Heat as an inducer of heat stroke
The classic model of heat stroke was centered on the notion that once a critical core temperature is reached that is damaging to cells, the hypothalamus decreases the neural drive to muscles. This decreases heat production and, therefore, core temperature. So, in essence, there is a safety mechanism built within the hypothalamus that prevents core temperature from exceeding a certain point that could be detrimental to the cells of the body. While this is true, there are a couple of issues that contradict this model. First, people often experience heat stroke at workloads they have previously tolerated, both in terms of performance and heat stress. Second, core temperature doesn't seem to share a relationship with the severity of symptoms experienced once heat stroke is triggered, but there is a strong relationship between symptom severity and circulating inflammatory cytokines(2).The immune system as an inducer of heat stroke
These factors have caused researchers to propose a dual model of heat stroke that has a heat induced pathway and an immune system induced pathway. There doesn't appear to be a specific core temperature at which heat stroke is induced between individuals or within the same individual, and many of the clinical manifestations of heat stroke are identical to those found in sepsis, a whole body inflammatory response to infection. It is believed that endotoxemia, the leakage of lipopolysaccharide(LPS) from the gut in to the circulation due to increased intestinal permeability, drives this inflammatory process. This has led scientists to develop an endotoxemia model of heat stroke where hyperthermia initiates heat stroke by increasing intestinal permeability, but endotoxemia drives the clinical progression. It is believed that this model of heat stroke is the primary cause as the vast majority of people who experience heat stroke are not reaching the critical core temperature that is damaging to cells(2).When an endurance athlete competes or performs an intense training run, blood is diverted from the gastrointestinal tract and toward the muscles to power the activity and toward the skin to dissipate heat via sweat. In addition to these changes in circulation, the immune system is also suppressed. This combination of physiological changes, in addition to mechanical jarring of the area, increases intestinal permeability and causes LPS to leak in to the circulation(2, 3, 4, 5). These issues are exacerbated when runs are prolonged, in the heat, and under conditions of dehydration(3). Since LPS drives the immune system nuts, and the immune system is suppressed, it is believed that pushing through causes LPS levels to increase further, and sepsis occurs.
The immune system and chronic endurance exercise
This may sound like a whole bunch of doom and gloom for people undertaking endurance exercise, but the body adapts. A chronic adaptation to long term endurance training is an increase in anti-LPS antibodies(2, 4). This means training at or above the threshold that causes LPS to leak from the GI tract in to the circulation causes the body to deal with LPS better. However, this brings up a couple of interesting questions. Why would a well trained, experienced runner experience heat stroke during a run of tolerable intensity? Also, how can some trained athletes tolerate levels of heat that induce heat stroke in others?Internal vs. external environmental conditions
Obviously external environmental conditions, especially in extremely hot environments, could be at play, but what about internal environmental conditions? In other words, maybe it isn't the state of the environment that is causing the problem, maybe it's the physiological state of the athlete. One potential contributing factor is obvious; training during an infection. The trio of an existing infection, an acutely depressed immune system, and LPS leaking from the gut in to the circulation could negatively impact heat tolerance causing once manageable workloads to cause unmanageable levels of LPS. There is data to support the evidence that immune disturbances can lead to transient heat intolerance(2). Furthermore, many animal studies show that heat tolerance is improved and heat stroke can be averted up to a point when animals are given therapies to help deal with LPS. Animals given therapy to bolster LPS clearance are better able to tolerate heat and do not succumb to heat stroke until temperatures exceed 43.8C, which is considered the critical temperature for cell damage(2). In a small study, all monkeys who were given anti-LPS antibodies were able to survive at 43.5C but only 16% of control monkeys lived as the rest succumbed to heat stroke(6). When core temperature was raised to 43.8C, all of the monkeys died but the treated monkeys lived 5 times longer than the controls.Gut health as a contributing factor
Another avenue worth exploring is the health of the gut. Many factors affect intestinal permeability under what would be considered resting conditions including the use of anti-inflammatory drugs, antibiotic use, and diet. A recent study looking at the use of ibuprofen found that intestinal permeability after exercise was greater when an athlete took ibuprofen than when they did not(7). This is important because many athletes use anti-inflammatories as a training tool to help reduce inflammation, and this study shows that there may be drawbacks to using this approach.Antibiotic use is known to change the ecology of the gut by modulating gut bacteria. Changes in gut bacteria can lead to alterations in intestinal permeability as many of the byproducts of bacterial fermentation are known to help maintain intestinal barrier integrity. Elimination of a keystone species may impair an athlete's ability to maintain intestinal barrier integrity and lead to greater levels of LPS during exercise and, thus, decreased heat tolerance. This is not to say you shouldn't take antibiotics, but you should only take them when needed and maintain a diet high in fiber when doing so because it will support the bacteria that are responsible for maintaining intestinal barrier integrity.
Diet as a preventative therapy
This brings us to diet, one of the most important "therapies" a person can use to maintain optimal intestinal barrier integrity. A proper diet helps maintain intestinal barrier integrity by optimizing gut bacteria, providing nutrients that gut bacteria can use to uphold the intestinal barrier, and limiting the types of food that can increase intestinal permeability. Under optimal conditions, the intestinal barrier is maintained by tight junctions, areas between cells that don't allow contents of the intestine, including LPS, in to the bloodstream. These tight junctions can be dissolved under certain conditions, and the fermentation of soluble fiber and resistant starches by resident bacteria generate short-chain fatty acids that reseal these tight junctions.Certain foods can increase intestinal permeability, particularly ones that contain gluten. Gluten causes the release of zonulin, a protein that causes the tight junctions between cells of the intestine to dissolve. All humans secrete zonulin in response to gluten, but most people reseal the tight junctions rapidly, before significant levels of LPS enter the circulation. People with Celiac disease or a sensitivity to gluten have a delayed response which allows more LPS to enter the circulation and increase inflammation. Researchers believe that this delayed ability to reseal the tight junctions is due to local changes in gut bacteria.
Despite the mass hysteria surrounding gluten, I don't feel that everyone should avoid gluten. In limited quantities in an otherwise vegetable/fiber heavy diet, gluten is likely harmless for most people. However, there is nothing nutritionally novel about gluten that makes it a necessary part of your diet, and most people are likely overeating it while undereating higher quality foods like vegetables.
Chronic alcohol intake is another thing that can increase intestinal permeability and cause damage to the cells of the intestine both directly and as a result of bacterial fermentation(8). The concern here isn't that people are getting loaded before their runs and this impacts their ability to regulate core temperature. The primary concern is that people who chronically ingest alcoholic beverages, particularly beer, may be changing their gut ecology over time in a way that may reduce their ability to reseal tight junctions after distance runs.