Exercise-induced gastrointestinal dysfunction in endurance athletes   

FUNCTIONAL SPORTS NUTRITION - JULY/AUGUST 2018

Having just completed her dissertation research project as a final year student at CNELM, Katherine Caris-Harris shares her mechanism review, incorporating the functional medicine model, that investigates the role of exercise-induced endotoxemia in lower GI dysfunction in endurance athletes.

If you do endurance sports, it is likely that you will have experienced gastro-intestinal dysfunction at some point, either in a race or during training. Gastro-intestinal dysfunction (GID) can vary in severity from mild nausea and cramping to vomiting and diarrhoea, and is frequently cited as a reason for not finishing a race (1). The growth in endurance sports such as marathons, both standard and ultras, and Ironman competitions over the last few years has made this an area of increasing interest, but the exact mechanisms involved remain unclear. Previous studies have linked reduced splanchnic blood flow (SBF), exacerbated by heat stress and ischemia, to GID, but there is a large heterogeneity in results, making it hard to establish firm links.

The purpose of this research project was to examine the evidence using a systematic search process of review, animal, human and intervention studies to determine the main pathways involved in GID, and to identify potential nutritional interventions. The functional medicine model was used as an overlay, as it is likely that the aetiology is multi-factorial, so it is helpful in explaining some of the disparity in results seen, while also allowing greater clinical application for practitioners.   

Mechanisms

After a thorough search of the review literature, a decision was made to narrow the focus to lower GID only, where the involvement of the principal upstream pathways of ischemia and heat stress were clear. However, how they interlinked and led to GID, was less clear. To try to establish a clearer link, two additional downstream pathways, involving tumour-necrosis-factor-alpha (TNFα) and interleukin-6 (IL6) were chosen for further examination, also based on the initial evidence found. Further details of the mechanisms considered can be seen in Figure 1. 

  • - The ischemic pathway is activated by the sympathetic nervous system during endurance exercise and it results in reduced splanchnic blood flow (SBF), as blood is shunted to working muscles. It has been estimated that SBF can be reduced by up to 80 per cent during maximum intensity exercise (2), although it is unlikely that many endurance athletes would be working at this output over longer distances. Reduced SBF results in hypo-perfusion of the gastrointestinal tract, leading to ischemia and cellular hypoxia and increased reactive oxygen species (ROS), contributing to an overload of an individual’s anti-oxidant systems (3). One of the key ROS’s induced is hydrogen peroxide, which has been shown to not only activate nuclear-factor-kappa-B, up-regulating potentially pro-inflammatory cytokines such as IL6, but also to induce phosphorylation of occludin, reducing gastrointestinal tight junction integrity (4), potentially causing intestinal permeability.
  • - The heat stress pathway is activated by an elevated core temperature during prolonged exercise, which can result in oxidative damage, subsequent activation of key phosphorylation enzymes, and further disruption to epithelial cell tight junction integrity (4,5).

Mechanism diagram

Figure 1 - Final mechanism diagram of pathways involved in gastro-intestinal dysfunction in sport

The activation of these pathways results in two key events: 1) increased intestinal permeability and 2) reduced ability to neutralise elevated blood lipopolysaccharides (LPS). LPS can trigger the release of potentially inflammatory cytokines, such as IL6 and TNFα, which have been linked to GID (6). Interleukin 6 (IL6) has both anti- and pro-inflammatory functions and it is suggested that its pyrogenic properties attenuate the endotoxaemic response via its role as a thermo-regulatory sensor in the gut, and subsequent signalling via the hypothalamus-pituitary-adrenal axis. It has been postulated that IL6 is responsible for altered pain perception and potential GID symptoms, such as cramping (7). TNFα has been shown to damage the sodium-potassium pump on intestinal epithelial cells, resulting in reduced water absorption, increased fluid secretion and diarrhoea (8).

Examining the evidence

Examining the evidence for these theories was not easy. The animal studies were in many cases inconclusive, often with little supportive evidence or translatability to endurance athletes. Although there were still limitations to the human studies, not least the definition of ‘endurance’, more could be drawn from these studies, helping to highlight areas for potential intervention and further research. Overall the studies indicated: 

  • - Broad evidence linked endotoxaemia with increased intestinal permeability and tight junction damage (5,9,10,11) and subsequent gastrointestinal dysfunction (12,13).
  • - A role for the ischemic pathway via measurement of certain key antioxidant enzymes or corresponding biomarkers, indicating increased lipopolysaccharide load in the body during endurance exercise (14,15).
  • - A clear role for the heat stress pathway, but whether environmental heat aggravated endotoxaemia was less clear (16).
  • - A potential role for IL6 linking gastrointestinal dysfunction in endurance athletes (17,18) and IL6 with endotoxaemia (19), with the gut-brain axis cited as a potential mechanism.
  • - Inconclusive evidence for the role of TNFα, but the short half-life of TNFα (and difficulty measuring it) should be considered.

Nutritional intervention

The nutritional intervention search was based around studies using probiotics because it was felt that they offered the best multi-targeted approach. An increasing body of research suggests that probiotics can modulate tight junction integrity and the gut-brain axis, and up-regulate antioxidant enzyme production, all pertinent to the evidence found. There were two randomised controlled studies found that were particularly pertinent, both of which supported the role of probiotics in gastrointestinal health (20, 21).

The first by Roberts et al (20) looked at the effect of a 12 week intervention of mixed strain probiotics (30bn CFU with fructo-oligosaccharides), with and without antioxidants (N-acetyl-carnitine and alpha-lipoic acid), on 30 participants prior to a long-distance triathlon. The probiotic group plus probiotic + antioxidant group reported significantly reduced gastrointestinal episodes during the race and significantly reduced endotoxins both pre- and post-race. It was postulated by the authors that the provision of the Lactobacillus genus may provide a more favourable immune response by activating toll-like-receptor-2 (TLR2), which acts in opposition to toll-like-receptor-4. The role for commensal bacterial stimulation of TLR2 in the gut epithelium as a regulator of epithelial integrity is supported elsewhere (22). The addition of fructo-oligosaccharides is potentially significant, by providing additional benefits via an increase in short-chain-fatty acids, which are known to have a complex interplay with gut microbiota and can affect tight junction integrity directly.

A further 14 week randomised controlled trial on endurance-trained men by Lamprecht et al (21), using an alternative multi-specie probiotic (10bn CFU), showed a significant decrease in zonulin expression, supporting results from Roberts et al. Other studies reviewed used predominately single-strain species and were of shorter duration, with less significant results. While it is well accepted that moderate exercise can positively impact the composition of the microbiome via enhancement of the number of beneficial microbial species and enrichment of diversity, less is known about the impact of more ‘extreme’ exercise. Very interestingly, a recent experiment by magazine group Outside, where faecal samples from various groups of athletes were sent to the American Gut Project for examination, suggested that those who compete in similar sports have similar gut bacteria (23). 

The functional medicine model

Antecedents and mediators, which may predispose an athlete to gastrointestinal dysfunction, include: history of antibiotic use, the use of non-steroidal anti-inflammatory drugs (NSAIDs) during and outside of a race, genetic predisposition, training status, body fat mass, perception of pain, lifestyle (particularly stress/total-load), plus the athlete’s diet, including nutrient deficiencies and any other underlying heath issues. A summary of some of the main factors are laid out in Table 1, using the functional medicine model systems-based approach.  

‘Stress’, in its various guises of physical, psychological and physiological inputs to the body, is frequently high in athletes, particularly age-groupers who are pushing themselves to their limit in all areas of their lives. Stress plays a role in our gut health via reduced levels of secretory IgA (24), which for endurance athletes is already under assault from prolonged training. Secretory IgA has been shown to impact the balance of our gut microbiota, potentially acting, as discussed above, via the gut-brain axis to lead to gastrointestinal dysfunction. However, it’s worth noting that this is likely to be only one of multiple mechanisms.     

With a rise in reported food intolerances and allergies (25), gluten, which has been shown to reduce tight junction integrity via the upregulation of zonulin (26), is receiving a lot of attention and should certainly be a consideration for athletes, where a high-energy intake is required and consumption of gluten is possibly high. A review paper by Lis et al (27) looked at the impact of gluten on an athlete and the unique stress that this places on their body. The researchers found that the number of athletes who follow a gluten-free diet is actually four times higher than the 5-10 per cent of the general population who are following a gluten-free diet. Despite this observation, they suggested that no clinical evidence currently existed for the benefits of a gluten-free diet. However, the many confounders, such as other unknown food intolerances, including cross-reactivity and lack of compliance (intentional or otherwise), and alteration in short-chain-carbohydrate consumption, should all be considered in assessing this outcome.  

Genetic predisposition of athletes is also a large consideration in this area, and with testing now widely available, it can be used where appropriate to help determine nutritional protocols for gastrointestinal health. 

Table 1 GI

Table 1 - Role of the functional medicine model systems on intestinal permeability and endotoxin levels during endurance exercise

To Conclude

There is much research still to be done in the area of probiotic supplementation, specifically in relation to endurance athletes and understanding further the therapeutic benefits of individual strains. However, there is clear evidence that multi-strain probiotics (30bn CFU) over a period of 12 weeks or more can improve tight junction integrity and thus potentially lower the risk of gastrointestinal dysfunction in endurance athletes, with potential further benefit with the addition of antioxidants. Other nutritional interventions of interest, but not explored here, include l-glutamine, nucleotides, antioxidants and bovine colostrum. A word of warning on bovine colostrum, however; although it is not banned by WADA, it is ‘not recommended’ due to its high insulin-like growth factor content, so should be used with caution by those competing (28). An area of growing interest is that of nucleotide supplementation, where there is evidence that supplementation can increase sIgA levels and decrease cortisol post-training, compared to placebo (29, 30). However, in order to optimise outcomes, intervention decisions should ultimately be made on a case-by-case basis, with consideration to an athlete’s overall health, lifestyle, training-load, diet and unique biochemical make-up. 

References

  1. de Oliveira E et al (2014). Gastrointestinal complaints during exercise: prevalence, etiology, and nutritional recommendations. Sports Medicine 44(S1):79–85.
  2. de Oliveira E & Burini R (2014). Carbohydrate-dependent, exercise-induced gastrointestinal distress. Nutrients 6:4191–4199.
  3. van Wijck K et al (2011). Exercise-induced splanchnic hypoperfusion results in gut dysfunction in healthy men. PLoS ONE. 6(7):e22366.
  4. Zuhl M et al (2014). Exercise regulation of intestinal tight junction proteins. British Journal of Sports Medicine. 48(12):980–986.
  5. Lambert G (2008). Intestinal barrier dysfunction, endotoxemia, and gastrointestinal symptoms: The “Canary in the Coal Mine” during exercise-heat stress? In Thermoregulation and Human Performance (Vol. 53, pp. 61–73). Basel: KARGER.
  6. Lim C & Mackinnon L (2006). The roles of exercise-induced immune system disturbances in the pathology of heat stroke: the dual pathway model of heat stroke. Sports Medicine. 36(1):39–64.
  7. Vargas N & Marino F (2016). Heat stress, gastrointestinal permeability and interleukin-6 signalling - Implications for exercise performance and fatigue. Temperature. 3(2):240–251.
  8. Musch M et al (2002). T cell activation causes diarrhea by increasing intestinal permeability and inhibiting epithelial Na+/K+-ATPase. Journal of Clinical Investigation. 110(11):1739–1747.
  9. van Wijck K et al (2011). Exercise-induced splanchnic hypoperfusion results in gut dysfunction in healthy men. PLoS ONE. 6(7):e22366.
  10. Yeh Y et al (2013). Gastrointestinal response and endotoxemia during intense exercise in hot and cool environments. European Journal of Applied Physiology. 113(6):1575–1583.
  11. Tenhunen J et al (2003). Apparent heterogeneity of regional blood flow and metabolic changes within splanchnic tissues during experimental endotoxin shock. Anesthesia & Analgesia. 97(2):555–563.
  12. Stuempfle K et al (2016). Nausea is associated with endotoxemia during a 161-km ultramarathon. Journal of Sports Sciences. 34(17):1662–1668.
  13. Bruins M et al (2003). Effect of prolonged hyperdynamic endotoxemia on jejunal motility in fasted and enterally fed pigs. Annals of Surgery. 237(1):44–51.
  14. Holland A et al (2015). Influence of endurance exercise training on antioxidant enzymes, tight junction proteins, and inflammatory markers in the rat ileum. BMC Res Notes. 8:514.
  15. Bielefeldt K & Conklin J (1997). Intestinal motility during hypoxia and reoxygenation in vitro. Digestive Diseases and Sciences. 42(5):878–84.
  16. Gill S et al (2015a). The impact of a 24-h ultra-marathon on circulatory endotoxin and cytokine profile. International Journal of Sports Medicine. 36(8):688–695.
  17. Steege R & Kolkman J (2012). Review article: the pathophysiology and management of gastrointestinal symptoms during physical exercise, and the role of splanchnic blood flow. Alimentary Pharmacology & Therapeutics. 35(5):516–528.
  18. Gill S et al (2015b). Circulatory endotoxin concentration and cytokine profile in response to exertional-heat stress during a multi-stage ultra-marathon competition. Exercise Immunology Review. 21:114–128.
  19. Jeukendrup A et al (2000). 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. Clinical Science. 98:47–55.
  20. Tenhunen J et al (2003). Apparent heterogeneity of regional blood flow and metabolic changes within splanchnic tissues during experimental endotoxin shock. Anesthesia & Analgesia. 97(2):555–563.
  21. Roberts J et al (2016). An exploratory investigation of endotoxin levels in novice long distance triathletes, and the effects of a multi-strain probiotic/prebiotic, antioxidant intervention. Nutrients. 8(11):733.
  22. Lamprecht M et al (2012b). Probiotic supplementation affects markers of intestinal barrier, oxidation, and inflammation in trained men; a randomized, double-blinded, placebo-controlled trial. Journal of the International Society of Sports Nutrition. 9(1):45.
  23. Karczewski J et al (2010). Regulation of human epithelial tight junction proteins by Lactobacillus plantarum in vivo and protective effects on the epithelial barrier. AJP: Gastrointestinal and Liver Physiology. 298(6):G851–G859.
  24. Outside (2018). The high-performance secrets inside athletes' guts. Available online at: https://www.outsideonline.com/2274446/gut-check?utm_content=buffer9c640&utm_medium=social&utm_source=twitter.com&utm_campaign=buffer [Accessed 22 February 2018].
  25. Engeland C et al (2016). Psychological distress and salivary secretory immunity. Brain, Behavior, and Immunity. 52:11–17.
  26. Food Standards Agency (2017). Chief Scientific Adviser’s Science Report Issue five: Food allergy and intolerance [pdf]. Available online at: https://www.food.gov.uk/sites/default/files/fifth-csa-report-allergy.pdf [Accessed 22 February 2018]
  27. Barbaro M et al (2015). Irritable bowel syndrome: advancing our understanding. Zonulin serum levels are increased in non-celiac gluten sensitivity and irritable bowel syndrome with diarrhea. Retrieved from: https://www.fluidsiq.com/pdfs/Zonulin, IBS & Non Celiac Gluten Sensitivity.pdf
  28. Lis D et al (2016). Commercial hype versus reality: our current scientific understanding of gluten and athletic performance. Current Sports Medicine Reports. 15(4):262–8.
  29. Ostojic S & Obrenovic M (2012). Sublingual nucleotides and immune response to exercise. Journal of the International Society of Sports Nutrition. 9(1):31.
  30. McNaughton L et al (2006). The effects of a nucleotide supplement on salivary IgA and cortisol after moderate endurance exercise. The Journal of Sports Medicine and Physical Fitness. 46(1):84–89.