Exercise-induced gastrointestinal dysfunction in endurance athletes – Katherine Caris-Harris

Gastrointestinal health in athletes has become an important speciality subject for nutritional therapist Katherine Caris-Harris. In this article, she shares her mechanistic review of gastrointestinal dysfunction, incorporating the functional medicine model.

If you take part in endurance sports, it is likely that you will have experienced gastrointestinal dysfunction at some point, either in a race or during training. Gastrointestinal dysfunction 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). Over the last few years, the growth in endurance sports such as marathons, both standard and ultras, and Ironman competitions 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 gastrointestinal dysfunction, 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 scientific evidence for gastrointestinal dysfunction using a systematic search process of review, animal, human and intervention studies to determine the main pathways involved in gastrointestinal dysfunction 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 of gastrointestinal dysfunction

After a thorough search of the review literature, a decision was made to narrow the focus to lower gastrointestinal dysfunction, where the involvement of the principal upstream pathways of ischemia and heat stress was clear. However, how they interlinked and led to gastrointestinal dysfunction 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 antioxidant 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).
  
  

Figure 1 – Final mechanism diagram of pathways involved in gastrointestinal 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 gastrointestinal dysfunction (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 thermoregulatory 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 gastrointestinal dysfunction 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 for gastrointestinal dysfunction

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 interventions for gut health in athletes

The nutritional intervention search was based on 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. Two randomised controlled studies found were particularly pertinent, both of which supported the role of probiotics in gastrointestinal dysfunction to optimize 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 dysfunction 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 of 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 on gastrointestinal dysfunction. 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 applied to gut health

Antecedents and mediators, which may predispose an athlete to gastrointestinal dysfunction, include a 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 health issues. A summary of some of the main factors is 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 may be 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 endurance athletes may already be under assault from periods of 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 will likely be only one of multiple mechanisms in gastrointestinal dysfunction.     

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 with gastrointestinal dysfunction, 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 to 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 in gastrointestinal dysfunction.  

The 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 dysfunction to optimize gastrointestinal health. 

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

To conclude

Much research is still to be done in probiotic supplementation, specifically in relation to endurance athletes and further understanding 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.