Exercise-Induced Gastrointestinal Symptoms in Endurance Sports: A Review of Pathophysiology, Symptoms, and Nutritional Management

renuous exercise can be associated with “Exercise Induced Gastrointestinal Syndrome” (Ex-GIS), a clinical condition characterized by a series of gastrointestinal (GI) disturbances that may impact the physical and psychological performance of athletes. The pathophysiology comprises multi-factorial interactions between the GI tract and the circulatory, immune, enteric, and central nervous systems. There is considerable evidence for increases in the indices of intestinal damage, permeability, and endotoxemia associated with impaired gastric emptying, slowing of small intestinal transit, and malabsorption of nutrients. Heat stress and racing mode seem to exacerbate these GI disturbances. GI symptomatology that derives from strenuous exercise is similar to that of IBS and other GI functional disorders de ned in the Rome IV Criteria. To manage Ex-GIS, the exercise modality, state of dehydration, environmental temperature, concomitant therapies, and self-managed diet should be evaluated, and if risk elements are present, an attempt should be made to modify them. Multiple strategies can be successively adopted to manage Ex-GIS. Nutritional and behavioral interventions appear to be the principal ones to avoid symptoms during the exercise. The aim of this review will be

modality, state of dehydration, environmental temperature, concomitant therapies, and self-managed diet should be evaluated, and if risk elements are present, an attempt should be made to modify them. Multiple strategies can be successively adopted to manage Ex-GIS. Nutritional and behavioral interventions appear to be the principal ones to avoid symptoms during the exercise. The aim of this review will be to explore the pathophysiology, clinical aspect, and current literature on behavioral and nutritional strategies to manage Ex-GIS, regarding a gluten-free diet and low-fermentable oligo-, di-, and mono-saccharides and polyols (FODMAP) diet. Keywords:gastrointestinal symptoms; endurance sport; diet; IBS 1. Introduction Physical activity has many positive effects on health, especially on the musculoskeletal, cardiovascular, and gastrointestinal (GI) systems. Its effect depends on the intensity, dura- tion, and modality of physical activity. Mild- to moderate-intensity exercise with a regular duration (e.g., between 3.5 and 4 h per week) plays a protective role against colon cancer, diverticular disease, gallstones, and constipation [1,2]. On the other hand, strenuous exer- cise and endurance sports may cause exercise-induced gastrointestinal symptoms (Ex-GISs) in up to 70% of athletes, and they can manifest as upper symptoms (e.g., regurgitation, upper abdominal bloating, belching, epigastric pain, and heartburn) and lower symptoms (e.g., atulence, urge to defecate, lower abdominal bloating, abdominal pain, abnormal defecation including loose water stools, diarrhea, and fecal blood loss) [3]. Endurance exer- cise is considered a sport aimed at improving the ability to sustain intense physical activity over time, without signi cant loss of performance. Endurance includes different physical activities with different levels of intensity and thus workouts can differ greatly according to the disciplines practiced. Cycling, swimming, marathons, triathlons, running, mountain Dietetics2023,2, 289–307.

Dietetics2023,2 290 biking, and climbing are some of those considered endurance sports simply because they require an expenditure of energy for a long time [4]. Ex-GIS might result from responses to exercise that compromise gastrointestinal integrity and function and may even be the reason why some stop sports participation [3]. The mechanisms leading to GI discomfort during exercise are not yet fully understood [5]. Exercise responses may involve two different path- ways: a circulatory–gastrointestinal pathway [6] and aneuroendocrine–gastrointestinal pathway [7]. The combination of splanchnic hypoperfusion and altered enteric nervous system activity may result in a compromised GI system. The loss of epithelial integrity observed during strenuous physical exercise leads to increased intestinal permeability with bacterial translocation and in ammation. This alteration may negatively impact exercise performance and post-exercise recovery due to abdominal distress and impairment in the uptake of uid, electrolytes, and nutrients. Exercise may also have a substantial impact on gut microbiota (GM) composition and structure, but the role of the microbiota in exercise adaptation remains unknown [8]. Notable differences have been described between com- peting athletes and inactive people. Zhao et al. [9] examined the GM and fecal metabolites of amateur runners before and after a half marathon, and they showed shifts in the relative abundance of the GM at several different taxonomic levels [9]. Therefore, there is a need to integrate the evidence more comprehensively for all elements of exercise-associated GI disturbances. In this light, the purpose of this article is rstly, to review the physiological and pathophysiological changes of the GI tract during endurance exercise, exploring the pathophysiology of Ex-GIS; secondly, to describe the clinical aspects of the syndrome and its effect on athletes' performances; and thirdly, to review the current literature on behavioral and nutritional strategies to manage the condition, with particular regard to dietetic regimens adopted by athletes to reduce symptoms. 2. Methods Three databases (PubMed, MEDLINE, Cochrane, Canada) were searched for relevant publications. The search was performed up to March 2023. The search strings utilized for the chapter's introduction and pathophysiology of Ex-GIS, proposed mechanisms for GI distress, and gastrointestinal symptoms during exercise

strategies to manage the condition, with particular regard to dietetic regimens adopted by athletes to reduce symptoms. 2. Methods Three databases (PubMed, MEDLINE, Cochrane, Canada) were searched for relevant publications. The search was performed up to March 2023. The search strings utilized for the chapter's introduction and pathophysiology of Ex-GIS, proposed mechanisms for GI distress, and gastrointestinal symptoms during exercise were “endurance”, “endurance sports”, “endurance activity”, “gastrointestinal symptoms”, and “exercise-induced gas- trointestinal symptoms”. We identi ed studies published from 1965 to 2023. The search performed in PubMed returned 290 results, in MEDLINE 216 results, and in the Cochrane library 97 trials. The search strings utilized for the chapters nutritional and behavior strate- gies to reduce Ex-GIS and ef cacy of speci c diets applied by endurance athletes to avoid Ex-GIS were “endurance”, “endurance sports”, “endurance activity”, “diet”, and “nutri- tion”. We identi ed studies published from 1972 to 2023. The search performed in PubMed returned 2663 results, in MEDLINE 2197 results, and in the Cochrane library 1038 trials. The selection process began with the evaluation of the title and the abstract of the works. All the works in which the keywords and the purposes of the review were not present were excluded. In terms of inclusion criteria, only studies in the English language were selected. Studies that did not address the impact of diet on endurance performance or health-related parameters were excluded. Finally, the authors discussed the research ndings and selected the studies that were clinically and practically relevant for the purposes of this review. Based on our inclusion and exclusion criteria, we identi ed 142 research articles. 3. Pathophysiology of Ex-GIS: Proposed Mechanisms for GI Distress The pathophysiology of Ex-GIS includes two primary pathways: (I) the neuroendocrine–gastrointestinal pathway, involving an increase in sympathetic activa- tion, reducing overall GI functional capacity [3] and (II) the circulatory–gastrointestinal pathway, involving the redistribution of blood ow to working muscles and periph- eral circulation, subsequently reducing total splanchnic perfusion and nutrient absorp- tion [10,11]. It is still under debate whether the neuroendocrine pathway may affect the circulatory–gastrointestinalone and, in cascade, reduce the total splanchnic

an increase in sympathetic activa- tion, reducing overall GI functional capacity [3] and (II) the circulatory–gastrointestinal pathway, involving the redistribution of blood ow to working muscles and periph- eral circulation, subsequently reducing total splanchnic perfusion and nutrient absorp- tion [10,11]. It is still under debate whether the neuroendocrine pathway may affect the circulatory–gastrointestinalone and, in cascade, reduce the total splanchnic perfusion, or

Dietetics2023,2 291 whether the splanchnic hypoperfusion in response to the intensity/duration of muscle activity may in uence the neuroendocrine activation. It is plausible that the combination of the altered enteric nervous system activity and the splanchnic hypoperfusion may re- sult in GI symptoms and/or in acute or chronic health complications [5]. The proposed mechanisms for gastrointestinal discomfort are summarized in Figure.Dietetics 2023, 2, FOR PEER REVIEW 4 activation, reducing overall GI functional capacity [3] and (II) the circulatory– gastrointestinal pathway, involving the redistribution of blood flow to working muscles and peripheral circulation, subsequently reducing total splanchnic perfusion and nutrient absorption [10,11]. It is still under debate whether the neuroendocrine pathway may affect the circulatory–gastrointestinal one and, in cascade, reduce the total splanchnic perfusion, or whether the splanchnic hypoperfusion in response to the intensity/duration of muscle activity may influence the neuroendocrine activation. It is plausible that the combination of the altered enteric nervous system activity and the splanchnic hypoperfusion may result in GI symptoms and/or in acute or chronic health complications [5]. The proposed mechanisms for gastrointestinal discomfort are summarized in Figure 1. Figure 1. Proposed mechanisms for Ex-GIS pathophysiology. Abbreviations: Ex-GIS: exercise- induced gastrointestinal symptoms; VO2max: maximal oxygen consumption; SNS: sympathetic nervous system; ENS: enteric nervous system. 3.1. Neuroendocrine–Gastrointestinal Pathway The alteration of the enteric nervous system (ENS) activity, through a cascade of events, results in clinical complications and GI symptoms known as Ex-GIS. Physical activity induces sympathetic activation, which is considered the main cause of altered ENS activity [12,13]. The digestive system is controlled by the bidirectional activity of the central nervous system (CNS) and the ENS, both of which participate in the regulation of the various functions of the intestines. ENS can independently regulate GI functions without central input. Indeed, the ENS is considered a quasi-autonomous part of the nervous system including several neural circuits that control motor functions, local blood flow, and mucosal transport and secretions and modulate immune and endocrine functions [14]. Enteroendocrine cells (EECs), which are basal-granulated cells dispersed in the gut epithelium, represent the endocrine elements of the intestine and release gut peptides, such

input. Indeed, the ENS is considered a quasi-autonomous part of the nervous system including several neural circuits that control motor functions, local blood flow, and mucosal transport and secretions and modulate immune and endocrine functions [14]. Enteroendocrine cells (EECs), which are basal-granulated cells dispersed in the gut epithelium, represent the endocrine elements of the intestine and release gut peptides, such as cholecystokinin (CCK), glucagon-like peptide-1 (GLP-1), and peptide YY (PYY), all having an anorectic effect. Ghrelin, on the other hand, is an orexigenic peptide produced by the enteroendocrine cells in the oxyntic glands of the stomach and upper intestine; thus, its plasma levels are high before meals and are suppressed in response to food intake [15]. These neuropeptides act either in a paracrine fashion on both intestinal and neural cells in proximity or enter the bloodstream and can have peripheral effects, such as change in gastric emptying and gut motility [16]. Briefly, CCK is synthesized and released from I cells of the upper intestine in response to food intake. It slows down gastric emptying and stimulates pancreatic and gallbladder secretions. CCK exerts its satiety action primarily through the activation of vagal afferent fibers innervating Figure 1. Proposed mechanisms for Ex-GIS pathophysiology. Abbreviations: Ex-GIS: exercise- induced gastrointestinal symptoms; VO2max: maximal oxygen consumption; SNS: sympathetic nervous system; ENS: enteric nervous system. 3.1. Neuroendocrine–Gastrointestinal Pathway The alteration of the enteric nervous system (ENS) activity, through a cascade of events, results in clinical complications and GI symptoms known as Ex-GIS. Physical ac- tivity induces sympathetic activation, which is considered the main cause of altered ENS activity [12,13]. The digestive system is controlled by the bidirectional activity of the central nervous system (CNS) and the ENS, both of which participate in the regulation of the various functions of the intestines. ENS can independently regulate GI functions without central input. Indeed, the ENS is considered a quasi-autonomous part of the nervous system including several neural circuits that control motor functions, local blood ow, and mucosal transport and secretions and modulate immune and endocrine functions [14]. Enteroendocrine cells (EECs), which are basal-granulated cells dispersed in the gut

various functions of the intestines. ENS can independently regulate GI functions without central input. Indeed, the ENS is considered a quasi-autonomous part of the nervous system including several neural circuits that control motor functions, local blood ow, and mucosal transport and secretions and modulate immune and endocrine functions [14]. Enteroendocrine cells (EECs), which are basal-granulated cells dispersed in the gut epithe- lium, represent the endocrine elements of the intestine and release gut peptides, such as cholecystokinin (CCK), glucagon-like peptide-1 (GLP-1), and peptide YY (PYY), all having an anorectic effect. Ghrelin, on the other hand, is an orexigenic peptide produced by the enteroendocrine cells in the oxyntic glands of the stomach and upper intestine; thus, its plasma levels are high before meals and are suppressed in response to food intake [15]. These neuropeptides act either in a paracrine fashion on both intestinal and neural cells in proximity or enter the bloodstream and can have peripheral effects, such as change in gastric emptying and gut motility [16]. Brie y, CCK is synthesized and released from I cells of the upper intestine in response to food intake. It slows down gastric emptying and stimulates pancreatic and gallbladder secretions. CCK exerts its satiety action primarily through the activation of vagal afferent bers innervating both the stomach and the upper intestine [17,18]. CCK levels rapidly increase after food ingestion, present a peak a few minutes after meal initiation, and decline to baseline levels with meal termination [19]. In contrast, the other gut peptides have patterns of release and actions that are consistent with effects beyond the meal. Indeed, plasma levels of both PYY and GLP-1, which are synthesized and released from L cells located primarily in the distal intestine, occur more slowly, not peaking until after meal termination and remaining high for several hours after

Dietetics2023,2 292 a meal [20,21]. Both PYY and GLP-1 inhibit food intake. Few data are currently available regarding the modi cation of gut peptide levels in response to physical activity. Various animal and cell models have demonstrated that the activation of adenosine receptors in- duces the release of GLP-1 and PYY from EECs [22,23], and concentrations of both are increased during moderate- and high-intensity exercise. Moreover, exercise induces the vago-vagal re ex from the brain back to the gut [24], which plays a role in the ability of CCK to regulate gastric emptying and intestinal motility [25]. Some studies have evaluated the modi cations of gut peptide levels in response to different kinds of exercise. Halliday TM and colleagues demonstrated that circulating concentrations of the anorexic gut peptides, namely PYY and GLP-1, are increased following aerobic exercise as compared to resistance exercise and that circulating concentrations of the orexigenic gut peptide, namely ghrelin, are also higher following aerobic exercise and sedentary control vs. resistance exercise [26]. Other similar results were reported by Broom et al. [27] and Balaguera-Cortes et al. [28]; they both found blunted ghrelin responses to resistance exercise as compared to aero- bic exercise. Furthermore, enteric neurons contain receptors for GABA, serotonin, and dopamine, neuropeptides that have been found to be in uenced by exercise [29]. In detail, high-intensity exercise causes an increase in GABA concentrations in the sensorimotor cortex, while acute exercise increases plasma dopamine levels [30]. Although exercise induces changes in neuropeptides and may affect enteric neuron activation and function, it is not fully known whether exercise directly affects local levels of enteric neuropeptides. It is plausible that alterations in gastric emptying and gut motility during exercise are due, at least in part, to increased gut peptide secretion and action. Among the neurotransmitters, catecholamines and serotonin have recently been a topic of interest because of their roles in gut physiology and their potential roles in GI and CNS pathophysiology. There are three main catecholamines: norepinephrine (noradrenaline) and epinephrine (adrenaline), which are peripheral catecholamines, and dopamine, which is a central-acting catecholamine. As mentioned above, endurance exercise increases

peptide secretion and action. Among the neurotransmitters, catecholamines and serotonin have recently been a topic of interest because of their roles in gut physiology and their potential roles in GI and CNS pathophysiology. There are three main catecholamines: norepinephrine (noradrenaline) and epinephrine (adrenaline), which are peripheral catecholamines, and dopamine, which is a central-acting catecholamine. As mentioned above, endurance exercise increases sympathetic nervous system (SNS) activity, increasing the circulating concentrations of norepinephrine and epinephrine [31]. The main function of norepinephrine is in vascular smooth muscle; indeed, it mainly acts on the alpha receptors at all concentration ranges, and causes vasoconstriction, increased vascular resistance, and decreased overall blood ow to the intestine. Epinephrine instead acts in a dual way; at low doses, it stimulates the beta receptors, leading to vasodilation, meanwhile at high doses, it acts similarly to norepinephrine and causes vasoconstriction. Finally, dopamine receptor af nity is also concentration-dependent and, indeed, low dopamine levels cause vasodilation and increased splanchnic blood ow through interaction with D1 receptors, meanwhile at high doses, it acts like the other catecholamines and can be classi ed as a vasoconstrictor, decreasing splanchnic blood ow [29]. Serotonin exerts a wide range of actions on the GI tract by binding to seven classes of speci c receptors (5-HT1 to 5-HT7), each of which produces its own response. For instance, 5-HT4 agonists relieve visceral pain and increase intestinal motility [32], while the activation of 5-HT3 receptors following the ingestion of irritants causes a rise in serotonin release by EECs, which in turn increases peristalsis and causes diarrhea. Regarding exercise-induced motility changes, data available to date are not unique, and many variables need to be considered. The duration and intensity of exercise, for example, may have different effects on the ENS, and while a short duration (i.e., <60 min) appears to promote GI motility, more prolonged (i.e., up to 90 min) exercise may cause inhibition [5]. Likewise, low-intensity exercise has little effect on GI motility, meanwhile in more vigorous exercise, ESN and relative GI functions become progressively inhibited [5]. Therefore, it can be assumed that most changes occurring in the intestinal

and while a short duration (i.e., <60 min) appears to promote GI motility, more prolonged (i.e., up to 90 min) exercise may cause inhibition [5]. Likewise, low-intensity exercise has little effect on GI motility, meanwhile in more vigorous exercise, ESN and relative GI functions become progressively inhibited [5]. Therefore, it can be assumed that most changes occurring in the intestinal tract are intensity- and duration-dependent and that exercise stress of 2 h at 60% VO2max may represent the threshold at which signi cant GI perturbations manifest [5]. Speci cally, motility alterations have been observed in different levels of the GI tract, including the esophagus, the stomach, and the intestines, and generally are summarized as a slow gastric emptying and a delay of orocecal transit time (OCTT). In more detail, esophageal modi cations are represented by a decrease in

Dietetics2023,2 293 esophageal peristaltic activity, a decrease in lower esophageal sphincter tone, and increased transient lower sphincter relaxation, which together could be linked to gastro-esophageal re ux symptoms (GERD) experienced during exercise [33]. Effects on gastric emptying are less clear, and especially in this case, the intensity of physical activity appears to be the key regulator of the gastric emptying rate. Indeed, a very early work [34] reported no effect of moderate exercise on gastric emptying, while later studies demonstrated a reduction following very-high-intensity exercise or during intermittent activity [35]. En- durance sports, through stress and the potent sympathetic activation, cause the inhibition of gastric motility [36]. These data were also con rmed in an animal model, in which by decreasing the sympathetic activity through the electrical stimulation of the spinal cord, there was an increase in gastric emptying and intestinal transit [37]. Information about small intestine and colonic motility is scarce, and the impact of exercise on OCTT is unclear. For instance, Rao KA and colleagues measured OCTT using a telemetric pH sensor and demonstrated that symptomatic and asymptomatic runners presented similar small bowel and colonic transit times during rest and exercise sessions. Interestingly, the diarrhea seen in the study did not result from an accelerated colonic transit and hence the researchers concluded that other mechanisms must be sought [38]. In contrast, the OCTT measured with lactulose breath tests decreased in both running [39] and cycling [40,41]. Considering the heterogeneity of results and the complex interaction of hormonal and neurological factors in the control of motility, other studies are needed to better elucidate the effect of different kinds of exercise (duration, intensity, and mode) on OCTT [5]. 3.2. Circulatory–Gastrointestinal Pathways The splanchnic vasculature is a system with an extraordinary capacity to adapt to physiological stressors affecting vasodilation or constriction in response to neuroendocrine, humoral, and paracrine mechanisms [42]. During strenuous exercise, the release of nore- pinephrine generates splanchnic vasoconstriction, thereby raising total splanchnic vascular resistance [43]. Blood is rapidly redistributed from the splanchnic vasculature to the pe- riphery for use in tissues with increased activity during exercise, such as

This review explores the pathophysiology and management strategies for gastrointestinal symptoms in endurance sports.