I’ve been meaning to write this post for a while, but I’ve been putting it off until we approached the summer here in the Northern Hemisphere. What prompted this article was a series of email exchanges this past winter (his summer) with a young man living in Sydney, Australia.
Like many people who write me, it can often be difficult trying to determine what is causing their gastrointestinal problems. I always counsel people to get a full workup from a qualified medical professional. While this may eventually result in a diagnosis of irritable bowel syndrome (translation: as a doctor I have no idea why you have these symptoms), at least more serious diseases are ruled out.
After assuring me that he had undergone extensive testing, all of which came back negative, I inquired about his diet. He told me he was eating “Paleo,” but ate lots of non-gluten starches like tubers to fuel his athletic activity, which is a very smart thing to do. Trying to exercise when glycogen stores are depleted is no fun.
After a few more back and forth emails, he informed me that his problems seemed worse in the summer than in the winter. I found this a bit odd so I asked him to elaborate on his athletic activities.
He told me he was an avid runner and bicyclist, especially when summer came around. I responded that this was probably a big part of his problem, although I also suspected preexisting colon dysbiosis for reasons I won’t go into here.
Gastrointestinal distress is a very common symptom during athletic training and competition. Diarrhea, cramping, vomiting, nausea and stomach pain are typical in those who train hard. Several studies have documented these effects. (1) (2) Today I’ll cover why this is so.
Prolonged exercise increases core body temperature. As core temperatures approach 39 C (102 F), temperatures along the intestinal tract can reach 41 C (106 F) or higher and lead to damage of the epithelial layer lining the digestive tract.
During intense exercise, blood is redirected away from arteries feeding the gastrointestinal tract and kidneys and shuttled to working muscles and the skin to dissipate heat. This diversion of blood flow away from the intestinal tract explains the elevated temperatures in this area.
Intestinal temperatures over 40 C (104 F) have been shown to damage intestinal cells, shrink intestinal villi and are capable of causing massive bleeding. (3) (4) The increase in intestinal permeability causes translocation of lipopolysaccharides (LPS) from gram-negative gut pathogens first to the liver, and if severe enough, to systemic circulation.
This in turn triggers an immune response that results in the release of inflammatory cytokines like tumor necrosis factor alpha (TNF-α), interferon alpha (IFN-α) and interleukin 6 (IL-6).
The increase of TNF-α along the digestive tract will reduce the absorption of water and cause diarrhea. These inflammatory cytokines have also been positively associated with nausea, vomiting and stomach cramping among endurance athletes during competitive events. (5) Intestinal injury can occur in as little as ten minutes of high-intensity exercise, which is defined as exercising at 70% of maximal oxygen uptake (VO2).
Disassembly of intestinal tight junction proteins is thought to occur due to the rapid breakdown of adenosine triphosphate (ATP) to adenosine monophophate (AMP) in intestinal cells. This causes a release of hydrogen peroxide, a potent free radical and disruptor of intestinal tight junction proteins.
This series of events explains a lot about observed health outcomes in those who consistently engage in high levels of physical exercise. As you recall, endotoxemia always increases cortisol secretion by its stimulation of the hypothalamic-pituitary-adrenal (HPA) axis.
Increase in cytokine secretion, especially IL-6, results in a number of hormonal and immune consequences that are all too common in endurance athletes. These include:
- elevated resting cortisol levels (6)
- shifting of immune responses to favor TH2 immunity over TH1 immunity
- depressed immune function
- increases in prolactin and growth hormone secretion
- inhibition of the hypothalamic-pituitary-gonadal axis
- depressed reproductive function in both men and women
- lower testosterone levels in men
- infrequent or absent menstruation in women before the age of menopause
- increased risk of developing osteopenia and osteoporosis
- delayed puberty/menarche in the overly-active young
- increased risk of coronary disease
- low serum T3 thyroid hormone and increased reverse T3, i.e. euthyroid sick syndrome.
Clearly, there is a dark side to overdoing exercise that few care to mention or acknowledge. Kinda hard to sell CrossFit memberships, gym equipment or athletic gear if you bring up these exercise-related side-effects.
This cascade of events, however, is not solely mediated by exercise intensity. Another important factor is ambient temperature.
A recent study out of Singapore sought to determine how ambient temperature affected both intestinal permeability and endotoxemia during strenuous exercise. (7)
Fifteen college students were recruited for this trial. The researchers subjected each subject to a treadmill test to determine their maximum volume of oxygen uptake (VO2max) and calculate their 70% VO2max rate for the duration of the study.
Participants were familiarized with the experimental protocol by running 45 minutes on a treadmill at 70% VO2max in a controlled climate chamber set to 33 degrees Celsius (91.4 F) with a relative humidity of 50%.
Having visited Singapore in the past, this would be a cool day for these folks as relative humidity in that city-state typically hovers between 80% to 90%.
About a week later, all subjects underwent two separate treadmill trials. One in the same hot environment as above, and the other at a cooler 25 degrees Celsius (77 F) with a relative humidity of 60%. Each run lasted an hour.
After both treadmill tests, all subjects rested and had their blood drawn three times over the course of five hours to measure plasma lipopolysaccharide concentrations and levels of the tight junction protein claudin-3 (CLDN3), which served as a proxy for increased intestinal permeability. During the run, core body temperatures were monitored by a sensor the participants had swallowed the night before.
Out of the fifteen participants, one wussed out and failed to complete the two 60-minute runs. No mention as to why is noted in the research paper, although sheer boredom may have had something to do with it.
Of the remaining fourteen participants, blood samples from four were unusable (due to lysis) leaving just the blood samples of ten participants to be analyzed. This is an admittedly small sample, but still revealing nonetheless.
Here we see depicted core body temperatures and heart rate of all participants during both phases of the treadmill run. Circles represent the hot environment and squares the cool one.
At 30 minutes, core body temperatures begin to diverge and escalate in those running in the hot room. No surprise here. Heart rate was also higher when the test was conducted in the hot room.
This graphs the intestinal tight junction protein claudin-3. Levels were higher in the hot phase of the trial right after exercise, decreasing in relation to the cool phase at hour two and normalizing after 5 hours.
Now, while increased intestinal permeability occurred during both phases of the trial, these changes in gut-barrier function could not wholly account for the increases seen in LPS concentrations during the hot treadmill run. Instead, what these researchers found was that these participants had a harder time clearing endotoxins. This is the opposite of what usually occurs in highly trained athletes where aerobic fitness is negatively associated with endotoxemia. Why would this be the case?
These scientists speculate that it may be because trained athletes are subjected to frequent exposure of sub lethal doses of LPSs during intense exercise. This, in turn, enhances the clearance of LPSs from the blood by increasing anti-LPS antibodies. In other words, hormesis writ large.
Now another reason this may be so is due to the state of liver health. A trained athlete is not likely to have a liver shot through with gobs of fat, unlike a sedentary individual.
Now there are exceptions to everything, of course. I don’t care how athletic you are, if you have a habit of binge drinking, have hepatitis,or suffer from gut dysbiosis, your liver is going to be at a disadvantage when clearing LPSs. Nonetheless, being physically fit is going to provide you a better chance of clearing these toxins from circulation than being a couch potato.
However, it’s still the case that many fit athletes like our Australian friend have GI trouble when intensely exercising. Limiting endurance exercise when the weather is hot is certainly an option to consider. Unfortunately, many competitive events are conducted during the summer months so this may not be an option for those who wish to participate.
There is research centered around increasing heat shock protein (HSP) levels in athletes to lessen the effects of exercise-induced endotoxemia. HSPs are intracellular molecular complexes that aid in the synthesis of proteins and cell maintenance.
One HSP in particular, HSP70, prevents the breakdown of the tight junction protein occludin. It also protects intestinal cells from hydrogen peroxide and damage caused by low cellular oxygen.
Several agents have been tested to increase HSP70 levels, but with mixed results. Cow milk colostrum was shown to up-regulate HSP70 in one study. (8) However, another study found that colostrum actually increased intestinal permeability (9). That said, dairy proteins have been shown to increase gut-barrier function as I wrote here.
Zinc supplementation has shown promise in rat studies. (10) Zinc has also been proven to prevent increased intestinal permeability after the ingestion of nonsteroidal anti-inflammatory drugs (NSAIDs). However, it’s still unclear if this effect is mediated by increases in HSP70 or something else.
Glutamine amino-acid supplementation in rats has been shown to increase the expression of HSP70 and reduce intestinal permeability. (11) Glutamine has been used for years to treat IBS and IBD and is certainly an option to consider for those who exercise at a high intensity.
We all know that beneficial gut flora maintains intestinal tight junctions. What we don’t know, however, is whether supplementing with either probiotics and/or prebiotics can maintain gut-barrier function during strenuous exercise. There are as yet no published studies that I’m aware of testing this hypothesis. Nevertheless, I suspect doing so would help and recommended to my Australian pen pal that he begin adding both probiotics and prebiotics to his daily routine.
Now that I’ve talked about some agents that may decrease intestinal permeability in athletes, I want to talk about some that increase permeability, and are best avoided when engaging in intense exercise.
Quercetin, a plant-derived flavonoid, has been shown to block increases in HSP70. (12) Apart from being found in quercetin supplements, foods high in quercetin include apples, blueberries, cherries, cranberries and onions. Although an antioxidant, it is probably best to avoid supplementing with it if intense physical exercise is anticipated.
NSAIDs like ibuprofen should be avoided like the plaque. Unfortunately, many athletes live on these medications to dampen pain from exercise-related injuries. Our Australian friend made extensive use of these drugs, so I recommended he switch his pain medication.
Polyunsaturated fat (PUFA) consumption should also be minimized. Unfortunately, this is exactly opposite to the advice given by most health “experts” who have scared the population away from consuming saturated fat.
PUFAs are easily prone to oxidation when subjected to heat, hydrochloric acid and light. Eating foods high in these fats will increase intestinal permeability by promoting lipid peroxidation in intestinal cells, not to mention lipid peroxidation in liver cells under inflammatory stress.
This also holds true for omega-3 PUFAs as they are even more unsaturated than omega-6s and therefore more susceptible to oxidation. If you are physically active, saturated and monounsaturated fats are far less likely to promote endotoxemia than are PUFAs.
Fructose-heavy sport drinks are very popular among the physically active. And indeed, fructose is more efficiently converted to glycogen than is glucose, making it ideal for rapidly replenishing these stores. Unfortunately, fructose rapidly breaks down ATP to AMP resulting in elevations of hydrogen peroxide, which increases gut permeability.
Finally, I need to mention gluten-grains. Gluten increases zonulin expression, which increases intestinal permeability. In those carrying either the HLA-DQ2 or the HLA-DQ8 genetic haplotype (about 50% of the U.S. population), the expression of zonulin is prolonged after eating foods containing this protein.
While I am a big believer in carb loading to fuel athletic performance, chowing down on loads of gluten-containing food is probably not a very bright idea before, during or after intense physical exercise, assuming your goal is to lessen endotoxemia. Look to non-gluten carbs to fuel your athletic performance like rice or tubers and leave the bagels, doughnuts, beer and pizza for your clueless competitors.
Finally, it goes without saying that exercising outdoors when summer temperatures are off the charts is a recipe for disaster. Stories of heat stroke death are a common feature in newspapers and television newscasts every summer here in the United States. Sadly, many of these victims are young. There is a good reason public health authorities warn against strenuous exercise when outdoor temperatures approach those of hell.
Yet because of a prevalent belief that exercise is always beneficial no matter what, many fail to heed these warnings. I can’t tell you how many times I’ve seen students from the local high school running around my neighborhood when temperatures are north of 100 degrees Fahrenheit. If those were my kids, I’d tell the coach where he could shove his training techniques.
Returning to our Australian friend, he’s still happily exercising down under, but with none of the GI problems of the past. Avoiding NSAIDs, resolving his gut dysbiosis and sensibly restricting his outdoor athletic activities when temperatures soar, have helped resolve his intestinal issues. Here’s hoping the same for any of you suffering from similar complaints.