowel syndrome scores significantly correlated with elevated levels of stress, depression, serum cortisol and anxiety.
I already mentioned that two soldiers became too ill to complete the study. The depression of immune function caused by elevated cortisol would not only predispose a person to developing an upper respiratory infection, but also increase the risk of developing a gut infection.
The majority of our immune cells are located in the GI tract, so any lessening of immune function here would impair this defensive network from guarding against swallowed pathogens or pathogens that might migrate up from the colon and settle in the small intestine.
Apart from suppressing immune function, a major characteristic of cortisol is its catabolic effect. What I mean by this is that cortisol actively causes the breakdown of body protein (not to mention some types of fat, as well as bone) to fuel the production of glucose in the liver (gluconeogenesis). However, these amino acids are not just derived from muscle tissue. Cells and tight-junction proteins comprising the gut wall would also experience greater dissolution as cortisol levels rise.
I would also expect a diminution in the production, or active breakdown, of the protective mucus layer lining the intestinal tract. Both the breakdown of cells and mucus at the level of the gut wall would contribute to increased permeability, endotoxemia and the development of gastrointestinal infections separate and apart from the immune suppressive effects typically brought about by higher cortisol secretion.
As increased gut permeability is inherently inflammatory, it would encourage the growth of intestinal pathogens that thrive in inflamed conditions, especially those rich in lipopolysaccharides, as well as fuel an overgrowth in fungal organisms. Simultaneously, this inflamed environment would hinder the growth and health of gram-positive beneficial bacteria like lactobacillus and bifidobacteria. Given enough time and depletion of beneficial gut flora, intestinal dysbiosis results.
The development of disordered gut flora and leaky gut, would in turn, react back on the immune system to fuel further cortisol release thus perpetuating a vicious cycle.
Earlier, I alluded to the finding that corticotropin-releasing hormone levels were not observed to be significantly different between combat and non-combat periods. This suggests that the leaky gut-stimulated release of cortisol is only partly mediated by hypothalamic secretion of this hormone:
This familiar graphic is from the aforementioned post on endotoxins and the HPA axis. Here we see how gut pathogens stimulate the secretion of cortisol by two separate routes. First, by increasing the release of inflammatory cytokines like IL-6 and IL-1 that directly act upon the hypothalamus and cause it to release corticotropin-releasing hormone.
Secondly, by the synthesis of prostaglandins (PGE2s) that directly stimulate the adrenals to increase cortisol production. Prostaglandins are bioactive lipids derived from polyunsaturated fatty acid (PUFA) metabolism. They play a key role in immune response, cell division and wound healing.
It appears from the results of this study that the synthesis of these prostaglandins, most likely in the liver, plays a bigger role than CRH in stimulating adrenal secretion of cortisol. Keep in mind that class-two prostaglandins are derived from omega-6 PUFAs, which are abundantly found in vegetable oils made from corn, sunflower, cottonseed, peanut, safflower and soybean. Another good reason, apart from the copious generation of free radicals due to lipid peroxidation, to severely restrict omega 6s in your diet.
Now, before I wrap this up I do want to mention some limitations of this study. First, there was a failure to measure baseline intestinal permeability before training began. In the discussion section, the researchers mention this, but give no clear explanation as to why.
Given the tight schedule these recruits were no doubt adhering to, it may not have been feasible to get these data points without disrupting their training. Hell, I’m surprised the researchers could accomplish as much as they did given the highly regimented and bureaucratic nature of most armies.
Whatever the reason, it’s an unfortunate omission. It may very well be the case that those who went on to develop the worst intestinal symptoms were already primed by a gut dysbiosis that had yet to consciously register as GI upset. This could have accounted for the results observed.
In fact, I would hypothesize that many, if not most, people who go on to develop overt gastrointestinal disease—be it IBS, Crohn’s, ulcerative colitis or small intestinal bacterial overgrowth—are already afflicted by hidden gut dysbiosis.
Reason for believing so comes from examining the medical histories of those who are diagnosed with celiac disease. Many celiacs exhibit no gastrointestinal symptoms prior to diagnosis. That means no gas or bloating or change in bowel habits. Zero, zip, nada.
Instead, their symptoms are often psychological or manifest in other ways totally unrelated to digestive function. It is for this very reason that it takes an average of eleven years in the United States of bouncing from one doctor to the next before a correct diagnosis is made in those suffering with this autoimmune disorder.
It is not a mere coincidence that many people who go on to develop an intestinal disease often suffer from allergies, autoimmune disease, anxiety, depression, insomnia, obesity, anorexia, skin disease, etc. prior to their gastrointestinal disease diagnosis. Many of these conditions are present well before gut symptoms come to the forefront.
Certainly, that was the case for me. Up through my late 40s, I prided myself on being able to eat anything I wanted without ill effect. Well, that isn’t entirely true. I was already feeling some GI discomfort, but shrugged it off as a normal part of aging that could easily be dealt with by downing some Pepto Bismol®. However, my life up to this point was not yet held hostage to my gut.
When I look back at my recurring sinus infections, headaches, insomnia, skin outbreaks, propensity to catch a cold and intolerance to an increasing number of environmental allergens, it’s now clear that the alien that had taken up residence in my gut, and made itself acutely known when I reached 50, had been there all along. Unfortunately, no one, including the many physicians I saw during these episodes, had any inkling that these symptoms were related to a gut flora gone wonky.
So failing to screen for increased intestinal permeability in these young soldiers before the start of this study is a failure I hope is rectified in future trials of this type. Making the assumption that they had no preexisting gut dysbiosis because they reported no gastrointestinal complaints during screening is unwarranted. In science, as in life, assuming is likely to make an ass out of you and me.
Another limitation of this study was its small size. Replicating these results using a larger number of participants would make the results more convincing. And doing so under conditions not confounded by the addition of ambient heat would clarify what part of these results could be safely ascribed to psychological stress assuming diet is held constant.
A final limitation of this study is that it was restricted to men. Women are especially prone to gut dysbiosis. How their guts react to stress in comparison to men is still an unanswered question, but one of huge importance. As child bearers, stress would be expected to impact the type of gut flora they pass on to their offspring both during and after pregnancy. And as we’ve all learned, the composition of this gut flora has long-term health implications for these children.
As I wrote in this post, studies in both animals and humans have found that supplementation with prebiotics and probiotics reduces the stress response. This isn’t too surprising as both prebiotics and probiotics strengthen gut-barrier function and inhibit pathogen colonization of the digestive tract.
It would be great to see a similar study done in soldiers where one group was given both prebiotics and probiotics before and during boot camp, matched against a group that received neither. I suspect that stress-related gastrointestinal upset would be reduced in the former. However, whether doing so could entirely blunt a stress response remains to be seen.
Finally, the variability in gastrointestinal symptoms observed in these recruits no doubt has a genetic component. Nevertheless, we’re still in the dark ages as to which genes are involved. Adding to the confusion is the fact that our gut flora contains 100 times more genetic material than we do. We know that this genetic information is shared with our genome. And we also know that these organisms are capable of shaping native gene expression by turning some genes on or off. I’m afraid fully unraveling the mystery of these genetic interactions will occur long after we’ve departed this earthly plane.
The intense stress response and increased gut permeability seen in these soldiers is similar to what many people experience, albeit under far different circumstances. From the recently widowed, to the parent who just lost a child, to those undergoing a romantic breakup, to people experiencing financial hardship, to those employed in dangerous civilian occupations—stress can easily set in motion a cascade of physiological responses that can increase intestinal permeability.
The big reason sensible exercise, meditation, having a pet, being in a loving relationship or social group and getting a good night’s sleep are all good for you is because these activities and social relationships reduce stress and the risk of developing a leaky gut and chronic endotoxemia. Knowing what we know about the negative impact psychological stress has on the gut and gut flora composition in both animals and humans, it’s imperative that we find effective ways to deal with this stress as well as nurture and care for the beneficial organisms that keep the gut wall intact and us healthy.