Exercise and Endotoxemia

Also see:
Can Endurance Sports Really Cause Harm? The Lipopolysaccharides of Endotoxemia and Their Effect on the Heart
Endotoxin: Poisoning from the Inside Out
Prolonged military-style training causes changes to intestinal bacteria, increases inflammation
Stress — A Shifting of Resources
Ray Peat, PhD on the Benefits of the Raw Carrot
Protection from Endotoxin
Endotoxin-lipoprotein Hypothesis
Protective Bamboo Shoots
The effect of raw carrot on serum lipids and colon function
How does estrogen enhance endotoxin toxicity? Let me count the ways.
Bowel Toxins Accelerate Aging
Exercise Induced Stress
Carbohydrate Lowers Exercise Induced Stress
Exercise and Effect on Thyroid Hormone
Exercise Induced Menstrual Disorders
Ray Peat, PhD: Quotes Relating to Exercise
Ray Peat, PhD and Concentric Exercise
Potential Adverse Cardiovascular Effects from Excessive Endurance Exercise

“Digestion is quickly shut down during stress…The parasympathetic nervous system, perfect for all that calm, vegetative physiology, normally mediates the actions of digestion. Along comes stress: turn off parasympathetic, turn on the sympathetic, and forget about digestion.” -Robert Sapolsky

Quotes by Ray Peat, PhD:
‎”Incidental stresses, such as strenuous exercise combined with fasting (e.g., running or working before eating breakfast) not only directly trigger the production of lactate and ammonia, they also are likely to increase the absorption of bacterial endotoxin from the intestine. Endotoxin is a ubiquitous and chronic stressor. It increases lactate and nitric oxide, poisoning mitochondrial respiration, precipitating the secretion of the adaptive stress hormones, which don’t always fully repair the cellular damage.”

“Bacterial endotoxin causes some of the same effects as adrenalin. When stress reduces circulation to the bowel, causing injury to the barrier fun ction of the intestinal cells, endotoxin can enter the blood, contributing to a shock state, with further impairment of circulation.”

“The amount of injury needed to increase the endotoxin in the blood can be fairly minor. Two thirds of people having a colonoscopy had a significant increase in endotoxin in their blood, and intense exercise or anxiety will increase it. Endotoxin activates the enzyme that synthesizes estrogen while it decreases the formation of androgen (Christeff, et aI., 1992), and this undoubtedly is partly responsible for the large increases in estrogen in both men and women caused by trauma, sickness or excessive fatigue.”

“Our innate immune system is perfectly competent for handling our normal stress induced exposures to bacterial endotoxin, but as we accumulate the unstable fats, each exposure to endotoxin creates additional inflammatory stress by liberating stored fats. The brain has a very high concentration of complex fats, and is highly susceptible to the effects of lipid peroxidative stress, which become progressively worse as the unstable fats accumulate during aging.”

“During moderate exercise, adrenalin causes increased blood flow to both the heart and the skeletal muscles, while decreasing the flow of blood to other organs. The increased circulation carries extra oxygen and nutrients to the working organs, while the deprivation of oxygen and glucose pushes the other organs to a catabolic balance. This simple circulatory pattern achieves to some extent the same kind of redistribution of resources, acutely, that is achieved in more prolonged stress by the actions of the glucocorticoids and their antagonists.”

J Appl Physiol. 1988 Jul;65(1):106-8.
Strenuous exercise causes systemic endotoxemia.
Bosenberg AT, Brock-Utne JG, Gaffin SL, Wells MT, Blake GT.
Eighteen triathletes were studied before and immediately after competing in an ultradistance triathlon. Their mean plasma lipopolysaccharide (LPS) concentrations increased from 0.081 to 0.294 ng/ml (P less than 0.001), and their mean plasma anti-LPS immunoglobulin G (IgG) concentrations decreased from 67.63 to 38.99 micrograms/ml (P less than 0.001). Both pretriathlon plasma LPS and anti-LPS IgG levels were directly related to the intensity of training (P less than 0.02 and P less than 0.01, respectively). It is possible that training-induced stress led to some leakage of LPS into the circulation, which, in turn, resulted in self-immunization against LPS. The effects on athletic performance in relation to exercise-induced changes in plasma LPS and anti-LPS IgG levels require further investigation.

Can J Physiol Pharmacol. 1998 May;76(5):479-84.
The gut as a potential trigger of exercise-induced inflammatory responses.
Marshall JC.
Multiple lines of evidence support the hypothesis that ischemia-induced impairment of normal gut barrier function, with loss of the normal tonic counterinflammatory influence of the gut immune system, contributes to the expression of uncontrolled inflammation in critically ill victims of trauma and overwhelming infection. The clinical syndrome known as the systemic inflammatory response syndrome (SIRS), which embodies uncontrolled inflammation in trauma and sepsis, is reproduced in its entirety by vigourous exercise, raising the possibility that the gut may also play a role in exercise-induced inflammation. Both strenuous exercise and systemic sepsis result in impairment of the normal gut barrier to luminal microorganisms, and result in elevated circulating levels of bacterial endotoxin. Under normal circumstances, the immune tissues of the gut-liver axis inhibit the expression of a host response to foodstuffs in the gut lumen, or to the indigenous microbial flora of the gut wall. This influence is an active, energy-requiring process. Both strenuous exercise and critical illness are associated with gut ischemia, providing a common biologic basis for the initiation of a dysregulated inflammatory response. Although direct evidence supporting or refuting the hypothesis that the gut can serve as a trigger for systemic inflammation following strenuous exercise is sparse, the similarities in the clinical manifestations of SIRS and exercise, and the promising results of prophylactic or therapeutic gut-directed strategies in critical illness, suggest that similar approaches may provide benefit for individuals engaged in extreme physical exercise.

J S Afr Vet Assoc. 1988 Jun;59(2):63-6.
Endotoxaemia in racehorses following exertion.
Baker B, Gaffin SL, Wells M, Wessels BC, Brock-Utne JG.
Endotoxins (lipopolysaccharides-LPS) and anti-endotoxin IgG antibodies were measured in racehorses before and after races of 1,000, 2,000 and 2,800 m. Results show that the mean plasma concentration of endotoxin increased significantly (p less than 0.02) while the anti-LPS IgG concentration decreased significantly (p less than 0.005) in all horses following the races. Pre-race and post-race anti-LPS IgG levels in racing-fit racehorses were significantly higher than in untrained horses (p less than 0.05). The possibility therefore exists that training-induced stress leads to leakage of LPS into the systemic circulation which results in self-immunisation against LPS. The effects of plasma LPS and anti-LPS IgG concentrations on performance of racehorses require further studies.

Clin Sci (Lond). 1997 Apr;92(4):415-22.
Mild endotoxaemia and the inflammatory response induced by a marathon race.
Camus G, Poortmans J, Nys M, Deby-Dupont G, Duchateau J, Deby C, Lamy M.
1. To address the question of whether endotoxaemia could be involved in the inflammatory response induced by long-term strenuous exercise, 18 male marathon runners [mean age 41 +/- 2 (SEM) years] were studied. Their performance in the marathon ranged from 2 h 46 min to 4 h 42 min. 2. Four venous blood samples were drawn: at rest, just before the race (baseline); within 15 min following the completion of the marathon; after 1 h of recovery; and the morning after the race. 3. The following humoral markers of the inflammatory response to exercise were measured: polymorphonuclear myeloperoxidase (MPO), anaphylatoxin C5a (C5a), tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6). Plasma endotoxin was measured by a sensitive and rapid chromogenic Limulus assay. All inflammatory markers were significantly increased (P < 0.001) after the race, reaching in most cases peak values in the first blood sample drawn following the completion of the marathon [MPO, 298 +/- 19 ng/ml (SEM); C5a, 1.45 +/- 0.32 ng/ml; TNF-alpha, 20 +/- 3 pg/ml; IL-6, 88 +/- 13 pg/ml] when compared with baseline [MPO, 146 +/- 16 ng/ml (SEM); C5a, 0.27 +/- 0.2 ng/ml; TNF-alpha, 12 +/- 1.5 pg/ml: IL-6, 1.0 +/- 0.5 pg/ml]. Traces of plasma endotoxin (ranging from 5 to 13 pg/ml, with one exceptionally high value of 72 pg/ml measured in one runner) were detected in seven subjects within the first hour of recovery. An ELISA method was used to determine the endogenous IgG antibodies toward a range of Gram-negative bacterial lipopolysaccharides (LPSs) of different sizes and structures. A transient decrease in certain anti-LPS activities, mainly against rough LPS, occurred in most cases in the first blood sample drawn after the race. There was no correlation between the magnitude of the inflammatory response to exercise, as assessed by the increase in blood levels of humoral markers of inflammation, and the changes in circulating endotoxin levels of anti-LPS IgG activity following the race. 4. From these results, we conclude that the mild, transient endotoxaemia detected in some of our subjects does not play a major role in the observed inflammatory response to a marathon competition.

Clin Sci (Lond). 2000 Jan;98(1):47-55.
Relationship between gastro-intestinal complaints and endotoxaemia, cytokine release and the acute-phase reaction during and after a long-distance triathlon in highly trained men.
Jeukendrup AE, Vet-Joop K, Sturk A, Stegen JH, Senden J, Saris WH, Wagenmakers AJ.
The aim of the present study was to establish whether gastro-intestinal (GI) complaints observed during and after ultra-endurance exercise are related to gut ischaemia-associated leakage of endotoxins [lipopolysaccharide (LPS)] into the circulation and associated cytokine production. Therefore we collected blood samples from 29 athletes before, immediately after, and 1, 2 and 16 h after a long-distance triathlon for measurement of LPS, tumour necrosis factor-alpha and interleukin-6 (IL-6). As the cytokine response would trigger an acute-phase response, characteristic variables of these responses were also measured, along with creatine kinase (CK) to obtain an indicator of muscle damage. There was a high incidence (93% of all participants) of GI symptoms; 45% reported severe complaints and 7% of the participants abandoned the race because of severe GI distress. Mild endotoxaemia (5-15 pg/ml) was evident in 68% of the athletes immediately after the race, as also indicated by a reduction in IgG anti-LPS levels. In addition, we observed production of IL-6 (27-fold increase immediately after the race), leading to an acute-phase response (20-fold increase in C-reactive protein and 12% decrease in pre-albumin 16 h after the race). The extent of endotoxaemia was not correlated with the GI complaints or the IL-6 response, but did show a correlation with the elevation in C-reactive protein (r(s) 0.389; P=0.037). Creatine kinase levels were increased significantly immediately post-race, and increased further in the follow-up period. Creatine kinase levels did not correlate with those of either IL-6 or C-reactive protein. It is therefore concluded that LPS does enter the circulation after ultra-endurance exercise and may, together with muscle damage, be responsible for the increased cytokine response and hence GI complaints in these athletes.

Am J Physiol Gastrointest Liver Physiol. 2012 Jul 15;303(2):G155-68. doi: 10.1152/ajpgi.00066.2012. Epub 2012 Apr 19.
Physiology and pathophysiology of splanchnic hypoperfusion and intestinal injury during exercise: strategies for evaluation and prevention.
van Wijck K, Lenaerts K, Grootjans J, Wijnands KA, Poeze M, van Loon LJ, Dejong CH, Buurman WA.
Physical exercise places high demands on the adaptive capacity of the human body. Strenuous physical performance increases the blood supply to active muscles, cardiopulmonary system, and skin to meet the altered demands for oxygen and nutrients. The redistribution of blood flow, necessary for such an increased blood supply to the periphery, significantly reduces blood flow to the gut, leading to hypoperfusion and gastrointestinal (GI) compromise. A compromised GI system can have a negative impact on exercise performance and subsequent postexercise recovery due to abdominal distress and impairments in the uptake of fluid, electrolytes, and nutrients. In addition, strenuous physical exercise leads to loss of epithelial integrity, which may give rise to increased intestinal permeability with bacterial translocation and inflammation. Ultimately, these effects can deteriorate postexercise recovery and disrupt exercise training routine. This review provides an overview on the recent advances in our understanding of GI physiology and pathophysiology in relation to strenuous exercise. Various approaches to determine the impact of exercise on the individual athlete’s GI tract are discussed. In addition, we elaborate on several promising components that could be exploited for preventive interventions.

PLoS One. 2011;6(7):e22366. doi: 10.1371/journal.pone.0022366. Epub 2011 Jul 21.
Exercise-induced splanchnic hypoperfusion results in gut dysfunction in healthy men.
van Wijck K, Lenaerts K, van Loon LJ, Peters WH, Buurman WA, Dejong CH.
BACKGROUND:
Splanchnic hypoperfusion is common in various pathophysiological conditions and often considered to lead to gut dysfunction. While it is known that physiological situations such as physical exercise also result in splanchnic hypoperfusion, the consequences of flow redistribution at the expense of abdominal organs remained to be determined. This study focuses on the effects of splanchnic hypoperfusion on the gut, and the relationship between hypoperfusion, intestinal injury and permeability during physical exercise in healthy men.
METHODS AND FINDINGS:
Healthy men cycled for 60 minutes at 70% of maximum workload capacity. Splanchnic hypoperfusion was assessed using gastric tonometry. Blood, sampled every 10 minutes, was analyzed for enterocyte damage parameters (intestinal fatty acid binding protein (I-FABP) and ileal bile acid binding protein (I-BABP)). Changes in intestinal permeability were assessed using sugar probes. Furthermore, liver and renal parameters were assessed. Splanchnic perfusion rapidly decreased during exercise, reflected by increased gap(g-a)pCO(2) from -0.85±0.15 to 0.85±0.42 kPa (p<0.001). Hypoperfusion increased plasma I-FABP (615±118 vs. 309±46 pg/ml, p<0.001) and I-BABP (14.30±2.20 vs. 5.06±1.27 ng/ml, p<0.001), and hypoperfusion correlated significantly with this small intestinal damage (r(S) = 0.59; p<0.001). Last of all, plasma analysis revealed an increase in small intestinal permeability after exercise (p<0.001), which correlated with intestinal injury (r(S) = 0.50; p<0.001). Liver parameters, but not renal parameters were elevated.
CONCLUSIONS:
Exercise-induced splanchnic hypoperfusion results in quantifiable small intestinal injury. Importantly, the extent of intestinal injury correlates with transiently increased small intestinal permeability, indicating gut barrier dysfunction in healthy individuals. These physiological observations increase our knowledge of splanchnic hypoperfusion sequelae, and may help to understand and prevent these phenomena in patients.

Aliment Pharmacol Ther. 2012 Mar;35(5):516-28. doi: 10.1111/j.1365-2036.2011.04980.x. Epub 2012 Jan 10.
Review article: the pathophysiology and management of gastrointestinal symptoms during physical exercise, and the role of splanchnic blood flow.
ter Steege RW, Kolkman JJ.
BACKGROUND:
The prevalence of exercise-induced gastrointestinal (GI) symptoms has been reported up to 70%. The pathophysiology largely remains unknown.
AIM:
To review the physiological and pathophysiological changes of the GI-tract during physical exercise and the management of the most common gastrointestinal symptoms.
METHODS:
Search of the literature published in the English and Dutch languages using the Pubmed database to review the literature that focused on the relation between splanchnic blood flow (SBF), development of ischaemia, postischaemic endotoxinemia and motility.
RESULTS:
During physical exercise, the increased activity of the sympathetic nervous system (SNS) redistributes blood flow from the splanchnic organs to the working muscles. With prolonged duration and/or intensity, the SBF may be decreased by 80% or more. Most studies point in the direction of increased SNS-activity as central driving force for reduction in SBF. A severely reduced SBF may frequently cause GI ischaemia. GI-ischaemia combined with reduced vagal activity probably triggers changes in GI-motility and GI absorption derangements. GI-symptoms during physical exercise may be prevented by lowering the exercise intensity, preventing dehydration and avoiding the ingestion of hypertonic fluids.
CONCLUSIONS:
Literature on the pathophysiology of exercise-induced GI-symptoms is scarce. Increased sympathetic nervous system activity and decreased splanchnic blood flow during physical exercise seems to be the key factor in the pathogenesis of exercise-induced GI-symptoms, and this should be the target for symptom reduction.

Br J Sports Med. 2012 Oct;46(13):931-5. Epub 2011 Oct 20.
Abdominal symptoms during physical exercise and the role of gastrointestinal ischaemia: a study in 12 symptomatic athletes.
ter Steege RW, Geelkerken RH, Huisman AB, Kolkman JJ.
BACKGROUND:
Gastrointestinal (GI) symptoms during exercise may be caused by GI ischaemia. The authors report their experience with the diagnostic protocol and management of athletes with symptomatic exercise-induced GI ischaemia. The value of prolonged exercise tonometry in the diagnostic protocol of these patients was evaluated.
METHODS:
Patients referred for GI symptoms during physical exercise underwent a standardised diagnostic protocol, including prolonged exercise tonometry. Indicators of GI ischaemia, as measured by tonometry, were related to the presence of symptoms during the exercise test (S+ and S- tests) and exercise intensity.
RESULTS:
12 athletes were specifically referred for GI symptoms during exercise (five males and seven females; median age 29 years (range 15-46 years)). Type of sport was cycling, long-distance running and triathlon. Median duration of symptoms was 32 months (range 7-240 months). Splanchnic artery stenosis was found in one athlete. GI ischaemia was found in six athletes during submaximal exercise. All athletes had gastric and jejunal ischaemia during maximum intensity exercise. No significant difference was found in gastric and jejunal Pco(2) or gradients between S+ and S- tests during any phase of the exercise protocol. In S+ tests, but not in S- tests, a significant correlation between lactate and gastric gradient was found. In S+ tests, the regression coefficients of gradients were higher than those in S- tests. Treatment advice aimed at limiting GI ischaemia were successful in reducing complaints in the majority of the athletes.
CONCLUSION:
GI ischaemia was present in all athletes during maximum intensity exercise and in 50% during submaximal exercise. Athletes with GI symptoms had higher gastric gradients per mmol/l increase in lactate, suggesting an increased susceptibility for the development of ischaemia during exercise. Treatment advice aimed at limiting GI ischaemia helped the majority of the referred athletes to reduce their complaints. Our results suggest an important role for GI ischaemia in the pathophysiology of their complaints.

Ned Tijdschr Geneeskd. 2008 Aug 16;152(33):1805-8.
[Gastrointestinal ischaemia during physical exertion as a cause of gastrointestinal symptoms].
[Article in Dutch]
ter Steege RW, Kolkman JJ, Huisman AB, Geelkerken RH.
Gastrointestinal (GI) symptoms are reported by up to 70% of endurance athletes. Although exercise leads to decreased gastrointestinal blood flow, GI-ischaemia is rarely reported as a cause. Mucosal ischaemia may result in nausea, abdominal cramps and bloody diarrhoea. After exercise, reperfusion damage and endotoxaemia may cause systemic symptoms as well. In three patients, two women aged 46 and 25 respectively and a man aged 40, with a heterogeneous presentation of exercise induced GI-symptoms, GI-ischaemia was demonstrated using gastric exercise tonometry. Gastric tonometry is mandatory for the diagnosis and follow-up. In the first patient, an isolated celiac artery stenosis was found; after incision of the left crus of the diaphragm, she was asymptomatic and the results of gastric tonometry improved. The other two patients had non-occlusive ischaemia associated with high exercise intensity. Reduction of the exercise intensity resulted in the complaints disappearing.

Med Sport Sci. 2012;59:47-56. doi: 10.1159/000342169. Epub 2012 Oct 15.
Exercise, intestinal barrier dysfunction and probiotic supplementation.
Lamprecht M, Frauwallner A.
Athletes exposed to high-intensity exercise show an increased occurrence of gastrointestinal (GI) symptoms like cramps, diarrhea, bloating, nausea, and bleeding. These problems have been associated with alterations in intestinal permeability and decreased gut barrier function. The increased GI permeability, a so-called ‘leaky gut’, also leads to endotoxemia, and results in increased susceptibility to infectious and autoimmune diseases, due to absorption of pathogens/toxins into tissue and the bloodstream. Key components that determine intestinal barrier function and GI permeability are tight junctions, protein structures located in the paracellular channels between epithelial cells of the intestinal wall. The integrity of tight junctions depends on sophisticated interactions between the gut residents and their expressed substances, the intestinal epithelial cell metabolism and the activities of the gut-associated lymphoid tissue. Probiotic supplements are an upcoming group of nutraceuticals that could offer positive effects on athlete’s gut and entire health. Some results demonstrate promising benefits for probiotic use on the athlete’s immune system. There is also evidence that probiotic supplementation can beneficially influence intestinal barrier integrity in acute diseases. With regard to exercise-induced GI permeability problems, there is still a lack of studies with appropriate data and a gap to understand the underlying mechanisms to support such health beneficial statements implicitly. This article refers (i) to exercise-induced intestinal barrier dysfunction, (ii) provides suggestions to estimate increased gut barrier permeability in athletes, and (iii) discusses the potential of probiotic supplementation to counteract an exercise-induced leaky gut.

Chest. 1992 May;101(5 Suppl):223S-225S.
Regional flow responses to exercise.
Carù B, Colombo E, Santoro F, Laporta A, Maslowsky F.
Both neural and humoral systems participate in the control of blood flow to various organs. Exercise places the greatest demands on the circulation. At rest, in humans, skeletal muscle receives somewhere between 15% and 20% of cardiac output, while during maximal exercise, this percentage reaches a value of 80% to 90%. The active human muscles have a high-flow capacity that exceeds the capacity of the heart to pump blood. Measurements in single human muscle have indicated that blood flow may be inhomogenous, that is, probably depending on variations of the vasomotor tone of the muscle mediated by humoral and neural factors. Exercise raises cardiac output and coronary blood flow, which rise linearly with increases in heart rate. In normal young men, coronary blood flow averages 280 ml/min/100 g of the left ventricle and reaches as high as 390 ml/min during moderately severe exercise, requiring about 85% of maximal heart rate. In nonexercising organs, the blood flow decreases at about 20% to 40% of the resting values, being the net result of competing vasoconstrictor and vasodilator drives.

Sports Med. 1993 Apr;15(4):242-57.
Is the gut an athletic organ? Digestion, absorption and exercise.
Brouns F, Beckers E.
Digestion is a process which takes place in resting conditions. Exercise is characterised by a shift in blood flow away from the gastrointestinal (GI) tract towards the active muscle and the lungs. Changes in nervous activity, in circulating hormones, peptides and metabolic end products lead to changes in GI motility, blood flow, absorption and secretion. In exhausting endurance events, 30 to 50% of participants may suffer from 1 or more GI symptoms, which have often been interpreted as being a result of maldigestion, malabsorption, changes in small intestinal transit, and improper food and fluid intake. Results of field and laboratory studies show that pre-exercise ingestion of foods rich in dietary fibre, fat and protein, as well as strongly hypertonic drinks, may cause upper GI symptoms such as stomach ache, vomiting and reflux or heartburn. There is no evidence that the ingestion of nonhypertonic drinks during exercise induces GI distress and diarrhoea. In contrast, dehydration because of insufficient fluid replacement has been shown to increase the frequency of GI symptoms. Lower GI symptoms, such as intestinal cramps, diarrhoea–sometimes bloody–and urge to defecate seem to be more related to changes in gut motility and tone, as well as a secretion. These symptoms are to a large extent induced by the degree of decrease in GI blood flow and the secretion of secretory substances such as vasoactive intestinal peptide, secretin and peptide-histidine-methionine. Intensive exercise causes considerable reflux, delays small intestinal transit, reduces absorption and tends to increase colonic transit. The latter may reduce whole gut transit time. The gut is not an athletic organ in the sense that it adapts to increased exercise-induced physiological stress. However, adequate training leads to a less dramatic decrease of GI blood flow at submaximal exercise intensities and is important in the prevention of GI symptoms.

Curr Sports Med Rep. 2012 Mar-Apr;11(2):99-104. doi: 10.1249/JSR.0b013e318249c311.
Upper gastrointestinal issues in athletes.
Waterman JJ, Kapur R.
Gastrointestinal (GI) complaints are common among athletes with rates in the range of 30% to 70%. Both the intensity of sport and the type of sporting activity have been shown to be contributing factors in the development of GI symptoms. Three important factors have been postulated as contributing to the pathophysiology of GI complaints in athletes: mechanical forces, altered GI blood flow, and neuroendocrine changes. As a result of those factors, gastroesophageal reflux disease (GERD), nausea, vomiting, gastritis, peptic ulcers, GI bleeding, or exercise-related transient abdominal pain (ETAP) may develop. GERD may be treated with changes in eating habits, lifestyle modifications, and training modifications. Nausea and vomiting may respond to simple training modifications, including no solid food 3 hours prior to an athletic event. Mechanical trauma, decreased splanchnic blood flow during exercise, and non-steroidal anti-inflammatory drugs (NSAID) contribute to gastritis, GI bleeding, and ulcer formation in athletes. Acid suppression with proton-pump inhibitors may be useful in athletes with persistence of any of the above symptoms. ETAP is a common, poorly-understood, self-limited acute abdominal pain which is difficult to treat. ETAP incidence increases in athletes beginning a new exercise program or increasing the intensity of their current exercise program. ETAP may respond to changes in breathing patterns or may resolve simply with continued training. Evaluation of the athlete with upper GI symptoms requires a thorough history, a detailed training log, a focused physical examination aimed at ruling out potentially serious causes of symptoms, and follow-up laboratory testing based on concerning physical examination findings.

Aliment Pharmacol Ther. 2012 Mar;35(5):516-28. doi: 10.1111/j.1365-2036.2011.04980.x. Epub 2012 Jan 10.
Review article: the pathophysiology and management of gastrointestinal symptoms during physical exercise, and the role of splanchnic blood flow.
ter Steege RW, Kolkman JJ.
BACKGROUND:
The prevalence of exercise-induced gastrointestinal (GI) symptoms has been reported up to 70%. The pathophysiology largely remains unknown.
AIM:
To review the physiological and pathophysiological changes of the GI-tract during physical exercise and the management of the most common gastrointestinal symptoms.
METHODS:
Search of the literature published in the English and Dutch languages using the Pubmed database to review the literature that focused on the relation between splanchnic blood flow (SBF), development of ischaemia, postischaemic endotoxinemia and motility.
RESULTS:
During physical exercise, the increased activity of the sympathetic nervous system (SNS) redistributes blood flow from the splanchnic organs to the working muscles. With prolonged duration and/or intensity, the SBF may be decreased by 80% or more. Most studies point in the direction of increased SNS-activity as central driving force for reduction in SBF. A severely reduced SBF may frequently cause GI ischaemia. GI-ischaemia combined with reduced vagal activity probably triggers changes in GI-motility and GI absorption derangements. GI-symptoms during physical exercise may be prevented by lowering the exercise intensity, preventing dehydration and avoiding the ingestion of hypertonic fluids.
CONCLUSIONS:
Literature on the pathophysiology of exercise-induced GI-symptoms is scarce. Increased sympathetic nervous system activity and decreased splanchnic blood flow during physical exercise seems to be the key factor in the pathogenesis of exercise-induced GI-symptoms, and this should be the target for symptom reduction.

Exerc Immunol Rev. 1999;5:78-95.
The gastrointestinal system–an essential target organ of the athlete’s health and physical performance.
Berg A, Müller HM, Rathmann S, Deibert P.
An athlete’s ability to reach maximum performance is a direct result of physical and muscular performance, muscular and systemic stress tolerance, control and regulation of immune function, and adaptation to physical stress. In this complex sense, the gastrointestinal (GI) tract is also part of the system that controls and regulates adaptation and regeneration of the athlete. A well-balanced GI immune system and an optimized immune competence may protect the athlete from harmful pathogens; it may also protect against dietary as well as inhaled antigens. However, under conditions of mechanical and biochemical stress, the integrity of the GI mucosal block, particularly the epithelial hood, can be damaged, leading to a pathological uptake of toxic or immunogenic substrates. This may occur in endurance athletes, since gut symptomatology, nausea, vomiting, pain, bloating, diarrhea, cramping, and bleeding can be observed in up to half of all participants in endurance events. In addition, composition of stool and fecal microflora in endurance athletes has shown that there may be a specific need for nutritional support for mucosal immunity in highly trained but chronically stressed athletes. Proper diet during training and competition is a significant factor in guarding against GI symptoms and exercise-induced gastrointestinal side effects that may compromise immune competence and physical performance. The present review presents some important suggestions on the possible role of the GI tract in human performance and stress tolerance, and offers new insights about the influence of food quality on the immune system of the gut.

Am J Gastroenterol. 1999 Jun;94(6):1570-81.
Gastrointestinal symptoms in long-distance runners, cyclists, and triathletes: prevalence, medication, and etiology.
Peters HP, Bos M, Seebregts L, Akkermans LM, van Berge Henegouwen GP, Bol E, Mosterd WL, de Vries WR.
OBJECTIVE:
The aim of this study was to determine the prevalence of exercise-related gastrointestinal (GI) symptoms and the use of medication for these symptoms among long-distance runners, cyclists, and triathletes, and to determine the relationship of different variables to GI symptoms.
METHODS:
A mail questionnaire covering the preceding 12 months was sent to 606 well-trained endurance type athletes: 199 runners (114 men and 85 women), 197 cyclists (98 men and 99 women), and 210 triathletes (110 men and 100 women) and sent back by 93%, 88%, and 71% of these groups, respectively. Symptoms were evaluated with respect to the upper (nausea, vomiting, belching, heartburn, chest pain) or lower part of the GI tract (bloating, GI cramps, side ache, urge to defecate, defecation, diarrhea). For statistical analysis, Mann-Whitney U test, Fisher exact test, or Student t test were used.
RESULTS:
Runners experienced more lower (prevalence 71%) than upper (36%) GI symptoms during exercise. Cyclists experienced both upper (67%) and lower (64%) symptoms. Triathletes experienced during cycling both upper (52%) and lower (45%) symptoms, and during running more lower (79%) than upper (54%) symptoms. Bloating, diarrhea, and flatulence occurred more at rest than during exercise among all subjects. In general, exercise-related GI symptoms were significantly related to the occurrence of GI symptoms during nonexercise periods, age, gender, diet, and years of training. The prevalence of medication for exercise-related GI symptoms was 5%, 6%, and 3% for runners, cyclists, and triathletes, respectively.
CONCLUSIONS:
Long-distance running is mainly associated with lower GI symptoms, whereas cycling is associated with both upper and lower symptoms. Triathletes confirm this pattern during cycling and running. The prevalence of medication for exercise-related GI symptoms is lower in the Netherlands in comparison with other countries, in which a prevalence of 10-18% was reported. More research on the possible predisposition of athletes for GI symptoms during exercise is needed.

Br J Sports Med. 1988 Jun;22(2):71-4.
Gastrointestinal disturbances in marathon runners.
Riddoch C, Trinick T.
The purpose of this survey was to investigate the prevalence of running-induced gastrointestinal (GI) disturbances in marathon runners. A questionnaire was completed by 471 of the estimated 1,750 competitors in the 1986 Belfast City Marathon. Eighty-three per cent of respondents indicated that they occasionally or frequently suffered one or more GI disturbances during or immediately after running. The urge to have a bowel movement (53%) and diarrhoea (38%) were the most common symptoms, especially among female runners (74% and 68% respectively). Upper GI tract symptoms were experienced more by women than men (p less than 0.05) and more by younger runners than older runners (p less than 0.01). Women also suffered more lower GI tract symptoms than men (p less than 0.05) with younger runners showing a similar trend. Both upper and lower tract symptoms were more common during a “hard” run than an “easy” run (p less than 0.01) and were equally as common both during and after running. Of those runners who suffered GI disturbances, 72% thought that running was the cause and 29% believed their performance to be adversely affected. There was no consensus among sufferers as to the causes of symptoms and a wide variety of “remedies” were suggested. GI disturbances are common amongst long-distance runners and their aetiology is unknown. Medical practitioners should be aware of this when dealing with patients who run.

Am J Physiol Regul Integr Comp Physiol. 2008 Aug;295(2):R611-23. doi: 10.1152/ajpregu.00917.2007. Epub 2008 Jun 18.
Mild endotoxemia, NF-kappaB translocation, and cytokine increase during exertional heat stress in trained and untrained individuals.
Selkirk GA, McLellan TM, Wright HE, Rhind SG.
This study examined endotoxin-mediated cytokinemia during exertional heat stress (EHS). Subjects were divided into trained [TR; n=12, peak aerobic power (VO2peak)=70+/-2 ml.kg lean body mass(-1).min(-1)] and untrained (UT; n=11, VO2peak=50+/-1 ml.kg lean body mass(-1).min(-1)) groups before walking at 4.5 km/h with 2% elevation in a climatic chamber (40 degrees C, 30% relative humidity) wearing protective clothing until exhaustion (Exh). Venous blood samples at baseline and 0.5 degrees C rectal temperature increments (38.0, 38.5, 39.0, 39.5, and 40.0 degrees C/Exh) were analyzed for endotoxin, lipopolysaccharide binding protein, circulating cytokines, and intranuclear NF-kappaB translocation. Baseline and Exh samples were also stimulated with LPS (100 ng/ml) and cultured in vitro in a 37 degrees C water bath for 30 min. Phenotypic determination of natural killer cell frequency was also determined. Enhanced blood (104+/-6 vs. 84+/-3 ml/kg) and plasma volumes (64+/-4 vs. 51+/-2 ml/kg) were observed in TR compared with UT subjects. EHS produced an increased concentration of circulating endotoxin in both TR (8+/-2 pg/ml) and UT subjects (15+/-3 pg/ml) (range: not detected to 32 pg/ml), corresponding with NF-kappaB translocation and cytokine increases in both groups. In addition, circulating levels of tumor necrosis factor-alpha and IL-6 were also elevated combined with concomitant increases in IL-1 receptor antagonist in both groups and IL-10 in TR subjects only. Findings suggest that the threshold for endotoxin leakage and inflammatory activation during EHS occurs at a lower temperature in UT compared with TR subjects and support the endotoxin translocation hypothesis of exertional heat stroke, linking endotoxin tolerance and heat tolerance.

Am J Physiol Gastrointest Liver Physiol. 2017 Mar 23:ajpgi.00066.2017. doi: 10.1152/ajpgi.00066.2017. [Epub ahead of print]
Changes in intestinal microbiota composition and metabolism coincide with increased intestinal permeability in young adults under prolonged physiologic stress.
Karl JP, Margolis LM, Madslien EH, Murphy NE, Castellani JW, Gundersen Y, Hoke AV, Levangie MW, Kumar R, Chakraborty N, Gautam A, Hammamieh R, Martini S, Montain SJ, Pasiakos SM.
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The magnitude, temporal dynamics, and physiologic effects of intestinal microbiome responses to physiologic stress are poorly characterized. This study used a systems biology approach and multiple-stressor military training environment to determine the effects of physiologic stress on intestinal microbiota composition and metabolic activity, and intestinal permeability (IP). 73 Soldiers were provided three rations/d with or without protein- or carbohydrate-based supplements during a four day cross-country ski march (STRESS). IP was measured before and during STRESS. Blood and stool samples were collected before and after STRESS to measure inflammation, stool microbiota, and stool and plasma global metabolite profiles. IP increased 62%±57% (mean±SD, P<0.001) during STRESS independent of diet group, and was associated with increased inflammation. Intestinal microbiota responses were characterized by increased α-diversity, and changes in the relative abundance of >50% of identified genera, including increased abundances of less dominant taxa at the expense of more dominant taxa such as Bacteroides. Changes in intestinal microbiota composition were linked to 23% of metabolites that were significantly altered in stool after STRESS. Pre-STRESS Actinobacteria relative abundance, and changes in serum IL-6 and stool cysteine concentrations, collectively, accounted for 84% of the variability in the change in IP. Findings demonstrate that a multiple-stressor military training environment induced increases in IP that were associated with alterations in markers of inflammation, and with intestinal microbiota composition and metabolism. Observed associations between IP, the pre-stress microbiota, and microbiota metabolites suggest targeting the intestinal microbiota could provide novel strategies for preserving IP during physiologic stress.