Did you know that acute exercise causes leaky gut? In the first two articles of this series, I discussed how exercise impacts the gut microbiota and the gut immune system. In this article, I’ll discuss how acute and chronic exercise differentially impact gut barrier function, why it matters, and how we can support gut health during exercise.
Why is gut barrier function important?
Imagine your body as a doughnut. Your body is the “meat” of the doughnut, and the hole in the middle is your gut. In other words, we can actually think of the contents of the gut as actually being outside the body. The gut wall is essentially the first line of defense between the outside world and your bloodstream. It selectively allows nutrients, ions, and water into the body, while keeping bacteria, pathogens, and dietary antigens out.
For many years, it was thought that a breach of this innate defense system and the influx of bacteria into the bloodstream was something that only occurred in sepsis, a life-threatening infection. In recent years, we’ve come to realize that intestinal permeability, or “leaky gut” as it is commonly called, is associated with a wide range of diseases, including acne, allergies, inflammatory bowel disease, irritable bowel syndrome, obesity, and neurological diseases.1 A breach of the gut barrier leads to the influx of bacteria, bacterial cell wall components, and dietary antigens into the blood, where they can trigger chronic, systemic inflammation.
Incredibly, this gut barrier that is so crucial to maintaining our health is only one cell thick – about the width of a human hair! Special protein complexes called tight junctions form a “seal” between adjacent cells and act as gatekeeper to make sure that nothing other than nutrients gets through. Many factors can alter the gut environment and influence this monolayer of cells – including exercise.
Blood and oxygen flow during exercise
When you exercise, your body redistributes the blood and oxygen in your body. Circulatory networks that provide blood to the gut, stomach, liver, spleen, and kidneys constrict, reducing the flow of blood to these organs. Oxygenated blood is diverted towards the muscles to perform work and to the skin to increase body heat loss as sweat. Exercise can lead to a decrease in intestinal blood flow of more than 50%.2
The lack of blood flow to an organ (in this case, the gut) is called ischemia, and the lack of oxygen is called hypoxia. Both ischemia and hypoxia are major stressors to the gut, increasing production of reactive oxygen species and activating signaling pathways that result in gut permeability. The degree of ischemia and hypoxia is directly dependent on the intensity of the exercise, with significant gut ischemia occurring in as little as 10 minutes of high-intensity exercise.3,4
Exercise also raises the core temperature of the body and causes heat stress, particularly if it is long duration endurance activity or exercise performed in the heat.5 Heat stress activates signaling pathways that reduce the resistance of tight junction proteins between adjacent gut epithelial cells. Hyperthermia has been shown to cause widespread damage to intestinal epithelial cells, including shrinking of the absorptive villi, sloughing off of cells, and bleeding.6
Acute exercise increases intestinal permeability
Thus, intestinal permeability is a direct result of ischemia and hypoxia. Over a dozen studies have now shown, in both humans and animal models, that an acute bout of exercise significantly increases gut barrier permeability.
One research group assessed blood flow to the area surrounding the gut during a fairly intense 60-minute cycling bout (70% VO2 max) and during 60 minutes of recovery. They found that a lack of blood flow, or hypoperfusion, occurred about 10-20 minutes into the exercise period, with complete reperfusion of the area occurring within 10 minutes of recovery.3 Small intestinal damage was not evident until 40 minutes of continuous exercise. An hour after exercise, intestinal permeability was significantly elevated from baseline levels.
Kicking up the intensity or the heat amplifies the damage to the small intestine. One study found that running to exhaustion in a hot environmental chamber produced massive elevations in markers of small intestinal damage and bacterial translocation.7 Another found significantly increased permeability with high-intensity exercise (80% VO2max), but not with light or moderate intensity exercise (40 or 60% VO2 max).8
Regular exercise training may protect the gut barrier
With all this permeability, it might seem as though exercise negatively impacts gut health. However, as with other effects of exercise, it appears to be a hormetic effect, where exercise acts as an acute stressor that stimulates positive adaptation. In other words, exercise may acutely increase gut permeability, but regular, progressive exercise training stimulates positive adaptations that likely improve gut barrier function over the long-term.
Researchers have discovered one such mechanism that may prepare gut epithelial cells to survive the challenging environmental conditions of exercise. Heat shock proteins, or HSPs, act as little “chaperones” in the cell, assisting with protein synthesis, assembly, and degradation, and maintaining the viability and proliferative capacity of the cell. Increased HSPs in the gut has been shown to prevent the breakdown of tight junction proteins and protect the cytoskeleton of intestinal epithelial cells from hypoxia and hyperthermia-related damage.9,10
HSPs are increased in athletes after endurance competitions, and immune cells of trained athletes show a greater HSP response to heat stress:11,12
“The enhanced heat shock response in the athletes at rest may represent an activation of the protective resources in immune cells from denaturing heat. It may be interpreted as a training-induced mechanism of adaptation or as acquired thermotolerance.“ 11
But do these HSPs actually translate to improved gut barrier function with regular exercise training? Preliminary findings suggest that it might. Highly trained athletes have been shown to have lower levels of circulating LPS, a component of bacterial cell walls, in the blood.13 Lim et al. found that two weeks of a 20% increased training load in endurance runners reduced resting blood LPS levels, possibly due to improved immune clearance of LPS.14
Unpublished data from our lab also suggest that a six-week exercise intervention reduces LPS binding protein, particularly in obese individuals. This was related to the increased abundance of gut microbes that are known to produce the short-chain fatty acid butyrate, a metabolite that is known to improve gut barrier function. In my dissertation research, I hope to answer this question and further elucidate the exercise – gut barrier function connection.
Gut barrier protective agents
I’m also interested in how specific nutrients might be able to improve the gut’s response to exercise. Some that have already been studied include:
Bovine colostrum: Colostrum is a pre-milk fluid produced in the mammary glands that contains enzymes, antibodies, growth factors, and nutrients. Three randomized crossover studies performed by the same research group found that 14 days of supplementation with bovine colostrum (BC) prevented gut permeability and reduced markers of gut damage during a high-intensity 20-minute run.15,16 However, two other studies found no benefit of colostrum supplementation,17,18 and one randomized control trial found that 8 weeks of bovine colostrum supplementation during an exercise training program actually worsened gut barrier function.19 The reason for the discrepancy in these findings is poorly understood, and more research is needed.
Zinc: In rats, zinc carnosine increases HSPs in the gut, prevents epithelial damage, and reduces intestinal permeability.20 It is thought to be critical for assembly of the tight junctions that form a seal between adjacent cells,21 yet 90% of athletes have suboptimal zinc status.22 One study found that two weeks of zinc supplementation improved exercise-induced gut permeability by 70%.23
Glutamine: Glutamine is an important fuel for gut epithelial cells. Supplementation with glutamine in rats increases HSP70 expression in the GI tract in response to hyperthermia and reduces gut permeability at 6 and 24 hours post-exposure.24 In a 2014 crossover study, Zuhl et al. demonstrated that 7 days of glutamine supplementation completely prevented exercise-induced gut permeability. In vitro, glutamine increased expression of HSP70 and tight junction proteins.25 Other crossover studies have found similar benefits of glutamine supplementation.26,27
Arginine: The amino acid arginine enhances the production of nitric oxide, which helps to dilate the blood vessels and improve blood flow. In mice exposed to hyperthermia, arginine supplementation completely prevented a 12-fold increase in intestinal permeability.28 A single dose of L-citrulline, a precursor to arginine, has been shown to prevent hypoperfusion and small intestinal damage in humans.29
Curcumin: According to one study, supplementation with 500 mg/day of curcumin, the anti-inflammatory bioactive compound in the spice turmeric, attenuates small intestinal damage after exercise and reduces levels of pro-inflammatory cytokines.30
Fluids: A 2008 study found that fluid restriction during exercise significantly exacerbated intestinal permeability and markers of epithelial damage.31 Drinking cool or cold water, in particular, may further reduce small intestinal damage compared to room temperature water, by buffering the rise in core temperature.32
Agents that exacerbate exercise-induced gut permeability
There are also several nutrients and other factors that may exacerbate exercise-induced gut permeability. These include:
Quercetin: Antioxidants have been shown to blunt muscle adaptation to exercise.33 Interestingly, the same may occur in the gut. The flavanol quercetin exerts anti-inflammatory and antioxidant effects and has been shown to improve tight junction function and increase gut barrier resistance. However, quercetin potently attenuates the heat shock protein response and prevents heat acclimation in humans:
“This study adds to a growing body of literature that suggests antioxidant dietary supplementation may inhibit exercise-driven adaptations in otherwise healthy athletic populations. Our data suggest dietary quercetin supplementation impaired the cellular and systemic adaptations associated with both thermotolerance and heat acclimation in exercising humans.“ 34
Immunogenic foods: Certain food components, including wheat, lactose, and casein, have been shown to cause damage to the intestinal barrier, especially in those with food intolerances. Studies that have assessed the absorption of multiple macronutrients after exercise have found that proteins seem to be particularly able to cross the gut barrier:
“Despite an apparently small increase in sugar permeability […], exercise clearly increased the excretion of the casein-derived peptide, BCM7. […] These findings indicate that the intestinal passage of proteins and (or) their fragments is more prone to effects of exercise compared to the absorption of sugars…” 35
This might sound like a good thing – after all, you need protein to build muscle – but large dietary proteins like casein in the bloodstream cannot be taken up by the muscle. Instead, they trigger an immune response, causing widespread inflammation. Production of antibodies to these dietary proteins in the blood by the immune system may also contribute to future food sensitivities. In severe cases, this can cause exercise-induced, food-dependent anaphylaxis.36
Carbohydrate gels and sports drinks: One study in 2016 found that ingestion of carbohydrate gels during exercise enhanced markers of gastrointestinal wall damage.37 Likewise, concentrated glucose solutions have been shown to cause damage to the intestinal barrier.
Psychological stress: Stress is well-known to cause gut barrier permeability. While exercising can be an effective stress management technique, the strain of training and competing can often do the opposite:
“Competitive events could also cause increases in mental stress not seen in laboratory studies which could exacerbate GI symptoms due to further decreases in splanchnic blood flow, direct changes to intestinal bacterial composition or effects on GI transit time via the central nervous system.” 26
NSAIDs: I cringe when I see athletes popping Motrin or Advil before a training session or competition. Several studies have shown unequivocally that NSAIDs like ibuprofen dramatically exacerbate exercise-induced gut permeability and do not improve muscle recovery:
“…ibuprofen use compared to nonuse by athletes competing in a 160-km race did not alter muscle damage or soreness, and was related to elevated indicators of endotoxemia and inflammation.” 38
Overall, combining vigorous exercise with mental stress, NSAIDs, and a nutrient-poor diet high in refined carbohydrates, simple sugars, and food additives is a recipe for chronic gut inflammation, leaky gut, and systemic inflammation. While certain practices like carbohydrate loading, sports gels, or “if it fits your macros” might help you race well or keep you lean, they are counterproductive to maintaining a healthy gut barrier and long-term overall health.
On the other hand, combining a nutrient-dense diet rich in gut-supporting micronutrients with a progressive exercise training program will stimulate positive adaptation in the gut, increase exercise tolerance, and improve gut barrier function.
To sum up, here are a few practical, evidence-based takeaways based on the research I discussed:
- Don’t eat immediately before or after exercise. Consuming food prior to exercise enhances the risk of permeability and GI symptoms. As a general rule, avoid eating anything substantial 2 hours before exercise and at least 45 minutes after exercise. While there is scant literature on resistance training and gut permeability, downing a protein shake immediately after a heavy lift is probably not a good idea.
- Hydrate with pure water and electrolytes. Concentrated sugary drinks like Gatorade increase gut permeability and are the worst way to fuel your body as an athlete. If you are performing a long-distance event and need to refuel, try something free of additives, raw honey or a low concentration glucose-water solution.
- Avoid NSAIDs. They don’t help with muscle soreness, may blunt the beneficial adaptation response to exercise training, and cause intestinal permeability. What more should I need to say?
- Consider supplementing. Glutamine, zinc, and curcumin are all very safe to try therapeutically and can increase the gut barrier function, both at rest and during intense exercise.
- Choose intensity wisely. If you’re trying to improve your gut health, it’s probably best to keep exercise to a moderate intensity and for shorter periods of time. Build up intensity slowly and allow your gut to adapt to the stress of exercise.
- Do something you enjoy. Exercise should help relieve stress, not be the cause of more! If exercise is more stressful than enjoyable, you may be doing more harm to your gut than good.
That’s all for now! If you found this article helpful, be sure to subscribe to my weekly newsletter so you never miss a post. In part 4 of this series, I’ll be discussing the role of exercise in gut diseases like IBD and colon cancer.
- König, J. et al. Human Intestinal Barrier Function in Health and Disease. Clin. Transl. Gastroenterol. 7, e196 (2016).
- Bradley, S. E. et al. The effect of exercise on the splanchnic blood flow and splanchnic blood volume in normal man. Clin. Sci. 15, 457–463 (1956).
- van Wijck, K. et al. Exercise-induced splanchnic hypoperfusion results in gut dysfunction in healthy men. PloS One 6, e22366 (2011).
- Otte, J. A., Oostveen, E., Geelkerken, R. H., Groeneveld, A. B. J. & Kolkman, J. J. Exercise induces gastric ischemia in healthy volunteers: a tonometry study. J. Appl. Physiol. 91, 866–871 (2001).
- Rowell, L. B., Brengelmann, G. L., Blackmon, J. R., Twiss, R. D. & Kusumi, F. Splanchnic blood flow and metabolism in heat-stressed man. J. Appl. Physiol. 24, 475–484 (1968).
- Lambert, G. P. et al. Selected contribution: Hyperthermia-induced intestinal permeability and the role of oxidative and nitrosative stress. J. Appl. Physiol. Bethesda Md 1985 92, 1750–1761; discussion 1749 (2002).
- Barberio, M. D. et al. Systemic LPS and inflammatory response during consecutive days of exercise in heat. Int. J. Sports Med. 36, 262–270 (2015).
- Pals, K. L., Chang, R. T., Ryan, A. J. & Gisolfi, C. V. Effect of running intensity on intestinal permeability. J. Appl. Physiol. Bethesda Md 1985 82, 571–576 (1997).
- Dokladny, K., Lobb, R., Wharton, W., Ma, T. Y. & Moseley, P. L. LPS-induced cytokine levels are repressed by elevated expression of HSP70 in rats: possible role of NF-kappaB. Cell Stress Chaperones 15, 153–163 (2010).
- Musch, M. W., Sugi, K., Straus, D. & Chang, E. B. Heat-shock protein 72 protects against oxidant-induced injury of barrier function of human colonic epithelial Caco2/bbe cells. Gastroenterology 117, 115–122 (1999).
- Fehrenbach, E. et al. Transcriptional and translational regulation of heat shock proteins in leukocytes of endurance runners. J. Appl. Physiol. 89, 704–710 (2000).
- Fehrenbach, E. et al. HSP expression in human leukocytes is modulated by endurance exercise. Med. Sci. Sports Exerc. 32, 592–600 (2000).
- Lira, F. S. et al. Endotoxin levels correlate positively with a sedentary lifestyle and negatively with highly trained subjects. Lipids Health Dis. 9, 82 (2010).
- Lim, C. L. et al. The effects of increased endurance training load on biomarkers of heat intolerance during intense exercise in the heat. Appl. Physiol. Nutr. Metab. Physiol. Appl. Nutr. Metab. 34, 616–624 (2009).
- March, D. S. et al. Intestinal fatty acid-binding protein and gut permeability responses to exercise. Eur. J. Appl. Physiol. 117, 931–941 (2017).
- Marchbank, T. et al. The nutriceutical bovine colostrum truncates the increase in gut permeability caused by heavy exercise in athletes. Am. J. Physiol. Gastrointest. Liver Physiol. 300, G477-484 (2011).
- Morrison, S. A., Cheung, S. S. & Cotter, J. D. Bovine colostrum, training status, and gastrointestinal permeability during exercise in the heat: a placebo-controlled double-blind study. Appl. Physiol. Nutr. Metab. Physiol. Appl. Nutr. Metab. 39, 1070–1082 (2014).
- McKenna, Z. et al. Bovine colostrum supplementation does not affect plasma I-FABP concentrations following exercise in a hot and humid environment. Eur. J. Appl. Physiol. 117, 2561–2567 (2017).
- Buckley, J. D., Butler, R. N., Southcott, E. & Brinkworth, G. D. Bovine Colostrum Supplementation During Running Training Increases Intestinal Permeability. Nutrients 1, 224–234 (2009).
- Mahmood, A. et al. Zinc carnosine, a health food supplement that stabilises small bowel integrity and stimulates gut repair processes. Gut 56, 168–175 (2007).
- Zhong, W., McClain, C. J., Cave, M., Kang, Y. J. & Zhou, Z. The role of zinc deficiency in alcohol-induced intestinal barrier dysfunction. Am. J. Physiol. Gastrointest. Liver Physiol. 298, G625-633 (2010).
- Micheletti, R., Rossi, R. & Rufini, S. Zinc status in athletes: Relation to diet and exercise. in 2001. of the International Society of Sports Nutrition (2005).
- Davison, G., Marchbank, T., March, D. S., Thatcher, R. & Playford, R. J. Zinc carnosine works with bovine colostrum in truncating heavy exercise-induced increase in gut permeability in healthy volunteers. Am. J. Clin. Nutr. 104, 526–536 (2016).
- Singleton, K. D. & Wischmeyer, P. E. Oral glutamine enhances heat shock protein expression and improves survival following hyperthermia. Shock Augusta Ga 25, 295–299 (2006).
- Zuhl, M. N. et al. Effects of oral glutamine supplementation on exercise-induced gastrointestinal permeability and tight junction protein expression. J. Appl. Physiol. Bethesda Md 1985 116, 183–191 (2014).
- Pugh, J. N. et al. Glutamine supplementation reduces markers of intestinal permeability during running in the heat in a dose-dependent manner. Eur. J. Appl. Physiol. 117, 2569–2577 (2017).
- Zuhl, M. et al. The effects of acute oral glutamine supplementation on exercise-induced gastrointestinal permeability and heat shock protein expression in peripheral blood mononuclear cells. Cell Stress Chaperones 20, 85–93 (2015).
- Costa, K. A. et al. L-Arginine Supplementation Prevents Increases in Intestinal Permeability and Bacterial Translocation in Male Swiss Mice Subjected to Physical Exercise under Environmental Heat Stress. J. Nutr. 144, 218–223 (2014).
- van Wijck, K. et al. L-citrulline improves splanchnic perfusion and reduces gut injury during exercise. Med. Sci. Sports Exerc. 46, 2039–2046 (2014).
- Szymanski, M. C., Gillum, T. L., Gould, L. M., Morin, D. S. & Kuennen, M. R. Short-term dietary curcumin supplementation reduces gastrointestinal barrier damage and physiological strain responses during exertional heat stress. J. Appl. Physiol. 124, 330–340 (2017).
- Lambert, G. P. et al. Fluid restriction during running increases GI permeability. Int. J. Sports Med. 29, 194–198 (2008).
- Snipe, R. M. J. & Costa, R. J. S. Does the temperature of water ingested during exertional-heat stress influence gastrointestinal injury, symptoms, and systemic inflammatory profile? J. Sci. Med. Sport (2018). doi:10.1016/j.jsams.2017.12.014
- Merry, T. L. & Ristow, M. Do antioxidant supplements interfere with skeletal muscle adaptation to exercise training? J. Physiol. 594, 5135–5147 (2016).
- Dokladny, K., Moseley, P. L. & Ma, T. Y. Physiologically relevant increase in temperature causes an increase in intestinal epithelial tight junction permeability. Am. J. Physiol. Gastrointest. Liver Physiol. 290, G204-212 (2006).
- JanssenDuijghuijsen, L. M. et al. The effect of endurance exercise on intestinal integrity in well-trained healthy men. Physiol. Rep. 4, (2016).
- Loibl, M., Schwarz, S., Ring, J., Halle, M. & Brockow, K. Definition of an exercise intensity threshold in a challenge test to diagnose food-dependent exercise-induced anaphylaxis. Allergy 64, 1560–1561 (2009).
- Sessions, J. et al. Carbohydrate gel ingestion during running in the heat on markers of gastrointestinal distress. Eur. J. Sport Sci. 16, 1064–1072 (2016).
- Nieman, D. C. et al. Ibuprofen use, endotoxemia, inflammation, and plasma cytokines during ultramarathon competition. Brain. Behav. Immun. 20, 578–584 (2006).