Exercise induced gastrointestinal damage: The influence of exercise intensity and sex hormones

Background

A large proportion of endurance and ultra-endurance athletes experience exercise induced gastrointestinal syndrome. One aspect of this syndrome is physical damage to the intestinal mucosa, a semi-permeable barrier regulating homeostasis through fluid and nutrient flux while providing protection against pathogenic bacteria. During strenuous exercise the primary driver of exercise induced gastrointestinal damage (EIGD) is intestinal ischaemia caused by the redistribution of blood flow away from the gastrointestinal tract and toward the working muscles and skin. EIGD may result in impaired nutrient absorption, gastrointestinal symptoms, systemic inflammation and an increase in systemic endotoxin, thus impacting an athlete’s performance during training and competition, and delaying recovery. EIGD has also been implicated in the pathophysiology of exercise-associated collapse and heatstroke in athletes.

The role of exercise intensity, exercise modality, and sex on perturbations to the intestinal barrier requires further elucidation. Although ‘strenuous’ activity is known to result in EIGD, the trajectory of that damage, including the identification of a potential intensity threshold for damage, is yet to be established. The impact of exercise mode on EIGD is also unknown, although running appears to result in greater frequency and severity of gastrointestinal symptoms and is also thought to elicit greater mechanical damage than cycling. It is also unclear if EIGD differs between males and females. During exercise, splanchnic hypoperfusion results in intestinal ischaemia; in clinical settings in which traumatic intestinal ischaemia occurs, hormones such as oestrogen play a protective role. Our understanding of the impact of sex on EIGD, however, is limited.

The primary aim of this thesis is to explore the relationships between EIGD, exercise intensity, and sex hormones.

Methods

Five studies were conducted to address this aim. Studies 1 and 2 were randomised, crossover trials aiming to 1) quantify gastrointestinal damage with increasing exercise intensity, and 2) determine if running increased gastrointestinal damage more than cycling. Participants completed three cycling trials at different intensities (60 min at 40%, 60% and 80% V̇O2max) or one running and one cycling trial (45 min at 70% V̇O2max). Venous blood samples were collected pre- and post-exercise to measure gastrointestinal damage via intestinal fatty acid binding protein (I-FABP).

Study 3 was the development of a clinical trial protocol, and a subsequent pilot study, to investigate the effects of sex hormones on EIGD. Females with a natural, eumenorrheic menstrual cycle attended the lab during the early follicular, late follicular and mid-luteal phases of their menstrual cycles and ran for 60 min at 90% of their second ventilatory threshold (VT2). Venous blood samples were collected pre- and post-exercise to measure I-FABP and sex hormones.

Study 4 was an analysis of intestinal damage and associated hormone data derived from plasma samples obtained from another research group when it became clear the COVID-19 pandemic would impact recruitment for the clinical trial. The plasma samples were from a study with female cyclists exercising during the mid-luteal menstrual phase and were analysed in our laboratory for I-FABP.

Study 5 was a field study at a local trail running festival. This provided an opportunity to investigate the effects of different race distances on EIGD. Pre- and post-race I-FABP, hormones and lactate were quantified and gastrointestinal symptoms recorded for runners in races of 12 km, 23 km, 45 km, 100 km and 160 km.

Following these studies, a literature audit was conducted to quantify female representation in the EIGD evidence base, and to determine the quality of methodological control in verifying the hormone profile of those participants.

Results

Studies 1 and 2 demonstrated that greater gastrointestinal damage occurred with exercise at higher proportions of V̇O2max, and this relationship between intensity and EIGD was very strong when intensity was defined as a proportion of VT2. In support of this, study 4 demonstrated that 105% of the gas exchange threshold, which at 66% V̇O2max was below VT2, was not sufficient to elicit EIGD. In study 5 (field study), I-FABP increased following all races with highest post-race concentrations following the 12 km race and a decreasing magnitude of change as distance increased. Post-race lactate was used as an indication of intensity and correlated with post-race I-FABP. Study 2 also demonstrated that running was not associated with greater gastrointestinal damage than cycling.

Interactions between I-FABP and hormones were evaluated in studies 3 and 5 (clinical trial and field study). In study 3 we had hypothesised the magnitude of change in oestrogen concentrations between the early follicular and late follicular phases of the menstrual cycle could reduce damage by 15%; there was in fact a 20% reduction in damage observed from early follicular to late follicular phases. In study 5 there was a strong negative relationship between post-race I-FABP greater than 1,000 pg∙mL-1, and both pre- and post-race oestradiol, suggestive of a threshold at which oestradiol may be protective.

The audit identified that females represent only 14% of the participants in EIGD research. Of 89 studies, 51 recruited only male participants, but zero were conducted using only female participants. None of the 51 studies were related to issues that were male-specific, and only three provided a reason for not including females. Six studies grouped data by sex and although no sex differences were identified, only one reported the data. Methodological control to verify hormonal status was limited with only two of 38 studies implementing best practice methodologies.

Conclusion

This thesis presents novel data on the effects of exercise intensity on EIGD and for the first time show that exercise intensity, when expressed as a percentage of ventilatory threshold, is strongly associated with intestinal damage. The findings suggest that running is unlikely to elicit greater damage than cycling when relative intensities are comparable. I suggest there is an effect of the menstrual cycle on EIGD and present data that demonstrates a relationship between oestrogen and EIGD in trail running. Finally, I highlight the need for not only a greater quantity, but a greater quality, of data relating to female athletes if we are to understand potential sex differences in EIGD.