Journal of Sports Medicine / 2018 / Article / Tab 5

Review Article

Interactions of Gut Microbiota, Endotoxemia, Immune Function, and Diet in Exertional Heatstroke

Table 5

Potential interactions among intestine anatomy/physiology, bacteria, immune function, diet, exercise stress, and the host genome as predisposing factors for exertional heatstroke (EHS).

Hypothetical involvement in EHS

Intestine anatomy & physiology(i)  Gut anatomy (i.e., crypts) and the surrounding mucus layer facilitate immune homeostasis, protects commensal species from bacterial competitors, and reseeds the IM after the ecosystem has been altered/depleted [331, 334].
(ii)  Epithelial membrane integral proteins (i.e., toll-like receptors) recognize bacteria and other microorganisms. Once activated, these receptors can recruit immune cells and produce cytokines, which in turn regulates the number and diversity of bacteria in the gut [335].
(iii) Disruption of normal bowel function as a result of infection or inflammation uncovers its critical importance for acid-base homeostasis and normal mucosal pH [336].
(iv) Hyperthermia damages membranes of intestinal epithelial cells [31], disrupts tight junctions [337], and increases permeability to LPS [32, 101]. This permeability change occurs at temperatures of 41.5–42.0°C when sustained for 60 min [31].
(v) Human nonexertional heatstroke patients (mean rectal temperature, 42.1°C) exhibit increased plasma LPS [68, 69].
(vi) The epithelial mucosa becomes acidic during intense, anaerobic exercise [73, 88, 180, 338].
(vii) Hypoxia in the intestinal mucosa releases highly reactive oxygen and nitrogen species that accelerate mucosal injury [45, 339]; similar hypoxia-induced production of ROS and RNS occurs in liver cells [44].

Bacteria(i)  Products of bacterial metabolism (a) increase intestinal permeability and plasma LPS concentration, (b) strengthen the epithelial cell barrier, and (c) modulate expression of both proinflammatory and anti-inflammatory genes [135]. Bacterial metabolic products influence both innate and adaptive immune cell functions [340].
(ii) Commensal bacteria produce short-chain fatty acids (which have anti-inflammatory properties in multiple immune cell types); they also synthesize vitamins and amino acids which influence immune function [130, 135].
(iii) In patients with chronic inflammatory bowel diseases (e.g., Crohn’s disease, ulcerative colitis) and alcoholic liver disease, the IM differs from control subjects, and plasma LPS is chronically elevated [152, 155, 244, 330].
(iv) An array of diseases and dysfunctions (e.g., atherosclerosis, burn injury) have been hypothetically associated with an imbalance of the composition, numbers, or habitat of the IM [11, 154, 330].
(v) Several bacterial activities have been linked to increased risk of gastric and colorectal cancer [154, 330].

Immune function(i)  The IM can modulate innate and adaptive immune responses at mucosal surfaces during infection, inflammation, and autoimmunity [170].
(ii) Changes in the crosstalk between the intestinal epithelium, the intestinal immune system, and gut microbes modulate systemic immunity [335].
(iii) LPS is released upon the death of Gram-negative bacteria. LPS is a potent stimulus for the release of cytokines. The resulting inflammatory response can alter thermoregulation and result in multiple-organ dysfunction [42]. LPS can cause death at plasma concentrations as low as 1 ng/mL [43].
(iv) Proinflammatory (TNF-α, IL-1β) and anti-inflammatory (IL-6, IL-10) cytokine concentrations in plasma are elevated during exercise-induced hyperthermia and exertional heatstroke [44].
(v) Severe EHS victims may succumb to a condition similar to sepsis [4143], mediated by leakage of LPS from the intestinal lumen into the circulation. This leads to an immune (i.e., cytokine) inflammatory response culminating in systemic hypotension, cardiovascular shock, and multiple organ failure [4446]. EHS fatalities among primates exhibit greater coagulopathy, inflammation, and tissue injury than hyperthermic survivors [42].
(vi) LPS also stimulates blood coagulation; thus EHS-induced microthrombosis and hemorrhage occur in tissues of the intestine, liver, lungs, kidneys, pancreas, spleen, skin, cornea, heart, brain, and adrenals [43, 4951].
(vii) Administration of immunomodulators, antibodies to endotoxin, and corticosteroids improve survival in animals with heatstroke and attenuate hemodynamic instability, but have not been studied in humans [44].
(viii) At rest, pre-hydration with an intravenous glucose-NaCl solution shifts cytokine (TNF-α, IL-1β, IL-8) responses to injected human endotoxin towards a more anti-inflammatory balance [123].

Diet(i)  Diet modulates inflammation and immune function at rest [103, 133] 
(ii) At rest, diet modulates the pH of colon mucosa, intestinal permeability, as well as glucose, insulin, and energy metabolism [135].
(iii) A change of diet rapidly alters IM composition [253, 256].
(iv) A high-fat, low-fiber Western diet promotes the overgrowth of gram-negative pathogens, with consequent increased intestinal translocation of bacterial LPS [153].
(v) Obesity and Type 2 diabetes are associated with a chronic low-grade inflammatory state, known as “metabolic endotoxemia” [341, 342] because these diseases involve translocation of LPS from the intestinal lumen into blood. Extensive research involving mice demonstrated that a 4-week high-fat diet chronically increased plasma LPS levels [153], and induced obesity and insulin resistance. Altering the IM of mice by antibiotic administration protected mice from fat mass development, glucose intolerance, insulin resistance, mild endotoxemia, inflammation [136].
(vi) Metabolic endotoxemia (interrelationships between LPS, a high-fat diet, obesity, and Type 2 diabetes) has been confirmed in multiple studies involving healthy and obese humans (publications reviewed by [40]).

Exercise stress (intensity & duration)(i)  Numerous studies have reported lower splanchnic and mesenteric blood flows during strenuous exercise; this can result in hypoxia, intestinal barrier disruption [34, 122, 180, 343]. This hypoxic state, evident in the intestinal villi and lobes of the liver, likely results in ATP depletion, acidosis, and altered membrane ion pump activity [43, 51, 339, 344].
(ii) EHS and non-exertional (classical) heatstroke often involve systemic acidosis [51, 345, 346].
(iii) During high intensity (80%  ; [87]) and prolonged (>9 h; [84, 86]) exercise, the incidence of endotoxemia (plasma LPS) increases.
(iv) Exercise-induced (running 60 min at 70%  ) mild dehydration (−1.5% body mass loss) increases intestinal permeability [122].
(v) Efficient energy metabolism (i.e., biochemical generation of ATP) is essential during prolonged or intense exercise. Bacteria may influence energy metabolism by modulating intestinal transit time (energy harvest); polysaccharide degradation to monosaccharides; glucose absorption into intestinal epithelial cells; de novo lipid production; FFA and glucose oxidation in liver, muscle, and adipose tissue [103].
(vi) Exercise relies on the uptake of glucose by skeletal muscle, mediated by insulin that is produced in the pancreas. In some adults (e.g., those with Type 2 diabetes), skeletal muscle and liver tissues exhibit resistance to the action of insulin.
(vii) The total amount of energy available to a cell is limited. Exercise and high body temperature cause Na+-K+- pumps to operate at a high rate. Eventually, cells can become energy depleted, they swell due to reduced water transport (implying a reduced pump activity), and rigor mortis sets in, implying energy depletion [34, 76]

IM, intestinal microbiota; LPS, lipopolysaccharide; TNF-α, tumor necrosis factor alpha; IL-1β, interleukin-1β; IL-6, interleukin-6; IL-10, interleukin-10; ROS, reactive oxygen species; RNS, reactive nitrogen species; FFA, free fatty acid; a major component of the cell wall of Gram-negative bacteria.

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