Sports Dietitians Australia and Ultra Sports Science Foundation Joint Position Statement: A Practitioner Guide to the Prevention and Management of Exercise-Associated Gastrointestinal Perturbations and Symptoms

Exercise-Induced Gastrointestinal Syndrome (EIGS)

The etiology and pathophysiology of EIGS is presented in Fig. 1 [3, 34]. EIGS comprises two primary pathophysiological pathways. The circulatory-gastrointestinal pathway describes the splanchnic hypoperfusion and gastrointestinal ischemia that occurs due to a redistribution of blood flow to skeletal muscle and peripheral circulation, addressing the metabolic and thermoregulatory demands of the exercise [35, 36]. Such typical physiological alterations in response to exercise may result in intestinal epithelial injury and hyperpermeability, as well as local and/or systemic inflammatory effects in response to translocated luminal originating pathogens, including but not limited to whole bacteria and/or bacterial endotoxins [33, 37–40]. The neuroendocrine-gastrointestinal pathway describes the stress response contribution to gastrointestinal integrity and functional disturbances, potentially via increases in sympathetic activation and stress hormone responses [26–29]. These neuroendocrine stress responses are synonymous with impaired gastrointestinal motility, transit, digestive function, and nutrient absorption [26–28, 41–46]. They are likely associated with negative impacts on the myenteric and/or submucosal plexuses of the enteric nervous system, and/or the independent intestinal smooth muscle activation of interstitial cells of Cajal (i.e., pace-maker cells of the gastrointestinal tract that are coupled with gastrointestinal smooth muscle and epithelial tissue) [47–49]. Two additional pathways have been proposed, but still warrant substantial investigation for clarity in pathophysiological contribution. These include the mechanical strain of exercise (i.e., jarring, jolting, macro- and micro-vibrations, and/or tissue friction) on the splanchnic area and exaggerated metabolic responses to exercise (i.e., increased pH). First, biomechanical abnormalities aligned with mechanical strain on the splanchnic area may impact the circulatory-gastrointestinal and neuroendocrine-gastrointestinal pathways and potentially lead to hypersensitivity of epithelial, connective, and/or surrounding tissues of the gastrointestinal tract [7, 50]. Second, metabolic acidosis associated with high intensity exercise and hypoglycemia associated with prolonged endurance exercise have been identified as culprits in exercise-associated nausea [51–53].

Fig. 1

Updated schematic description of exercise-induced gastrointestinal syndrome (EIGS) and links to exercise-associated gastrointestinal symptoms (Ex-GIS). Text boxes: Darkest grey, instigation and final outcome; dark grey, primary causal mechanisms; medium grey, secondary outcomes to the causal mechanisms; light grey, subsequent follow-on outcomes in response to the secondary outcomes. Beige arrows indicate EIGS pathway flow and direction, and black arrows indicate intra-EIGS linkage. ^aSpecialized antimicrobial protein-secreting (i.e., Paneth cells) and mucus-producing (goblet cells) cells aid in preventing intestinal-originating pathogenic microorganisms entering systemic circulation. ^bIncrease in neuroendocrine activation and suppressed submucosal and myenteric plexuses may result in epithelial cell loss and subsequent perturbed epithelial tight junctions [49, 54]. ^cSplanchnic hypoperfusion and subsequent intestinal ischemia and injury (including mucosal erosion) may result in direct (e.g., enteric nervous system and/or enteroendocrine cell) or indirect (e.g., braking mechanisms) alterations to gastrointestinal motility [27–29, 37, 55]. ^dGastrointestinal brake mechanisms: nutritive and non-nutritive residue along the small intestine, including the terminal ileum, results in neural and enteroendocrine negative feedback to gastric activity [44, 55–58]. ^eAggressive acute or low-grade, prolonged mechanical strain is proposed to contribute to disturbances to epithelial integrity (i.e., epithelial cell injury and tight junction dysregulation) and subsequent “knock-on” effects for gastrointestinal functional responses [50]. ^fMetabolic acidosis associated with high intensity exercise and hypoglycemia associated with prolonged endurance exercise may prompt Ex-GIS [51–53]. ^gLumen originating to circulatory translocation of pathogenic agents may include, but is not limited to: whole bacteria, bacterial endotoxins (e.g., lipopolysaccharide, lipid A, flagella, and/or peptidoglycan), exocrine originated digestive enzymes, and/or food protein allergens [38]. ^hBacteria and bacterial endotoxin MAMPs and stress induced DAMPs are proposed to contribute toward the magnitude of systemic immune responses (e.g., systemic inflammatory profile) [59]. *Primary role in EIGS pathophysiology still warrants substantial exploration and investigation. EIGS, exercise-induced gastrointestinal syndrome; GIS, gastrointestinal symptoms; MAMPs, microorganism molecular patterns; DAMPs, danger-associated molecular patterns. Adapted with permission from “Systematic review: exercise-induced gastrointestinal syndrome- implication for health and disease,” by R.J.S. Costa, R.M.J. Snipe, C. Kitic, and P. Gibson, 2017, Alimentary Pharmacology and Therapeutics, 46(3), pp. 246–265. Copyright 2017 by John Wiley & Sons Ltd. [3]

Exercise-Associated Gastrointestinal Symptoms (Ex-GIS)

One of the predominant outcomes of EIGS, which has been established to affect exercise performance and may provide an indication of something more clinically sinister, is Ex-GIS. Several reviews have reported on the incidence and severity of Ex-GIS predominantly in observational field studies, specifically in endurance and ultra-endurance activities that focus on running and/or cycling modalities in both elite and recreational populations [17, 20, 60–62]. Reported studies applied baseline and/or retrospective post-race gastrointestinal symptoms (GIS) subjective assessment tools of different origins and applications (e.g., established or in-house fabrications, Likert-type or visual analog scale). Considering the difference in methodological approach, it is not surprising that a large variation in symptom incidence and severity is evident. These range from negligible Ex-GIS incidence in a recreational endurance running event, [61] 4% after marathon competition, [20] and ≥ 93% in response to ultra-endurance event participation, [19, 63] with severity ranging from minor inconvenience to severe that warranted event withdrawal. These and other reports provide some indication that longer-duration exercise, especially when conducted in hot ambient conditions, tends to promote higher incidence rates of Ex-GIS [17]. Moreover, longer duration exercise bouts that require exogenous feeding tend to induce more Ex-GIS incidence despite a lower exercise intensity, which has been linked to individual variation in feeding tolerance [20, 41–43, 64–66]. To improve consistency in Ex-GIS interpretation within exercise gastroenterology research, the use of a standardized exercise-specific validated and reliable GIS assessment tool has been recommended [67, 68].

The type of Ex-GIS reported, in accordance with the ROME criteria for symptom type (i.e., currently ROME IV criteria), [69, 70] can be classified as either gastro-esophageal (i.e., upper-GIS): belching, heartburn (gastroesophageal reflux), upper-abdominal bloating or pain, urge to regurgitate, and/or regurgitation; intestinal (i.e., lower-GIS): flatulence, lower abdominal bloating or pain, urge to defecate, abnormal defecation, and/or fecal blood loss; and/or other symptoms not otherwise specified (i.e., nausea and acute transient abdominal pain—stitch) [68]. Despite mainstream dogma proposing that lower-GIS symptoms (e.g., diarrhea) are more commonly linked to exercise, the scientific literature does not support this notion, with upper-GIS consistently being more commonly reported during and/or immediately after exercise, both in laboratory controlled and field-based experimental models [17, 20, 42, 71–73]. In addition, nausea appears to be a frequently reported symptom in ultra-endurance activities, [19, 20, 63, 74] which is rarely reported in lesser exercise loads or experimental models [20, 44, 61, 65, 72]. Taken together, the available research suggests that the magnitude (i.e., exercise duration, intensity, and environmental factors) of exertional stress and requirement for feeding during the exercise plays a key role in Ex-GIS incidence and severity. The incidence type, severity, time of onset, and when symptoms subside may provide some indication of relationships between Ex-GIS and EIGS pathophysiology (Fig. 1).

EIGS and Ex-GIS Exacerbation Factors

Several extrinsic and intrinsic factors have now been identified and/or confirmed to exacerbate EIGS and Ex-GIS, ranging from minimal, to modest, to more extensive impact; which has been summarized in Table 1. Consensus impact was assigned on the basis of: (1) the number of research studies (i.e., cross-sectional analysis, exploratory, or intervention laboratory-controlled trials) investigating the impact of the exacerbation factor or factors on gastrointestinal and/or systemic perturbations to exercise; (2) the quality of experimental procedures and control of confounding factors in accordance with exercise gastroenterology research best-practice recommendations checklist [67]; (3) the magnitude of response (i.e., none, to modest, to clinically relevant minimal detectable change) of any identified gastrointestinal and/or systemic perturbations to exercise [33]. Assigned magnitude of impact on EIGS and/or Ex-GIS may include: unknown (?), minimal ( +), moderate (+ +), and extensive (+ + +). These factors and their potential magnitude of impact need to be considered when assessing the potential effectiveness of proposed prevention or management strategies for EIGS and Ex-GIS, and using such strategies for individual athlete therapeutic intervention. This is important, as these constitute potential confounding factors for exercise-associated disturbances to gastrointestinal integrity and function and systemic immune responses [12, 75].

Carbohydrate

Carbohydrate ingestion during prolonged exercise is common practice, and its effects on EIGS and Ex-GIS are therefore of interest. Carbohydrate ingestion immediately before or during exercise may attenuate disturbances to gastrointestinal integrity associated with EIGS through postprandial hyperemia [108, 112]. Carbohydrate ingestion during exercise also aids the maintenance of blood glucose that attenuates stress hormone responses and potential rises in systemic inflammatory cytokines; [73] thus, it may play a role in mitigating EIGS. On the contrary, excessive carbohydrate ingestion and the type of carbohydrate ingested during exercise may adversely affect the function of the gastrointestinal tract (e.g., delayed gastric emptying and/or malabsorption) and lead to Ex-GIS, subsequently impacting exercise performance (Sect. 9 and supplementary file 1).

The majority of research to date suggests that carbohydrate ingestion before and/or during exercise can minimize or prevent perturbations to gastrointestinal integrity [73, 114–116]. For example, carbohydrate doses of 15.0–22.5 g every 15–30 min (20–90 g/h) during cycling or running exercise of 1–2 h duration, with or without heat exposure (32–35 °C and 27–70% relative humidity (RH)), has attenuated the rise in plasma intestinal fatty acid binding protein (I-FABP; a surrogate biomarker indicative of intestinal epithelial cell injury) concentration and small intestine permeability (i.e., via dual-sugars test for lactulose to rhamnose (L:R) ratio) compared with ingestion of water alone [73, 114–117]. Two studies did not observe a reduction in I-FABP with carbohydrate intake of 27 g/h during 60 min running (70% V̇O_2max, 30 °C) and 108 g/h during 3 h cycling [118, 119]. However, these studies failed to show any substantial increase in I-FABP compared with the control, suggesting that the lack of effect may be due to insufficient thermophysiological impact rather than carbohydrate ingestion [67]. Moreover, another study that showed a reduction in I-FABP with carbohydrate intake compared with water failed to observe differences in splanchnic perfusion (i.e., gap between gastric and arterial pCO₂) by gastric tonometry [115], potentially owing to the lack of sensitivity of this method to detect difference in perfusion at the level of the intestinal villi. In the aforementioned studies, there has been no difference observed in markers of endotoxemia (i.e., lipopolysaccharide (LPS) and lipopolysaccharide binding protein (LBP)). However, Snipe et al. [73] observed an increased endogenous endotoxin core antibody (EndoCAb IgM) concentration with carbohydrate ingestion and depressed concentrations with water. This suggests potential activation of EndoCAb, which is associated with systemic appearance of pathogenic agents, was overused in the water trial, but not on the carbohydrate trial, irrespective of the post-exercise LPS concentration (i.e., via limulus amebocyte lysate gram-negative bacterial endotoxin determination). Only one study has explored systemic inflammatory responses in conjunction with other EIGS markers with carbohydrate intake and found attenuation of interleukin (IL)-6 compared with water intake, but no differences in the exertional-heat stress induced increases in proinflammatory (i.e., tumor necrosis factor alpha (TNFα) and IL-1β) or anti-inflammatory (i.e., IL-10 and IL-1ra) cytokines between the carbohydrate and water control trials [73]. Together, the current research shows good evidence that ingestion of moderate (20–60 g/h) and/or high (> 60 g/h) amounts of carbohydrates during exercise is an effective strategy to attenuate disturbances to gastrointestinal integrity and systemic responses. However, carbohydrate ingestion tolerance will dictate intake impact on gastrointestinal functional responses and Ex-GIS incidence and severity (Sect. 9 and supplementary file 1).

Grade of Evidence: I

Glutamine

The ingestion of protein (i.e., containing a variety of amino acids) and/or specific amino acids (and derivatives) may play a role in preventing EIGS through the provision of energy substrate to intestinal epithelial cells, regulation of intestinal barrier structure and function, and intestinal immune function [120]. The most well-researched singular amino acid to date for EIGS prevention or management is glutamine, on the basis of its provision as a primary fuel source for epithelial enterocytes [121]. Several studies have demonstrated that acute (0.25–0.9 g/kg fat-free mass (FFM) consumed 2 h before exercise) and prolonged (0.9 g/kgFFM/day for 7 days and 3 g L-glutamine with 0.69 g L-cysteine for 5 days) glutamine supplementation attenuated the modest rise in exercise-associated small intestine permeability in response to 60 min running at 65–75% V̇O _2max in 25–30 °C and 12–60% RH [122–125]. However, the studies failed to show any beneficial effects on luminal to systemic pathogenic translocation (e.g., bacterial endotoxin) and systemic inflammatory cytokine responses (e.g., TNFα). A dose response study demonstrated small reductions in plasma I-FABP concentration with higher (0.5 and 0.9 g/kgFFM), but not lower (0.25 g/kgFFM), acute glutamine supplementation compared with a non-nutritive placebo [122]. These findings contrast with other studies that have observed small, but significant reductions, in plasma I-FABP concentrations pre-exercise on the second day of exercise in the heat with low glutamine doses provided 1 h before exercise (0.15 g/kgBM) and post-exercise with prolonged (3 g/day L-glutamine with 0.69 g/day L-cysteine for 5 days) supplementation [123, 126]. It should be noted that values present in all studies for gastrointestinal integrity disturbance through the experimental procedure timeline were minor and of little clinical relevance [33, 67]. In contrast, several recent studies have shown no benefit to EIGS prevention and management with glutamine ingested before exercise. For example, 0.9 g/kgFFM L-glutamine ingested 60 min before a 20 km cycling time trial (~ 33 min) in 35 °C and 51% RH did not attenuate the post-exercise modest rise in plasma I-FABP, IL-6, or TNFα concentrations, and responses were not different to the non-nutritive placebo [127]. Similarly, ingestion of 0.3 g/kgFFM L-glutamine 60 min before 80 min treadmill walking at 6 km/h with 6% gradient in 35 °C and 30% RH and run to exhaustion (~ 22 min) at lactate threshold speed in 40 °C and 40% RH did not substantially attenuate disturbances to gastrointestinal integrity [128, 129]. Methodological limitations have been raised in these studies, questioning the results validity into real-world practice [67]. The majority of studies have not reported Ex-GIS with L-glutamine ingestion [122, 127–129]. However, a dose–response study showed increased Ex-GIS with glutamine ingestion at 0.9 compared with 0.6 and 0.3 g/kgFFM, which were more pronounced during the 2 h following ingestion [130]. Overall, there are conflicting findings on the effect of glutamine on EIGS, with any beneficial effects reported linked to magnitude of response being small and of no clinical relevance.

Grade of Evidence: III

Arginine and Citrulline

L-arginine and L-citrulline (i.e., L-arginine precursor) may enhance nitric oxide production at the intestinal villi microvascular compartment, with a proposed subsequent enhancement in splanchnic perfusion that would support the maintenance of gastrointestinal epithelial integrity during exercise [131, 132]. Laboratory-controlled research with L-arginine and EIGS outcomes is lacking. However, ingestion of 30 g/day L-arginine for 14-days before a marathon did not have any effect on small intestine permeability, fecal occult bleeding, or Ex-GIS compared with equivalent supplementation with glycine [132]. Although, it should be noted that small intestine permeability, assessed by urinary dual-sugar (i.e., lactulose and mannitol) probe was not significantly elevated post-marathon compared with pre-race. Whilst this study did not observe differences in Ex-GIS, a review of arginine side effects suggests that GIS, particularly diarrhea, may occur with L-arginine intake with single doses of > 9 g or daily doses of > 30 g/day [133]. Indeed, a small increase in Ex-GIS (i.e., nausea and fullness) with the addition of L-arginine to a carbohydrate electrolyte solution has been observed during prolonged (2.5 h) submaximal (50% peak power) cycling exercise [134].

L-citrulline may enhance L-arginine-derived nitric oxide production, as the ingestion of 10 g of L-citrulline 30 min before 60 min cycling at 70% maximum workload has been shown to modestly attenuate splanchnic hypoperfusion and attenuate the rise in plasma I-FABP concentration, but with no effect on gastric or small intestine permeability [131]. It is also noteworthy to report the attenuated hypoperfusion and epithelial injury on L-citrulline supplement intervention increased to similar values as placebo immediately post-exercise. Therefore, it is not clear whether the acute attenuation during exercise was due to mechanistic effects of the L-citrulline or simply just having nutrients (e.g., amino acid derivative) along the gastrointestinal tract, as per the mechanistic alignment with carbohydrate feeding before and during exercise (Sect. 4.1).

Grade of Evidence: II to III

Amino Acid Combinations

In response to the lack of clarity on the impact of singular amino acids or derivatives on biomarkers representative of EIGS, recent studies have investigated the impact of amino acid combinations on EIGS biomarkers. First, collagen peptides (10 g/day for 7 days and 45 min pre-exercise) did not influence a cluster of intestinal epithelial integrity biomarkers and inflammatory cytokines compared with a placebo in response to 70 min running at 70–90% V̇O_2max in 22 °C [135]. The application of a multiple amino acid (i.e., 4.5–6.4 g/L: valine, aspartic acid, serine, threonine, and tyrosine, with or without isoleucine) beverage intervention for 7 days, immediately pre-exercise, and during 2 h running at 60% V̇O _2max in ~ 35 °C attenuated intestinal epithelial cell injury, perturbations to bacterial and endotoxin profiles, and systemic inflammatory responses, but not circulatory bacterial DNA presence and/or alterations to systemic bacterial profile compared with the water control trial [136, 137]. Furthermore, the amino acid content within the beverage provisions did not substantially exacerbate Ex-GIS incidence and severity in response to the exertional-heat stress compared with water. It was reported that these beneficial effects may be due to the 7-day supplementation period promoting amino acid delivery before the stress exposure, subsequently improving the robustness and stability of the intestinal enterocyte cell membrane and/or tight-junction structure and function [108, 111, 112, 120, 138]. Additionally, intake during exercise may have supported villi microvascular perfusion via the nitric oxide pathway [109].

Grade of Evidence: II

Whole Protein

The ingestion of whole protein, which is more commonly consumed in foods during prolonged steady state exercise (e.g., ultra-endurance) [15, 16], has also been previously investigated for the prevention and management of EIGS. Whey protein hydrolysate (i.e., 14.8 g protein/serve) consumed before and every 20 min during 2 h running at 60% V̇O _2max in 35 °C and 27% RH attenuated plasma I-FABP concentration and small intestine permeability, and subsequently resulted in a more beneficial bacterial endotoxin profile, although these differences in plasma endotoxin concentration were not significant [73, 117]. It was speculated that these beneficial outcomes were potentially due to increased heat shock protein expression and/or stabilization of tight-junction protein complexes. While whole protein may be beneficial to EIGS outcomes linked to the circulatory–gastrointestinal pathway, such high intakes increased Ex-GIS compared with ad libitum water [73], which has feeding tolerance and performance implications [17, 42]. Although large doses of protein during exercise may induce and/or exacerbate Ex-GIS, smaller doses (i.e., 3 g every 15 min) co-ingested with glucose appear to be tolerable [139]. However, the impact of lower protein doses during exercise on EIGS markers still warrants investigation.

Grade of Evidence: II

Gluten-Free

Adherence to a gluten-free diet is prevalent amongst non-celiac athletes, with the primary reason of self-diagnosis of gluten sensitivity symptom (i.e., gastrointestinal origin) or non-symptom related benefits (i.e., improves overall health and/or ergogenic effect) [140]. A gluten-free diet restricts gluten, a storage form composite of gliadins and glutenins commonly found in wheat, rye, barley, and triticale. Unlike celiac disease, at present there is no established clinical diagnostic biomarker (i.e., allergic or autoimmune response) for non-celiac gluten sensitivity [141, 142]. Nevertheless, non-celiac athletes have reported symptomatic improvements at resting and during exercise after implementing a gluten-free diet. Such symptomatic improvements may be due to the subsequent adjunct reduction of fermentable oligo-, di-, and mono-saccharides and polyols (FODMAPs), specifically fructans and galactooligosaccharides [143–146]. Other possible reasons are a change in dietary habits per se. For example, Lis et al. [140] reported that athletes increased their fruit, vegetable, and gluten-free wholegrain consumption when they switched to a gluten-free diet. To date, there is only one study that investigated the effects of a gluten-free diet versus a gluten-containing diet in non-celiac athletes on markers of EIGS and Ex-GIS. Non-celiac competitive cyclists found no overall effect of 7 days gluten-free versus gluten-containing diet on intestinal epithelial injury, systemic inflammatory cytokines, and Ex-GIS in response to an exertional stress experimental model [147]. At present, there is no evidence supporting a gluten-free diet in nonceliac athletes in the prevention and management of EIGS and Ex-GIS.

Grade of Evidence: III

Fermentable Oligo-, Di-, and Mono-Saccharides and Polyols (FODMAP)

A low FODMAP diet is a well-recognized dietary intervention for managing diseases of gut–brain interaction (DGBI), namely irritable bowel syndrome (IBS)) [148–151]. Athletes who experience Ex-GIS often report similar symptom types as those with IBS; and commonly include flatulence, lower abdominal bloating and pain, and urge to defecate [3]. Many athletes often implement a low FODMAP diet pre-exercise as an effective strategy to reduce Ex-GIS [10, 11, 13, 152]. FODMAPs are rapidly fermentable short-chain carbohydrates, which are synonymous with increases in intestinal luminal gas, water, and metabolic by-products (e.g., short-chain fatty acids (SCFA)) [153, 154]. Collectively these biological changes result in luminal distension leading to lower-GIS symptoms in individuals with heightened visceral sensitivity [155]. Conversely, a low FODMAP diet is reported to reduce microbial diversity and total bacterial abundance [149], which may be counter productive to EIGS management. This is postulated to be due to diminished luminal content, fermentation, and SCFA production [29, 33]. Therefore, it is plausible that a lowered dietary intake of FODMAPs may support the management of Ex-GIS, but may negatively influence the pathophysiology of EIGS in susceptible athletes.

Owing to the increased energy requirements of athletes, the typical FODMAP dietary intake can be up to 81 g/day [144] compared with a typical westernized (i.e., Australian) diet of 24 g/day [153]. When adopting a low FODMAP diet (i.e., < 8 g/day of FODMAP), for either 6 days [11, 13, 152] or a short-term (i.e., 24–48 h) dietary intervention (i.e., ≤ 5 g/day) before exercise, [82, 156] a reduction in Ex-GIS severity before, during, and after exercise has been reported in response to exertional experimental models. Of interest, a 24-h low FODMAP diet before a substantial exposure to exertional-heat stress (i.e., 2 h running at 60% V̇O_2max in ~ 35 °C) showed greater intestinal injury along with a trend for a greater magnitude of bacterial endotoxin translocation, but did not impact systemic inflammatory responses compared with a high FODMAP diet. It has been proposed that the potential EIGS protective effects of a high FODMAP diet align with those mechanisms described with carbohydrate feeding before and during exercise in Sect. 4.1. In addition, they align with the increased SCFA concentrations observed in plasma and feces after high FODMAP diet adherence [28]. As discussed, there is evidence supporting the role of a short-term (i.e., 24–48 h) low FODMAP diet before exercise in reducing the severity of Ex-GIS, and there is also some evidence for a high FODMAP diet attenuating EIGS pathophysiology in athletes undertaking prolonged endurance-type exercise. Therefore, if implementing a short-term low FODMAP diet for the management of Ex-GIS severity, consideration must be given to other possible protective dietary influences on EIGS pathophysiology; namely, carbohydrate loading and/or carbohydrate feeding during exercise within tolerance levels.

Grade of Evidence: I

Low Carbohydrate High Fat (Ketogenic Targeted Diets)

Maximizing fat as a substrate for endurance exercise, via a ketogenic low-carbohydrate high-fat (LCHF) diet, originated in the early 1980s and has since been thoroughly investigated, primarily in respect to fuel kinetics and exercise performance [157]. For athletes undertaking prolonged endurance-based exercise, it is theorized that a LCHF diet may facilitate extended durations of exercise performance without the need for frequent ingestion of carbohydrate-based fuels, which seems a positive outcome in respect to lowering the gastrointestinal burden during exercise, and subsequently favoring the abolishment of Ex-GIS. However, there is currently a scarcity of research focusing on gastrointestinal responses to the application of LCHF dietary interventions. Although enhancing the ability for endogenous fat oxidation at the expense of not having to or limiting the need for exogenous carbohydrate intake during exercise seems promising, several concerning aspects can be raised. Following dietary lipid consumption, such as a high-fat meal, circulating bacterial endotoxins (i.e., LPS) concentrations have been observed to increase in human experimental models [158], linking high-fat diets with increased bacterial endotoxin entry from the intestinal lumen into systemic circulation. In addition, an increased circulating concentration of I-FABP is also commonly reported in diets aimed at increasing lipid intake and oxidation [159]. Although I-FABP is indicative of intestinal epithelial cell damage, its levels are generally proportionally linked to the rate of cellular fatty-acid metabolism [160].

In an athletic population, an increase in plasma I-FABP concentration was observed following an acute 6 days LCHF diet (i.e., < 50 g/day carbohydrate, energy availability = 40 kcal/kgFFM/day) at rest and in response to prolonged strenuous exercise (i.e., 25 km race walk) in elite race walkers compared with a high-carbohydrate diet (i.e., 65% carbohydrate, energy availability = 40 kcal/kgFFM/day) [161]. In addition, the proposed compromised epithelial barrier before and during exercise was further supported by increased concentrations of soluble CD14 (sCD14) and lipopolysaccharide binding protein (LBP), both surrogate biomarkers indicative of luminal to systemic bacterial endotoxin translocation, in the LCHF group versus the high carbohydrate group. This likely influenced systemic inflammatory responses [162]. Despite evidence of increased injury and compromise to the intestinal epithelial barrier in athletes following a LCHF diet, incidence of Ex-GIS was observed, but did not significantly differ compared with the high carbohydrate diet. It is important to highlight that the higher FODMAP content of the high carbohydrate diet may have inadvertently exacerbated Ex-GIS incidence and severity via malabsorption and bacterial fermentation (as per Sect. 5.2), and subsequently masked potential effects of LCHF on Ex-GIS via the observed intestinal epithelial perturbations. In addition, from a professional practice perspective, following 32 weeks on a LCHF diet, a world-class long-distance triathlete experienced the worst-ever performance outcomes following half-ironman and ironman competitions. He experienced negative subjective well-being, and his usual gastrointestinal disturbances were not alleviated [14]. On the basis of the current evidence to date, LCHF dietary interventions do not support the prevention or management of EIGS and Ex-GIS.

Grade of Evidence: II

Low Energy Availability

It is well-established that in medical conditions associated with acute or chronic periods of compromised nutritional intake (e.g., anorexia nervosa), gastrointestinal derangement and subsequent symptoms (e.g., gastro-esophageal and/or intestinal symptoms associated with disturbances to gastric motility, gastric emptying, and intestinal transit) are common manifestations [163, 164]. More recently, the exploration of athletes adhering to unmatched dietary and training regimes, synonymous with low energy intake, and/or high training and competition energy outputs has led to the greater knowledge and understanding of low energy availability (LEA), and the development of relative energy deficiency in sport (REDs) and its clinical consequences [165]. Clinical cases and exploratory research have revealed the multisystem impact of chronic LEA, including gastrointestinal disturbances and symptomatic outcomes potentially based on underlying neuroendocrine (e.g., altered and abnormal stress hormone responses) pathophysiology [166]. On the basis of these reports, it is plausible that individuals in a state of LEA and/or presenting diagnostic criteria for REDs may be more prone to EIGS and Ex-GIS as a result of the perturbed neuroendocrine–gastrointestinal pathway.

To date, only one study has investigated the effects of a short-term (i.e., 6 days) LEA intervention on gastrointestinal integrity biomarkers and Ex-GIS in elite race walkers [161]. Acute LEA (i.e., 65% carbohydrate, energy availability = 15 kcal/kgFFM/day) did not result in differing intestinal epithelial injury, bacterial endotoxin profile perturbations, or Ex-GIS compared with a high carbohydrate (i.e., 65% carbohydrate, energy availability = 40 kcal/kgFFM/day) diet over the dietary intervention period, in response to a 25 km race walk in temperate ambient conditions. Food and fluid were provided to mimic a race feeding regimen during exercise. It is possible that the short duration intervention may have resulted in these null effects, as longer-term LEA (i.e., timeline that impacts lean body mass and resting metabolic rate) results in more pronounced perturbations to physiological systems [165]. In addition, the provision of any carbohydrate dose during exercise may have also contributed to the lack of group differences [64, 73, 113–115]. Therefore, at this stage, it may be suggested that short-term LEA does not exacerbate EIGS or Ex-GIS; however, it is unknown if chronic LEA, leading to REDs, impacts how an individual gastrointestinal tract responds to exercise stress.

Grade of Evidence: III

Low Fiber (and/or Residue)

It is well recognized that manipulating (i.e., increasing, reducing, or altering type) the fiber (e.g., insoluble: lignin and cellulose; and soluble: arabinoxylan, beta-glucan, guar gum, inulin, and psyllium) and/or other residues (e.g., resistant starches such as amylose) of dietary intake plays a key role in symptomatic management of DGBI (e.g., gastrointestinal functional disorders—IBS) and inflammatory diseases of the gastrointestinal tract (e.g., inflammatory bowel conditions such as Crohn’s diseases and ulcerative colitis) [167–172]. Considering the neuroendocrine–gastrointestinal and circulatory–gastrointestinal pathways of EIGS presents similar pathophysiological manifestations as these disease states, respectively; it seems logical that manipulating the intake of dietary residues (i.e., insoluble and soluble fibers, and resistant starches) before exercise may influence EIGS and subsequent Ex-GIS outcomes. From a theoretical perspective, the consumption of dietary residues before and during exercise may promote both increased gastric and intestinal content that may lead to a direct (i.e., in situ content) or an indirect (i.e., gas production and water translocation aligned with bacterial fermentation of soluble fibers and resistant starches) increase in luminal pressure leading to intestinal hypersensitivity, local dysmotility, and/or ileal brake mechanisms, contributing to Ex-GIS [43, 55, 57, 58]. Nevertheless, considering the fermentable capacity of soluble fibers and resistant starches by commensal bacteria along the gastrointestinal lumen, effects may mimic those reported in research of dietary FODMAP content (see Sect. 5.2) and/or prebiotic supplementation (see Sect. 6.2) on EIGS and Ex-GIS outcomes, whether it be exacerbating Ex-GIS severity and/or providing a beneficial effect on gastrointestinal integrity.

To date, only one retrospective field-based observational study has reported on the relationship between dietary fiber intake and Ex-GIS occurrence during competition in endurance athletes (i.e., long-course triathlon) [6]. The results were limited to those triathletes that presented with “intestinal cramps” also consumed fiber-rich foods in the pre-event meal. Despite these limited observational field research findings, it is surprising that a recent experimental survey (n = 277) found that endurance athletes (15.2%) self-reported following a low fiber diet in the management of Ex-GIS, which was the highest reported management strategy [9, 10]. In addition, the cohort reported lowering dietary fiber intake leading into competition was the most successful strategy in their perceived reduction in Ex-GIS. Current sports nutrition recommendations caution athletes to be wary of high-fiber foods prior to competition owing to the possibility of increasing the risk of developing Ex-GIS [173]. It is unclear where such therapeutic information and adherence is coming from, but speculation may possibly lie with unquestioned social acceptance stemming from clinical research in DGBI (i.e., functional diseases/disorders of the gastrointestinal tract) management [167, 168, 170, 171] and/or broad-spectrum sports nutrition recommendations. Nevertheless, low-residue intake, using low-fiber and elemental-based dietary components, formed part of EIGS and Ex-GIS management in a recent case series on endurance and ultra-endurance athletes experiencing severe Ex-GIS [12]. Outcomes from the individually tailored therapeutic interventions suggested including low-fiber and residue foods and beverages within the dietary regime of certain case athletes reduced Ex-GIS incidence and severity in subsequent competitive events, leading to these athletes reporting performance improvements (e.g., event completions and victories). It is worth highlighting that other therapeutic-focused interventions formed part of the overall management plan within the case series (e.g., gut training, low FODMAP diet, measured and planned carbohydrate intake during exercise, and euhydration without fluid overload, among others), and likely also contributed to the positive outcomes. Owing to anecdotal evidence in professional practice, it is speculated that adherence to low-fiber and/or residue diets may lower the predisposition to Ex-GIS [11]. However, considering that there is no experimental evidence on this topic, well-conducted randomized controlled trials are needed to provide full insight into the impact of dietary fiber on EIGS and Ex-GIS outcomes.

Grade of Evidence: IV

Antioxidants

Oxidative stress may contribute to the exacerbation of exercise-associated intestinal epithelial injury and subsequent local inflammatory responses [174, 175]. As such, the increased activity of intestinal epithelium reactive oxygen species, during exercise and/or in the recovery period after exercise (i.e., splanchnic reperfusion), may facilitate epithelial cell injury and tight-junction protein rupture or dysfunction, leading to enhanced translocation of pathogenic agents into systemic circulation [3, 37, 138]. It has, therefore, been proposed that supplementing with nutrients that present antioxidative or anti-inflammatory properties before exercise may ameliorate the associated gastrointestinal disturbances. To date, supplements containing antioxidative or anti-inflammatory properties, including ascorbic acid, tocopherol, and capsaicin have been investigated.

Using a test–retest model, an acute dose of L-ascorbic acid (1000 mg) 2 h before an incremental cycling test to exhaustion reduced circulating gram-negative endotoxin concentration compared with a control trial 8 weeks prior [176]. Given the lack of crossover, no placebo control, and extensive time between trials, it is unclear if the modestly reduced post-exercise endotoxin levels are directly related to acute ascorbic acid ingestion. Another investigation determined the impact of 2 weeks tocopherol or soy lecithin placebo supplementation on intestinal permeability, fecal blood loss, and GIS following a marathon [177]. There was no significant change in intestinal permeability with tocopherol supplementation in response to the marathon. Additionally, no significant difference in heme-positive fecal samples was observed (tocopherol: 10% versus placebo: 20%). While abdominal cramping and pain were significantly reduced with tocopherol supplementation, heme-positive fecal samples were unrelated to Ex-GIS.

It has also been proposed that an intervention involving the administration of an antioxidant rich compound, capsaicin, may be effective in preventing and/or managing gastrointestinal epithelial injury [178]. Capsaicin is a proposed antioxidant and anti-inflammatory compound found within hot peppers and has been shown to increase blood perfusion in the gastrointestinal epithelium, albeit within animal models [178]. Thus, an increase in blood perfusion from capsaicin consumption has been hypothesized to ameliorate gastrointestinal epithelial injury in humans. A randomized control trial undertaken to assess the effect of capsaicin supplementation on sprinting performance and IL-6 response implemented an intervention where participants received 25.8 mg of capsaicin immediately prior to performing 15 × 30 m sprints at 35 s intervals at maximum effort [179]. It was determined that participants experienced increased Ex-GIS with supplementation; however, IL-6 response was unchanged pre- to post-exercise [179]. Taken together, and considering the limited studies in the area that do not meet the minimal best practice recommendations, [2] there is no clear evidence to suggest a period of antioxidant supplementation before an exercise bout prevents or can be used to manage EIGS and/or Ex-GIS.

Grade of Evidence: III to V

Biotics (Pre-, Pro-, and Syn-biotics)

It is a common belief among athletes and athlete support practitioners that a period of biotic supplementation, in the form of prebiotics (i.e., non-digestible material that can be fermented by bacteria in the lower gastrointestinal tract), probiotics (i.e., live bacteria which survives transit to colonize the lower gastrointestinal tract), or a combination referred to as synbiotics, will confer some beneficial effects to the gastrointestinal tract, particularly in response to exercise, when the gastrointestinal tract is compromised [180]. The mechanisms by which biotics may infer a beneficial effect on EIGS are associated with increasing the relative abundance of commensal bacterial along the gastrointestinal tract. This β-change may subsequently increase bacterial fermentation activity, leading to enhanced concentrations of luminal and/or plasma SCFA (e.g., acetate, butyrate, and propionate) [148, 181–183], newly termed post-biotics. Both fecal and plasma SCFA concentrations have been linked to protecting gastrointestinal integrity against exertional and exertional-heat stress [29, 33, 93]; although direct mechanistic explanation warrant further exploration and clarification.

A recent systematic literature review was undertaken to provide clarity on the impact of short or long-term biotic (i.e., pre-, pro-, syn-biotic) supplementation on markers of EIGS and Ex-GIS in response to exertional or exertional-heat stress [180]. However, no study that investigated the impact of prebiotic supplementation on EIGS and Ex-GIS was identified within the SLR. Recently, an 8-week prebiotic supplementation intervention (i.e., 16 g/day of a fructooligosaccharides, galactooligosaccharides, resistant starch, and dietary fiber formulation) prior to a 3 h exertional-heat stress experimental protocol resulted in a noticeable reduction in intestinal epithelial injury and luminal to systemic bacterial endotoxin translocation. However, it had no impact on attenuating systemic inflammatory response and did not influence gastrointestinal functional responses [184]. Additionally, the prebiotic supplementation did not further exacerbate Ex-GIS severity compared with the non-prebiotic-containing and low FODMAP placebo. It is important to note that the observed beneficial outcomes on ameliorating intestinal epithelial injury and bacterial endotoxin translocation with prebiotic supplementation were modest in nature, and overall exertional-heat stress associated gastrointestinal integrity perturbation were lower than previously reported [67]. This is likely attributed to the attenuating effects of carbohydrate feeding, as described in Sect. 4.1, which was provided in the first 2 h of the protocol.

Within the systematic literature review, probiotic and synbiotic supplementation interventions included single or multiple species/strains: B. animalis, B. bifidum, B. breve, B. lactis, B. longum, B. subtilis, E. faecium, L. acidophilus, L. brevis, L. casei, L. fermentum, L. helveticus, L. lactis, L. paracasei, L. plantarum, L. rhamnosus, L. salivarius, and/or S. thermophilus, with or without fructooligosaccharides (55.8 mg/dose) or inulin (2.3 g/dose). Bacterial doses ranged between × 10⁸ to × 10¹¹ colony forming units, with supplementation period ranging from 7 days to 3 months. Exercise protocols varied from an incremental cycling test to exhaustion, to an ultra-endurance triathlon event, as well as a military training protocol. Probiotic or synbiotic supplementation did not present any substantial beneficial effect compared with placebo or control on surrogate markers of intestinal epithelial injury. Inconsistent outcomes were observed with assessment markers of intestinal permeability with probiotic or synbiotic supplementation; with higher, lower, and no difference in outcomes between supplementation and placebo were reported. Of note, the reported beneficial effects of synbiotic supplementation on intestinal permeability was as a result of using the erroneous zonulin biomarker to quantify permeability [185–188]. No probiotic or synbiotic supplementation intervention reduced markers of exercise-associated endotoxemia compared with the study’s respective placebo or control. However, one intervention (seven days L. casei) reported a substantial increase in gram-negative bacterial endotoxin plasma concentration in response to 2 h steady-state treadmill running (60% V̇O_2max) in hot ambient conditions (34.0 °C, 32% RH) compared with a modest reduction in the placebo group [189]. The increased endotoxemia was speculated to be associated with a greater bacterial luminal load as a result of the 7 days L. casei supplementation dose (i.e., more bacterial endotoxin in the lumen available to translocate across the exercise-associated compromised epithelial barrier). There was no consistency in the impact of probiotic or synbiotic supplementation on systemic inflammatory responses, with no substantial differences reported in included studies. Regarding Ex-GIS, four out of the five studies within the SLR presented data indicative of no effect on Ex-GIS incidents and/or severity. One study reported lower Ex-GIS severity in the probiotic supplement group (i.e., 4 weeks, > 25 billion CFU/day from L. acidophilus CUL60, L. acidophilus CUL21, B. bifidum CUL20, B. animalis subsp. Lactis CUL34) in response to a simulated marathon. However, at closer inspection of the data and considering the methodological issues, it can be argued that the placebo group outperformed the probiotic supplementation group in regards to incidence of Ex-GIS and GIS in recovery from exercise. No study to date has assessed the impact of biotics on markers of gastrointestinal function. It was not surprising that no substantial differences were observed for EIGS markers, considering probiotic and synbiotic supplementation did not result in any changes in fecal bacterial composition (i.e., α-diversity and/or relative abundance), with only the supplemented strain or species showing increases in relative abundance. These increases, however, did not translate into increases in SCFA. The SLR concluded that probiotic supplementation with the strain or species studied does not substantially influence intestinal injury and permeability, subsequent systemic endotoxin or inflammatory cytokine responses, or GIS in response to exercise. As reported in the risk of bias assessment, many studies lacked adequate exertional and/or heat stress, or appropriate spectrum of biomarkers, to make definitive conclusions. Synbiotic supplementation appears to closely resemble the effects of probiotic, rather than prebiotic supplements, owing to the generally very small quantity of prebiotic ingredients included within the study intervention formulation.

Grade of Evidence: I to II

Bovine Colostrum

Bovine colostrum has been proposed to support the gastrointestinal system via promotion of villus development and mucosal thickness throughout the gastrointestinal tract [190]. As reported in animal experimental models, evidence suggests that bovine colostrum protects against intestinal hyperpermeability associated with non-steroidal anti-inflammatory drugs (NSAIDS) or hyperthermia [191, 192]. It is therefore plausible that bovine colostrum supplementation may contribute towards a management strategy for EIGS. Several randomized controlled trials have investigated the effect of acute and prolonged bovine colostrum supplementation on markers of EIGS, with conflicting findings reported in regards to intestinal epithelial injury and permeability outcomes in response to exercise. A wide variety of exertional stress protocols have been used, ranging from 20 min running at high intensity (up to 80% V̇O_2max) to 1.5 h combined cycling and running, and within diverse environmental conditions (i.e., ambient temperature ranging from 22 to 40 °C) [193–200]. Supplementation protocols included ingestion of bovine colostrum for 14 days at 20 g/day with or without zinc carnosine, [193–196] 8 weeks at 60 g/day, [199] and 7 days at 1.7 g/kgBM, [198] before the respective exercise protocol. The proposed protective effects of bovine colostrum were assessed via urinary L:R ratio for intestinal permeability, plasma I-FABP concentrations pre- to post-exercise, and exercise-induced systemic inflammatory response (i.e., cytokine profile). Research outcomes appear inconsistent, with some studies reporting modest positive effect with 14 days of supplementation at 20 g/day supplementation on mitigating L/R and/or the rise in I-FABP from pre- to post-exercise, compared with placebo [193–196]. However, other studies, using more substantial exercise models with or without the addition of heat exposure (e.g., 1.5 h cycling and running and 45 min exercise in 40 °C) demonstrated no beneficial effects of supplementation on markers of intestinal permeability or systemic inflammatory response [197–200]. Previous arguments in support of bovine colostrum in protecting the gastrointestinal tract (i.e., intestinal epithelial injury and permeability) in response to exercise are acknowledged [201]. However, several supplement intervention studies, with closer adherence to best practice recommendations for research methodologies, [67] have shown no beneficial outcomes compared with respective placebo or control [197–200]. In addition, a systematic literature review with meta-analysis that included exploration of measures related to EIGS (i.e., circulating immunoglobulins and leukocytes) reported none to fairly low impact of bovine colostrum supplementation intervention on these biomarkers [202]. Taken together, the current evidence suggests there is no strong and consistent evidence to recommend acute or prolonged supplementation with bovine colostrum to attenuate disturbances to the gastrointestinal integrity and/or systemic inflammatory responses associated with EIGS.

Grade of Evidence: II–III

Curcumin

Curcumin, the primary compound found in turmeric, is of interest owing to its anti-inflammatory properties and proposed function in strengthening intestinal endothelial tight junctions, demonstrated both in vitro and in vivo [203–205]. It also appears to attenuate proinflammatory LPS signaling pathways, moderating disturbance to gastrointestinal epithelial lining and resulting in reduced bacterial translocation. This potentially reduces systemic inflammatory responses [204, 205]. To date, only one study has investigated the potential role of curcumin in moderating markers synonymous with EIGS. It was observed that participants who supplemented with 500 mg/day of curcumin for 3 days had a significantly smaller increase in plasma I-FABP (absolute difference ~ 366 pg/mL) and IL-1ra (absolute difference ~ 8 pg/mL) after 60 min of moderate-intensity running in 37 °C ambient temperature compared with those who supplemented with placebo [206]. Unfortunately limitations, including insufficient exercise stress to induce substantial elevations in relevant biomarkers, confirmed by a rise in I-FABP under the minimal detectable change (MDC), [33] make it challenging to conclude if differences were of clinical and practical relevance. Therefore, more methodologically robust studies are required to unveil the preventative or mitigating potential of curcumin supplementation on EIGS. Given that limited research is available, it is currently not recommended as a first-line action for athlete application as a strategy for reducing EIGS.

Grade of Evidence: III

Anthocyanins

Anthocyanin, a bioactive flavonoid polyphenol, has been proposed to attenuate nuclear factor-kappa B (NF-κβ)-mediated inflammatory responses, including targeted effects on protecting gastrointestinal barrier integrity in human experimental models [207–210]. Moreover, ingestion (240 mg) of blackcurrant extract that contains a substantial anthocyanin dose (e.g., cyanidin-3-O-glucoside, cyanidin-3-O-rutinoside, delphinidin-3–100 O-glucoside, and delphinidin-3-O-rutinoside), [211] before exertional stress (i.e., 30 min rowing at 80% V̇O_2max), was reported to mitigate oxidative stress (e.g., plasma carbonyls), and inhibit LPS-stimulated cytokine secretion (i.e., TNFα and IL-6) and NF-κβ activation, compared with placebo [212]. It is therefore plausible that such supplementation before exercise may provide some attenuating effects on markers respective of exercise-associated gastrointestinal integrity perturbations. A recent study investigated the effects of 7 days of anthocyanin-rich blackcurrant extract administration (600 mg/day) on gastrointestinal integrity markers in response to exertional-heat stress (i.e., 60 min running at 70% V̇O_2max in 34 °C and 40% RH ambient conditions) [213]. Although, the supplementation intervention led to a significant reduction in intestinal epithelial injury (i.e., plasma I-FABP concentration) after exertional-heat stress compared with placebo, no differences were observed for small intestinal permeability (i.e., 4 h urinary L:R ratio), bacterial endotoxin translocation (i.e., sCD14 and LBP), or an array of systemic inflammatory responses biomarkers (i.e., IL-6, IL-10, and IL-1ra). Similar to other nutrition supplement studies attempting to manage exercise-associated perturbation to gastrointestinal integrity, it is important to note that the indication of overall intestinal epithelial injury, bacterial endotoxin translocation, and inflammatory cytokine biomarker values, in both the anthocyanin and placebo trials, were modest in nature. In addition, they were under the MDC previously proposed to warrant practical and clinical significance; which was likely associated with the modest exertional-heat stress model adopted [33, 67]. Taken together, it appears that the positive effect of acute intake of anthocyanin on in vitro pathogen challenge and inflammatory responses are not supported by a more prolonged supplementation period and its impact on in vivo biomarkers within human trials. In view of the current limited research available and the need for more robust experimental designs (e.g., more prolonged exertional-heat stress models to test supplementation hypothesis and adequate confounder control), it is currently not recommended as a first-line action for athlete application as a strategy for reducing EIGS.

Grade of Evidence: III

Nitrate

Gastrointestinal perfusion is dependent on macro- and micro-vascular activity throughout the splanchnic vasculature network, in which nitric oxide is a key regulator, inducing vasodilation [109, 214]. It can be proposed that increasing local availability of nitric oxide through nitrate supplementation may play a role in preventing and/or attenuating exercise-associated splanchnic hypoperfusion, and subsequent local ischemia. To date, only one study has investigated the effects of a nitrate-containing beverage (800 mg) on markers of splanchnic perfusion and ischemia, epithelial integrity, and Ex-GIS compared with carbohydrate (20 g sucrose) and water trials, in response to 60 min cycling at 70% W_max [115]. Participants were provided with a supplement dose 15 min pre-exercise and halfway through a 60 min cycle at 70% W_max. Despite a clear increase in plasma nitrate and nitrite, supplementation did not improve splanchnic perfusion, epithelial ischemic injury, or bacterial endotoxin translocation. Compared with water, nitrate supplementation resulted in a 50% increase in intestinal epithelial injury (i.e., plasma I-FABP concentration), whereas sucrose ameliorated intestinal epithelial injury. The percentage change in plasma I-FABP concentration pre- to post-exercise with a nitrate (299%) beverage was considerably larger compared with sucrose (179%). Ex-GIS were similar between groups. It appears that nitrate supplementation does not dampen, and may even exacerbate, intestinal epithelial injury during moderate duration exercise (≤ 1 h) when compared with water. However, it is important to note that the exercise model used within this study was insufficient to warrant substantial gastrointestinal perturbations and associated Ex-GIS of any relevance, [33] and thus no ideal experimental design has been undertaken to appropriately test nitrate supplement intervention in regard to EIGS mitigation or exacerbation [67].

Grade of Evidence: III

Pre-Exercise Hydration

Commencing exercise at 3.0% body mass loss via pre-exercise sauna exposure slowed gastric emptying during 90 min cycling at 70% W_max compared with starting exercise euhydrated [221]. Orocecal transit time (OCTT) and post-exercise small intestine permeability were similar between pre-exercise euhydration and hypohydration where fluid was ingested during exercise, although prior hypohydration resulted in greater Ex-GIS (i.e., nausea and upper abdominal pain) [221]. Moreover, pre-exercise hypohydration induced by limiting fluid intake to 0.5 L/day prior to 1 h cycling at 70% W_max, with no fluid intake during exercise, resulted in modestly higher intestinal epithelial injury (i.e., I-FABP: + 300 pg/mL, no statistical analysis presented) compared with pre-exercise euhydration achieved by habitual fluid intake [222]. On the basis of these findings, and considering the difficulties in consuming large volumes of fluid during certain exercise activities [173, 216, 217], it is recommended that individuals commence exercise activities in the euhydrated state. However, caution is warranted, as excessive pre-exercise fluid ingestion in the attempt to obtain euhydration may promote Ex-GIS, likely associated with increased gastrointestinal load. For example, fluid ingestion (1134 mL) immediately pre-exercise significantly increased the severity of exercise-related transient abdominal pain during the first 5 min of running compared with no fluid ingestion [223]. In addition, although the impact of hyperhydration status on markers of EIGS and Ex-GIS is unknown and warrants exploration, some of the strategies used to promote hyperhydration (e.g., glycerol supplementation and sodium intake) have been reported to instigate GIS (supplementary file 2) [224].

Grade of Evidence: II

Hydration During Exercise

In a recent study, an increase in post-exercise plasma I-FABP concentration was accompanied by varying magnitudes of increased systemic inflammatory cytokines with fluid restriction during 2 h running at 70% V̇O_2max (3.1 ± 0.7% body mass loss and P_Osmol > 300 mOsmol/kg) in temperate conditions when compared with programmed fluid ingestion rates that maintained euhydration (0.6 ± 0.6% body mass loss and P_Osmol < 300 mOsmol/kg) [41]. Hypohydration resulted in higher incidence and severity (82% and 240 mean summative accumulation during exercise, respectively) of total Ex-GIS compared with euhydration (64% and 176 mean summative accumulation during exercise, respectively). However, it is important to highlight that no significant difference was observed between the hypohydration and euhydration trials for Ex-GIS variables (i.e., trend at p = 0.058 and p = 0.068 for lower-GIS and lower abdominal pain, respectively). This can possibly be attributed to the large individual variation common to GIS reporting and/or that participant numbers were underpowered for such a subjective variable. Moreover, a separate study focused on ad libitum water intake during exercise (i.e., 2 h running at 60% V̇O_2max in temperate ambient conditions) to maintain euhydration. Although Ex-GIS incidence was similar (70%), symptom severity was much lower (58 mean summative accumulation during exercise), possibly suggesting that fluid intake behavior may impact Ex-GIS outcomes (i.e., forceful intake via programming versus ad libitum intake within comfort) [71]. Nevertheless, carbohydrate malabsorption, as determined by breath H₂, of the high-mixed carbohydrate meal given 2 h before exercise was pronounced with hypohydration, but not with euhydration; this likely explains the trend towards greater lower-GIS in the hypohydration trial compared with euhydration trial [41].

In another study, 1 h running at 70% V̇O_2max without fluid provisions significantly increased intestinal permeability compared with pre-exercise values; this was not significantly dampened by the provision of a carbohydrate beverage or a no-carbohydrate placebo beverage [225]. However, exercise-induced body mass loss was only 1.5%, likely linked to the modest exertional stress model used, which is not indicative of exercise-associated dehydration. Fluid provision during exercise resulted in greater feelings of fullness, but other GIS types were not affected. The optimal timing and volume of fluid provisions during exercise to reduce EIGS and Ex-GIS remains to be determined, but it is likely to be individualized [12]. Additionally, the effectiveness of fluid provision to reduce perturbations to gastrointestinal integrity may be dependent upon exercise duration or the extent of exercise-induced hypohydration. Considering hypohydration and excessive fluid intakes may contribute to EIGS and/or Ex-GIS, individuals should aim to establish a balance between individual tolerance levels to fluid intake during exercise and adequate fluid intake during prolonged exercise (> 1 h) to aid the maintenance of euhydration throughout.

Grade of Evidence: II

Heat Acclimation/Acclimatization

Heat acclimation/acclimatization (e.g., prolonged and repeated exposure to heat stress) appears to be an effective extrinsic heat mitigation strategy [226]. However, research to date is not supportive of its efficacy at mitigating EIGS. Intestine permeability was not different in response to a 45 min run at 50% V̇O_2max in 46 °C (20% RH) following 7-day (100 min exertional-heat stress) heat acclimation [227]. Permeability was not increased from rest and was measured by lactulose ingestion and excretion only, therefore making it difficult to interpret small intestine permeability outcomes. This study, however, showed a reduction in IL-6 and IL-10 cytokines that coincided with reduced thermoregulatory and cardiovascular strain. Further studies have also demonstrated that 5–10 days of heat acclimation (i.e., running in 41.4 °C, until a + 2 °C core body temperature increase and 60 min cycling at 50% V̇O_2peak in 35 °C and 50% RH or 40 °C and 25% RH) have been insufficient at attenuating I-FABP, gastric emptying rate, LPS, or the cytokine profile in response to heat stress or hypoxic (F_iO₂ = 0.14, 40 min cycle at 50% V̇O_2peak) exercise [228–230]. Considering the proposed benefits of heat acclimation/acclimatization at attenuating cardiovascular and thermoregulatory strain during exercise in the heat [226], further research with heat acclimation regimens of more prolonged exposure (e.g., > 10 days) and sufficient adaptive stimulus (e.g., ≥ 90 min/exposure) are required to elucidate if this is an effective strategy for attenuating EIGS and Ex-GIS.

Grade of Evidence: III

Internal Cooling

Internal cooling methods include the ingestion of cold fluids or ice slurry before (pre-cooling) and/or during (per-cooling) exercise. Internal cooling can lower pre-exercise core body temperature (e.g., when ingested prior to exercise) and create a heat sink that enables greater heat storage capacity, and subsequently, improved exercise performance in the heat [226]. Therefore, internal cooling methods may attenuate EIGS through directly lowering peak core body temperature and/or delaying the rise in core body temperature during exercise and heat stress load [83] with respect to exercise intensity and duration, ambient conditions of exercise adherence, and other thermoregulatory modifiers (e.g., air flow, clothing, and/or equipment). Internal per-cooling research has shown a suppressed rise in core body temperature (mean reduction of 0.3–0.4 °C) with water bolus ingestion with 0 °C and 7 °C water temperature compared with 22 °C water temperature given every 15 min during 2 h running at 60% V̇O_2max in 35 °C (25% RH). This resulted in modestly attenuated I-FABP and lower incidence (i.e., 67% versus 83%) and severity (i.e., 129 versus 235 summative accumulation) of upper-GIS symptoms; however, they did not reach statistical significance (i.e., trend at p = 0.066 and p = 0.087), respectively [231]. Additionally, no difference in cytokine profile was reported. These modest benefits with lower drink temperatures on intestinal injury and/or Ex-GIS (i.e., incidence and severity) are likely attributed to the modest suppressed rise in core body temperature; it can be speculated that it could potentially have been more beneficial if greater difference in core body temperature were observed [71, 83]. Further research has shown that ingestion of 617 g of a sports drink ice slurry during the cycle leg of a simulated Olympic distance triathlon in 32–34 °C (20–30% RH) attenuated intragastric body temperature and was well-tolerated, but no other markers of EIGS were reported [232]. One recent study reported no difference in markers representative of disturbed gastrointestinal integrity (i.e., I-FABP and LPS) with the frequent (i.e., pre-exercise and every 15 min) provisions of a carbohydrate–electrolyte ice slurry and respective carbohydrate–electrolyte beverage at ambient temperature during 45 min running at 60% V̇O_2peak that was followed by a second run until volitional exhaustion at 70% V̇O_2peak [233]. The research protocol of this study provided carbohydrates during exercise, which is aligned with attenuating exercise-associated disturbances to gastrointestinal integrity, as previously discussed in Sect. 4.1. Therefore, it is not surprising that no intervention outcomes were observed, since the study overall negated its primary research focus owing to this erroneous protocol oversight (i.e., carbohydrate provisions before and during exercise) in assessing the impact of internal per-cooling on markers of gastrointestinal integrity [67]. To date, internal cooling with cold water and ice slurry during exercise appears to be well-tolerated and contributes to suppressing the rise in core body temperature, which has positive associations and can predict the magnitude of EIGS and Ex-GIS [83]. Indeed, additional research using more robust experimental designs and control, ensuring that greater difference in core temperatures are achieved, and employing a wide array of EIGS markers is warranted.

Grade of Evidence: III

External Cooling

External cooling methods consist of the application of a cold medium such as ice vests/packs, cold towels, or cold-water immersion. These methods can reduce pre-exercise core body temperature and increase the core to skin temperature gradient [226]. Similarly to internal cooling, external cooling strategies may attenuate EIGS through directly lowering peak core body temperature and/or delaying the rise in core body temperature during exercise and heat stress load. Research on the gastrointestinal responses to external cooling methods is limited to systemic inflammatory cytokine responses, with one pre-cooling study demonstrating a small attenuation of IL-6 and IL-10 responses with 60 min cold water (20 ºC) immersion before 90 min of running at 65% V̇O_2max in 32 ºC (47% RH) [234]. While another study demonstrated no difference in IL-6 with application of an ice vest and cold towel before 30-min intermittent sprint exercise in the heat [235]. Further exploration into external pre- and per-cooling methods in isolation and in combination with internal cooling methods is warranted and may provide a more thorough insight into how cooling strategies may directly or indirectly impact markers of gastrointestinal integrity or function, systemic responses, and subsequent Ex-GIS. In addition, despite extensive research into the impact of cold (i.e., ≤ 0 °C) exposure, with and without exercise, on many physiological variables [236–239], the direct impact of external extreme cold stimulus and/or states of hypothermia on the gastrointestinal tract is still relatively unknown and warrants exploration.

Grade of Evidence: III

Repetitive Feeding Challenge

The various approaches to gut training target the gastrointestinal tract’s adaptive potential that may occur with this strategy, and its relevance in managing EIGS and/or Ex-GIS have been explored through a SLR [241]. First, increasing the stomach’s capacity and tolerance to larger gastric content could reduce the sensation of fullness. The ability for gastric adaptation to food intake volume is observed anecdotally or in non-exercise settings (e.g., competitive speed eating contests and eating disorders) [242–244]. Gut comfort and/or Ex-GIS improved among runners through daily repetitive ingestion of nutrients (90 g/h 2:1 glucose:fructose 10% w/v) and a high fat supplement (33 g fat, 9 g protein, and 9 g CHO per hour) during exercise for 1–2 weeks [42, 43, 106], and repeated ingestion of sweat rate-matched fluids [245]. Second, it is proposed that gut training can increase gastric emptying. Despite the existing evidence on nutrient-specific changes in gastric emptying in non-athletic human populations [246–248], this has yet to be proven within an exercise model. Third, a higher carbohydrate intake both during exercise and/or overall daily intake can increase intestinal absorptive capacity. Preliminary evidence in animal models showed nutrient-specific upregulation of intestinal transport proteins through taste-transduction pathways (e.g., type 1 taste G protein-coupled receptors (GPCRs), α-gustductin) [249–251].

Additionally, the increase in nutrient absorption, gastric emptying, and gastrointestinal motility may also be improved through the inhibition of the ileal break mechanism [55, 252, 253]. This is only indirectly supported by existing gut-training studies looking at breath H₂ concentrations, [42, 43, 65] and carbohydrate availability and oxidation [42, 254]. Specifically, carbohydrate malabsorption to a 90 g/h 2:1 glucose:fructose gut-challenge was reduced after gut training (i.e., 2 weeks of daily repeated feeding-challenge), but not on matched placebo [42, 43]. These findings were speculated to be caused by improved intestinal carbohydrate absorption, as supported by higher blood glucose concentration during exercise post-gut training, but not on matched placebo. This increased carbohydrate availability seen in Costa et al., [42] was not observed by increasing daily dietary carbohydrate intake for 28 days [254]. Moreover, carbohydrate malabsorption was not observed to any substantial relevant level (i.e., breath H₂: 5 ppm before gut training and 4 ppm post-gut training) in response to a formulated 87 g/h glucose feeding challenge during exercise [106, 255]. This suggests that fructose may be the prime culprit in the malabsorption observed in the initial trial of Costa et al. [42], irrespective of co-ingestion with glucose, and subsequent improved fructose absorption in the post-gut training trial (also see supplementary file 1, carbohydrate type). From a professional practical perspective, such outcomes have been observed in athlete support intervention (i.e., case study). In these, higher carbohydrate doses with the inclusion of fructose (25 g) result in greater carbohydrate malabsorption (10 ppm breath H₂) versus lower total carbohydrate and fructose (12.5 g) dose (6 ppm breath H₂) [64]. Lastly, the impact of a repetitive feeding challenge on intestinal epithelial integrity (i.e., plasma I-FABP concentration) has been explored, but no effects have been observed. There was a substantial amount of individual variation within studies for intestinal epithelial integrity markers, likely associated with differences in nutrient (e.g., carbohydrate) content and processing along the gastrointestinal tract during the experimental procedures [42, 65], as discussed in Sect. 4.1. Overall, the potential adaptations to gastrointestinal accommodation, motility, and absorption could lead to less Ex-GIS and better tolerance of nutrition during exercise, and subsequent enhanced exercise performance outcomes, as previously observed [42, 43]. To date, there is some evidence to support repetitive gut-challenge protocols in the prevention and management of EIGS and Ex-GIS [12, 241]. However, it appears to mainly benefit carbohydrate malabsorption and associated Ex-GIS, with more advanced gastrointestinal functional measures still warranting investigation and no impact on gastrointestinal integrity evident.

It is also important to highlight that intermittent fasting is now a common practice in the sporting community with the aim of modifying body composition without performance decrements [256]. Considering the potential physiological and biochemical adaptations associated with gut training are at the expense of substantial and constant nutrient provisions, it is unknown whether such fasting practices and subsequent reductions in nutrient exposure are counterproductive in regard to gastrointestinal functional responses, Ex-GIS, and their performance implications. Nevertheless, from a gastrointestinal and professional practice perspective, it appears that overall carbohydrate intake tolerance in the general active population equates to a liquid form at ≤ 1.0 g/kgBM/h in 6–10% w/v with a simple glucose formulation [42, 54, 66, 73, 117]. Greater carbohydrate volumes and concentrations and/or altered forms (e.g., other and/or multiple carbohydrate forms, semisolid to solid textures, and/or inclusion of other substances such as caffeine) appear to be at the discretion of individual tolerance and/or gut training to improve formulation specific tolerance (see supplementary file 1).

Grade of Evidence: I

Non-caloric Sweeteners

Similar to the mechanisms proposed for repetitive feeding challenge, consumption of non-caloric sweeteners may play a role in enhancing intestinal glucose uptake through the upregulation of active (i.e., SGLT1) and passive (GLUT5) transporters at the enterocyte apical surface, with or without upregulating GLUT2 at the basolateral surface, although this has primarily been observed in animal models [250, 257]. As such, enhancing glucose absorption and reducing the overall nutrient residue along the gastrointestinal tract may be linked to reducing Ex-GIS. Only one study to date has investigated the effects of sucralose supplementation (1 mM every 15 min for 2 h) prior to 2 h cycling at 48% V̇O_2peak [258]. No difference in overall Ex-GIS was observed in response to a carbohydrate challenge (1.2 g/kg/h maltodextrin) during exercise between the sucralose and control trials. While the exercise stress was insufficient to warrant any substantial gastrointestinal disturbance [67], it is important to note that GIS were only measured post-exercise retrospectively.

Grade of Evidence: III

Fluid Tolerance Training

Considering the plasticity of the stomach chamber to volume, repeated exposures to ingesting large fluid volumes (e.g. > 800 mL/h) may effectively improve stomach emptying rate and subsequent comfort. Ingesting a 4% w/v carbohydrate–electrolyte beverage every 10 min during running to match sweat losses (830 mL/h) increased stomach fullness from 2 (2.0: comfortable) to 2.3 (3: moderately uncomfortable), when compared with ingesting the beverage ad libitum (338 mL/h) [245]. A total of five repeated trials (every 7–11 days) of 90 min running at 65% V̇O_2max with volumes to match sweat loss significantly improved stomach comfort. Gastric emptying assessed on the first and fifth run remained unchanged, indicating that the improvement may be related to sensory factors and tolerance (e.g., desensitization) in coping with increased intragastric pressure.

Grade of Evidence: III