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Role of Gastrointestinal Permeability in Exertional Heatstroke

Lambert, G Patrick

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Exercise and Sport Sciences Reviews: October 2004 - Volume 32 - Issue 4 - p 185-190
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Heatstroke is the most catastrophic of the heat-related illnesses and can be classified as either classical heatstroke or exertional heatstroke (EHS). Classical heatstroke normally affects elderly individuals or persons with preexisting illnesses and usually involves prolonged or repeated exposure to warm temperatures (e.g., heat waves). EHS is more common in younger persons engaging in strenuous activity, usually in a warm environment. Most EHS cases are isolated, occurring under conditions tolerated by others. In all cases, however, the imposed thermal load is greater than the individual’s ability to dissipate the load, and dangerous levels of hyperthermia occur. Gastrointestinal (GI) damage is observed in many cases of both classical heatstroke and EHS. This review focuses specifically on the loss of GI barrier integrity during exercise-heat stress and its role in the cause and outcome of EHS.


Under normal conditions, absorption of solutes by the GI tract occurs by active transport and facilitated diffusion. Under certain conditions, small molecules also can be absorbed passively via the paracellular route (i.e., through tight junctions). However, many toxic substances found in the GI lumen (e.g., endotoxin) normally are restricted from these pathways. This restriction is the result of the presence of the GI barrier.

Definition of the GI Barrier and GI Permeability

The GI barrier consists of physical factors (i.e., enterocyte membranes and the tight junctions between them), physiologic factors (e.g., mucous secretion), and immunologic factors (e.g., tissue macrophages). Dysfunction of any of these factors can result in increased GI permeability. Such dysfunction can occur during a variety of situations, including trauma-related events (e.g., severe hemorrhage, burn injury) and pathophysiologic conditions (e.g., sepsis, heatstroke). The term GI permeability refers to nonmediated diffusion of large molecules (molecular weight, >150 Da) from lumen to blood. A low level of GI permeability is always present in healthy individuals, but a properly functioning immune system prevents adverse effects.

Assessment of GI Barrier Function and GI Permeability

In humans, GI permeability is most commonly assessed by urinary excretion of orally administered, nondigestible, nonmetabolizible probes. Substances such as lactulose (molecular weight, 342 Da) and rhamnose (molecular weight, 164 Da) are used for this purpose. Lactulose can pass only through the paracellular pathway, whereas rhamnose and can diffuse either transcellularly or paracellularly. The percentage of the ingested dose that is recovered in the urine is used as a measure of GI permeability for that size molecule. Differential urinary excretion of two probes (e.g., lactulose and rhamnose) also is commonly used to control for nonmucosal factors in permeability and excretion. For example, factors such as GI transit, body fluid distribution after GI absorption, and renal clearance of the two probes are assumed to be the same and are thus controlled for. The only difference, therefore, is in their route(s) of absorption (i.e., transcellular, paracellular, or both). The urinary excretion ratio (in a given amount of time) of the larger probe (e.g., lactulose, only absorbed via the paracellular route) to the smaller probe (e.g., rhamnose, absorbed both transcellularly and paracellularly) gives an indication of changes in paracellular permeability.

If gastric (stomach) permeability is of interest, urinary excretion of sucrose after oral administration also can be assessed. Because sucrose is not hydrolyzed in the stomach, increased recovery in the urine indicates gastric barrier dysfunction. Other probes that have been used in humans to measure paracellular permeability are polyethylene glycol, which can be obtained in various sizes (molecular weight, 400–4000 Da) and 51Cr-EDTA (molecular weight, 343 Da).

The presence of endotoxin in either the portal or systemic circulation also is an indicator of GI barrier disruption. Endotoxin, a highly toxic molecule derived from the cell wall of Gram-negative bacteria, normally is restricted from passage into the portal blood because of both its large size and phagocytosis by tissue macrophages.


A number of studies have documented GI barrier dysfunction after strenuous aerobic exercise. Brock-Utne et al. (2) were the first to observe significantly increased plasma endotoxin concentrations in ultraendurance athletes. More recently, it has been documented that even short-term maximal aerobic exercise (1) and prolonged moderate-intensity aerobic exercise when combined with nonsteroidal anti-inflammatory drug (NSAID) use (11) can increase GI permeability. It is not surprising, therefore, that GI barrier integrity also is likely to be affected in the acute stages of EHS, as indicated by acute EHS symptoms such as vomiting, diarrhea, and GI hemorrhage (15). The following sections discuss the variables that promote GI barrier dysfunction during exercise-heat stress and whether this condition is related to the onset of EHS.

Effect of Reduced Splanchnic Blood Flow

The cause for GI barrier dysfunction during exercise-heat stress likely is multifactorial, but as shown in Figure 1, the GI epithelium is compromised by reduced blood supply, which produces hypoxia and oxidative and nitrosative stress.

Figure 1.
Figure 1.:
The effects of various stresses created before, during, or after EHS on intestinal epithelial cells and tight junctions.

During exercise-heat stress, splanchnic blood flow decreases in a linear fashion with increasing exercise intensity. If hypoxia of the intestinal epithelium occurs, local acidosis and ATP depletion are possible (8). Such conditions promote GI barrier dysfunction by altering ion pump activity, opening tight junctions, damaging enterocyte membranes, and producing enterocyte necrosis. The type of GI epithelial damage likely caused by such factors is shown histologically in Figures 2 and 3.

Figure 2.
Figure 2.:
Light micrographs of intestinal villi from anesthetized control and heat-stressed rats. Epithelial damage (sloughing of enterocytes from villous tips due to necrosis) is evident with heat stress. Bars = 100 μm. (Reprinted from Lambert, G.P., C.V. Gisolfi, D.J. Berg, P.L. Moseley, L.W. Oberley, and K.C. Kregel. Selected Contribution: Hyperthermia-induced intestinal permeability and the role of oxidative and nitrosative stress. J. Appl. Physiol. 92:1750–1761, 2002. Copyright © 2002 American Physiological Society. Used with permission.)
Figure 3.
Figure 3.:
Transmission electron micrographs of small intestinal epithelial cells from anesthetized control and heat-stressed rats. Damage to the microvilli and cell membranes along with mitochondrial swelling and vacuolization is evident in the heat-stressed rats. Bar = 1 μm. (Reprinted from Lambert, G.P., C.V. Gisolfi, D.J. Berg, P.L. Mosely, L.W. Oberley, and K.C. Kregel. Selected Contribution: Hyperthermia-induced intestinal permeability and the role of oxidative and nitrosative stress. J. Appl. Physiol. 92:1750–1761, 2002. Copyright © 2002 American Physiological Society. Used with permission.)

Effect of Hyperthermia

Hyperthermia also can increase permeability of epithelia directly by opening tight junctions and damaging cell membranes (Fig. 1). Moseley et al. (13) showed in epithelial monolayers that tight junctions open significantly at temperatures of as low as 38.3°C, with large molecules able to penetrate the barrier at temperatures higher than 41.5°C. These data have been supported recently by further in vitro experiments (12). In this latter study, hyperthermia-induced GI barrier disruption in everted-gut sac preparations was documented by significantly increased permeability to fluorescent probes, along with histologic evidence of barrier damage. Hyperthermia also stimulates production of nitric oxide (NO) and other free radicals in the splanchnic region (9), substances known to open tight junctions when in high local concentrations.

Effect of Activated Immune Cells

Tissue macrophages and circulating monocytes activated by endotoxin secrete proinflammatory cytokines such as interleukin-1 (IL-1) and tumor necrosis factor-α (TNFα) while also producing increased amounts of NO and other free radicals. Activated T cells and natural killer cells release interferon γ. Exposure to such substances is known to reduce tight junction integrity. As depicted in Figure 1, the protein complex that comprises the tight junction, the actin cytoskeleton that regulates tight junction permeability, or both are the primary sites affected.

Is EHS Caused by GI Barrier Dysfunction?

Because the cause of EHS likely is multifactorial, a definitive link between GI barrier dysfunction and the onset of EHS is unclear. The most likely mediators, however, for such an association are: 1) the increased production of proinflammatory cytokines after exposure to gut-derived endotoxin, and 2) increased production of NO in the splanchnic region as a result of endotoxin exposure, or both. The role of increased proinflammatory cytokine production is discussed first.

IL-1 and TNFα also are known as endogenous pyrogens because of their ability to raise the hypothalamic thermoregulatory set point (i.e., they produce fever). It has been suggested that increases in these cytokines after endotoxin exposure (because of increased GI permeability) promotes EHS by reducing heat dissipation (i.e., cutaneous vasoconstriction and sweating cessation) during preexisting hyperthermia. Although animal experiments have supported this idea (7), other experiments have refuted it (3). Possibly the most compelling evidence against this hypothesis is that most humans continue to sweat during the acute stages of EHS. This would not be the case if endotoxemia and the release of endogenous pyrogens were mediating the situation.

It should be remembered, however, that individuals with a preexisting GI condition, bacterial infection, or other fever-producing illness may be at a greater risk of developing EHS. Based on the above hypothesis, normal thermoregulation may be compromised from the outset of an exercise bout because of preexisting fever or GI barrier dysfunction. Under such conditions, core body temperature may rise more rapidly, to higher levels, or both compared with healthy individuals in the same environmental conditions.

The second possible link between GI barrier dysfunction and the onset of EHS is an increase in production of NO in the splanchnic region (9). As previously discussed, endotoxin permeation of the GI barrier causes this effect. Increased NO concentrations produce vasodilation of the large splanchnic vascular bed, possibly resulting in severe hypotension. Accordingly, the latter effect commonly is observed in the initial stages of EHS.


GI barrier dysfunction produced before EHS likely worsens in the hours after collapse. Reperfusion of the GI tissue results in further injury via free radical production. The resulting epithelial damage further increases permeability to endotoxin, and release of proinflammatory cytokines is enhanced both locally and systemically. These cytokines likely accentuate the damage by stimulating greater production of free radicals from monocytes and macrophages. Thus, the mechanisms for loss of GI barrier function after EHS are similar to those preceding EHS. A viscous cycle of these events can occur, promoting continuous GI damage.

Even with return of core body temperature to normal, EHS victims may continue to decline as other organs become affected. Increased concentrations of blood enzymes, such as lactate dehydrogenase, creatine phosphokinase, alanine aminotransferase, and aspartate aminotransferase, are indicative of organ damage. Blood clotting disorders such as disseminated intravascular coagulation and hemorrhage (possibly as a consequence of consumptive coagulopathy) also are commonly observed in the hours after EHS-associated collapse. Disseminated intravascular coagulation is associated with the occurrence of adult respiratory distress syndrome after heat stroke. Other tissues and organs commonly affected after EHS are muscle (rhabdomyolysis), liver (hepatic failure), and kidneys (acute renal failure secondary to rhabdomyolysis and myoglobinuria). Thus, victims of EHS can experience multiple-organ failure, with a major contributing factor being GI barrier breakdown and endotoxemia. Probably the strongest evidence supporting this hypothesis is that monkeys treated with oral antibiotics (to reduced gut bacteria) do not become endotoxemic during experimental heatstroke (6), or, if administered antilipopolysaccharide hyperimmune plasma, they have increased survival rates compared with nontreated animals (5). The overall flow of events relating increased GI permeability to possible EHS-induced collapse and organ damage are depicted in Figure 4.

Figure 4.
Figure 4.:
Flow of events leading to GI barrier dysfunction and the possible consequences of such disruption.


If GI permeability is related to the pathogenesis of EHS, its outcome, or both, measures that reduce GI permeability may prove beneficial in reducing EHS occurrence and severity. Recently, a number of interventions have been shown to reduce GI permeability during exercise, heat stress, heatstroke, and the combination of exercise and NSAID use. Such interventions are described below and are shown in Table 1.

Possible countermeasures to conditions responsible for GI barrier dysfunction during exercise heat stress and EHS

Antioxidant Supplementation

Oxidative stress during both exercise and hyperthermia is well documented. In most cases, cellular antioxidants, antioxidant enzymes, or both scavenge the radicals before the development of significant cellular damage. In the GI tract, both ischemia and reperfusion and hyperthermia stimulate enhanced radical production and increased GI permeability. Use of an inhibitor of xanthine oxidase (the enzyme that produces superoxide anion) such as allopurinol has proven beneficial in limiting heat stress-induced increases in GI permeability in rats (10).

In humans, oral administration of antioxidant vitamins such as ascorbic acid (vitamin C) may be useful in reducing exercise-associated GI permeability. Although the results of studies using such vitamins to counteract exercise-induced oxidative stress have been inconclusive, Ashton et al. (1) recently reported that ingestion of 1000 mg ascorbic acid 2 h before short-term strenuous aerobic exercise significantly reduces postexercise plasma endotoxin concentrations.

Fluid Replacement

It is known that dehydration reduces splanchnic blood flow during thermal stress, which increases the risk of GI barrier dysfunction. Ingesting fluid replacement beverages during exercise-heat stress may improve GI blood flow, and thereby may reduce this effect. It is known that GI blood flow increases with feeding. Thus, energy-containing beverages may improve GI blood flow by stimulating this mechanism. Accordingly, ingestion of a carbohydrate-containing solution seems to reduce gastroduodenal permeability after exercise combined with NSAID use (11). More studies on the effects of both fluid and energy ingestion on GI blood flow and GI permeability during exercise-heat stress are warranted.

Dietary Bovine Colostrum and Goat Milk Powders

Prosser et al. (14) recently reported a significant reduction in heat stress-induced GI barrier dysfunction in rats after dietary supplementation with bovine colostrum, goat milk powders, or both. Bovine colostrum also attenuates GI permeability caused by NSAIDs in both humans and animals. Colostrum is the milk produced by a mother in the initial days after giving birth. It contains many important nutrients, antibodies, and growth factors for the infant and likely enhances normal neonatal GI tract growth. Antiviral and antibacterial components also are found in colostrum. Such substances likely are involved in the protective mechanism(s) of this substance against GI damage; however, the precise mechanism(s) by which bovine colostrum and goat milk works to maintain tight junction integrity is not known and suggests further study in this area.

IL-1 and TNFα Antagonists

As previously discussed, the release of proinflammatory cytokines resulting from internal exposure to GI-derived endotoxin is a major problem in the hours after EHS-induced collapse. Not surprisingly, animals receiving an IL-1 receptor antagonist have shown enhanced survival after experimentally induced heatstroke (4). In humans, similar studies have been conducted on sepsis patients. Because EHS commonly produces a sepsis-like condition, such a treatment may reduce complications related to GI barrier dysfunction, endotoxemia, and systemic inflammation. Unfortunately, administering an IL-1 receptor antagonist alone has not improved human sepsis survival. However, coadministration of an IL-1 receptor antagonist with soluble TNFα receptors has been beneficial in reducing mortality in mice. Such treatment may be beneficial in EHS patients, and further study in this area should be considered.

Exercise Training, Heat Acclimation, and Heat Shock

It is well known that aerobic exercise training improves cardiovascular capacity. It is generally accepted that this adaptation allows for greater splanchnic blood flow at a given absolute exercise intensity compared with the untrained state. Heat acclimation also likely improves blood flow to the GI tract under conditions of heat stress compared with the unacclimated state. This is the result of lower core body temperatures and heart rates, decreased cutaneous blood flow, and reduced sympathetic drive. Because maintenance of GI tissue perfusion is vital to the integrity of the GI barrier, such adaptations are important in attenuation of GI barrier disturbances. Thus, appropriate training and heat acclimation are likely vital to reducing GI barrier damage and its effects on the cause of EHS.

Heat shock proteins (HSPs) also are known to preserve the integrity of the GI barrier, and thus may reduce the risk of developing GI-related complications associated with EHS. In general, HSPs are cytoprotective against various cellular stresses (including hyperthermia and free radicals). HSPs are synthesized in many tissues following exercise and heat stress, including the gut. Such expression has been shown to protect against heat-induced loss of tight junction integrity (13) and ischemia and reperfusion injury of the gut. Accordingly, HSP27, one of the many families of HSPs, recently has been shown to localize in the area of cell–cell contact in heat-shocked cells. HSPs stabilize microfilaments and maintain the folding pattern of cellular proteins. So, as with exercise training and heat acclimation, induction of the heat-shock response (i.e., increased expression of HSPs) is important for maintenance of the GI barrier when conditions such as thermal and oxidative stress will be encountered.


Evidence indicates that GI barrier dysfunction contributes to EHS cause and outcome. During exercise-heat stress, blood flow to the GI tract is reduced and can lead to hypoxia, ATP depletion, and acidosis in the tissue. Hyperthermia further exacerbates this condition by damaging cell membranes, denaturing proteins, and enhancing production of free radicals. The overall result is loss of GI barrier integrity and the potential for GI-derived endotoxin to enter the internal environment. Endotoxin-induced NO release may produce splanchnic vasodilation leading to hypotension and circulatory collapse. Endotoxemia also initiates release of proinflammatory cytokines that can produce a systemic inflammatory cascade and multiple organ damage. Inhibiting endotoxin exposure or its internal effects improves heat stroke survival. Other nutritional, pharmacologic, and physiologic interventions also may reduce GI permeability and may reduce the occurrence or effects of EHS. Such countermeasures should be investigated more thoroughly.


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exercise; hyperthermia; endotoxin; cytokines; inflammation

©2004 The American College of Sports Medicine