Gut–Immune–Muscle Axis as a Framework Linking Exercise Stress, Intestinal Dysfunction, and Overtraining Syndrome in Athletes: A Narrative Review
DOI:
https://doi.org/10.12775/QS.2026.68.74432Keywords
Gut-muscle axis, Gut microbiota, Overtraining syndrome, Sports performanceAbstract
Elite athletic performance requires high training loads, but insufficient recovery in the context of accumulated stress may contribute to the development of overtraining syndrome (OTS). Current models associate OTS with neuroendocrine, immune, and inflammatory disturbances; however, these frameworks do not fully explain why individual athletes demonstrate different susceptibilities to impaired recovery.
The gastrointestinal tract represents a dynamic interface connecting physical stress, immune responses, and metabolic changes with skeletal muscle adaptation. At the centre of this interaction is the gut–immune–muscle axis, a framework that describes the continuous dialogue between intestinal microbes, epithelial barrier integrity, and skeletal muscle function.
Microbe-derived metabolites may act as important signalling molecules that contribute to metabolic regulation during exercise adaptation. However, when high training demands are considered, this finely balanced system may become disrupted. Reduced intestinal barrier integrity can then contribute to systemic inflammatory responses, providing a potential link between gastrointestinal stress, immune activation, and impaired recovery.
Increased intestinal permeability may facilitate the translocation of microbial-derived components, thereby activating systemic inflammatory signalling. During strenuous exercise, physiological stress on the gastrointestinal tract may further compromise epithelial barrier integrity, potentially amplifying these immune responses, thereby interfering with skeletal muscle remodelling and recovery processes.
In this review, the gut–immune–muscle axis is proposed as a framework connecting intestinal dysfunction, immune alterations, and exercise maladaptation. Gut-related mechanisms are unlikely to represent a direct cause of OTS; rather, they may function as important biological modifiers that influence an athlete’s capacity to tolerate and recover from excessive training stress.
References
1. Meeusen, R., Duclos, M., Foster, C., Fry, A., Gleeson, M., Nieman, D., Raglin, J., Rietjens, G., Steinacker, J., Urhausen, A.: Prevention, Diagnosis, and Treatment of the Overtraining Syndrome. Med. Sci. Sports Exerc. 45, 186–205 (2013). https://doi.org/10.1249/MSS.0b013e318279a10a
2. Kreher, J.: Diagnosis and prevention of overtraining syndrome: an opinion on education strategies. Open Access J. Sports Med. Volume 7, 115–122 (2016). https://doi.org/10.2147/OAJSM.S91657
3. Budgett, R.: Fatigue and underperformance in athletes: the overtraining syndrome. Br. J. Sports Med. 32, 107–110 (1998). https://doi.org/10.1136/bjsm.32.2.107
4. Kellmann, M., Bertollo, M., Bosquet, L., Brink, M., Coutts, A.J., Duffield, R., Erlacher, D., Halson, S.L., Hecksteden, A., Heidari, J., Kallus, K.W., Meeusen, R., Mujika, I., Robazza, C., Skorski, S., Venter, R., Beckmann, J.: Recovery and Performance in Sport: Consensus Statement. Int. J. Sports Physiol. Perform. 13, 240–245 (2018). https://doi.org/10.1123/ijspp.2017-0759
5. Weakley, J., Halson, S.L., Mujika, I.: Overtraining Syndrome Symptoms and Diagnosis in Athletes: Where Is the Research? A Systematic Review. Int. J. Sports Physiol. Perform. 17, 675–681 (2022). https://doi.org/10.1123/ijspp.2021-0448
6. SMITH, L.L.: Cytokine hypothesis of overtraining: a physiological adaptation to excessive stress? Med. Sci. Sports Exerc. 32, 317 (2000). https://doi.org/10.1097/00005768-200002000-00011
7. Gleeson, M.: Immune function in sport and exercise. J. Appl. Physiol. 103, 693–699 (2007). https://doi.org/10.1152/japplphysiol.00008.2007
8. Cadegiani, F.A., Kater, C.E.: Hormonal aspects of overtraining syndrome: a systematic review. BMC Sports Sci. Med. Rehabil. 9, 14 (2017). https://doi.org/10.1186/s13102-017-0079-8
9. Mailing, L.J., Allen, J.M., Buford, T.W., Fields, C.J., Woods, J.A.: Exercise and the Gut Microbiome: A Review of the Evidence, Potential Mechanisms, and Implications for Human Health. Exerc. Sport Sci. Rev. 47, 75–85 (2019). https://doi.org/10.1249/JES.0000000000000183
10. Barton, W., Penney, N.C., Cronin, O., Garcia-Perez, I., Molloy, M.G., Holmes, E., Shanahan, F., Cotter, P.D., O’Sullivan, O.: The microbiome of professional athletes differs from that of more sedentary subjects in composition and particularly at the functional metabolic level. Gut. 67, 625–633 (2018). https://doi.org/10.1136/gutjnl-2016-313627
11. Hughes, R.L., Holscher, H.D.: Fueling Gut Microbes: A Review of the Interaction between Diet, Exercise, and the Gut Microbiota in Athletes. Advances in Nutrition. 12, 2190–2215 (2021). https://doi.org/10.1093/advances/nmab077
12. Frampton, J., Murphy, K.G., Frost, G., Chambers, E.S.: Short-chain fatty acids as potential regulators of skeletal muscle metabolism and function. Nat. Metab. 2, 840–848 (2020). https://doi.org/10.1038/s42255-020-0188-7
13. Przewłócka, K., Folwarski, M., Kaźmierczak-Siedlecka, K., Skonieczna-Żydecka, K., Kaczor, J.J.: Gut-Muscle Axis Exists and May Affect Skeletal Muscle Adaptation to Training. Nutrients. 12, 1451 (2020). https://doi.org/10.3390/nu12051451
14. Gizard, F., Fernandez, A., De Vadder, F.: Interactions between gut microbiota and skeletal muscle. Nutr. Metab. Insights. 13, (2020). https://doi.org/10.1177/1178638820980490
15. Pals, K.L., Chang, R.-T., Ryan, A.J., Gisolfi, C. V.: Effect of running intensity on intestinal permeability. J. Appl. Physiol. 82, 571–576 (1997). https://doi.org/10.1152/jappl.1997.82.2.571
16. van Wijck, K., Lenaerts, K., van Loon, L.J.C., Peters, W.H.M., Buurman, W.A., Dejong, C.H.C.: Exercise-Induced Splanchnic Hypoperfusion Results in Gut Dysfunction in Healthy Men. PLoS One. 6, e22366 (2011). https://doi.org/10.1371/journal.pone.0022366
17. Thaiss, C.A., Zmora, N., Levy, M., Elinav, E.: The microbiome and innate immunity. Nature. 535, 65–74 (2016). https://doi.org/10.1038/nature18847
18. Costa, R.J.S., Snipe, R.M.J., Kitic, C.M., Gibson, P.R.: Systematic review: exercise‐induced gastrointestinal syndrome—implications for health and intestinal disease. Aliment. Pharmacol. Ther. 46, 246–265 (2017). https://doi.org/10.1111/apt.14157
19. Walsh, N.P., Gleeson, M., Shephard, R.J., Gleeson, M., Woods, J.A., Bishop, N.C., Fleshner, M., Green, C., Pedersen, B.K., Hoffman-Goetz, L., Rogers, C.J., Northoff, H., Abbasi, A., Simon, P.: Position statement. Part one: Immune function and exercise. Exerc. Immunol. Rev. 17, 6–63 (2011)
20. Mohr, A.E., Jäger, R., Carpenter, K.C., Kerksick, C.M., Purpura, M., Townsend, J.R., West, N.P., Black, K., Gleeson, M., Pyne, D.B., Wells, S.D., Arent, S.M., Kreider, R.B., Campbell, B.I., Bannock, L., Scheiman, J., Wissent, C.J., Pane, M., Kalman, D.S., Pugh, J.N., Ortega-Santos, C.P., ter Haar, J.A., Arciero, P.J., Antonio, J.: The athletic gut microbiota. J. Int. Soc. Sports Nutr. 17, (2020). https://doi.org/10.1186/s12970-020-00353-w
21. Clarke, S.F., Murphy, E.F., O’Sullivan, O., Lucey, A.J., Humphreys, M., Hogan, A., Hayes, P., O’Reilly, M., Jeffery, I.B., Wood-Martin, R., Kerins, D.M., Quigley, E., Ross, R.P., O’Toole, P.W., Molloy, M.G., Falvey, E., Shanahan, F., Cotter, P.D.: Exercise and associated dietary extremes impact on gut microbial diversity. Gut. 63, 1913–1920 (2014). https://doi.org/10.1136/gutjnl-2013-306541
22. Mancin, L., Wu, G.D., Paoli, A.: Gut microbiota–bile acid–skeletal muscle axis. Trends Microbiol. 31, 254–269 (2023). https://doi.org/10.1016/j.tim.2022.10.003
23. Saponaro, F., Bertolini, A., Baragatti, R., Galfo, L., Chiellini, G., Saba, A., D’Urso, G.: Myokines and Microbiota: New Perspectives in the Endocrine Muscle–Gut Axis. Nutrients. 16, 4032 (2024). https://doi.org/10.3390/nu16234032
24. Scheiman, J., Luber, J.M., Chavkin, T.A., MacDonald, T., Tung, A., Pham, L.-D., Wibowo, M.C., Wurth, R.C., Punthambaker, S., Tierney, B.T., Yang, Z., Hattab, M.W., Avila-Pacheco, J., Clish, C.B., Lessard, S., Church, G.M., Kostic, A.D.: Meta-omics analysis of elite athletes identifies a performance-enhancing microbe that functions via lactate metabolism. Nat. Med. 25, 1104–1109 (2019). https://doi.org/10.1038/s41591-019-0485-4
25. Lamprecht, M., Frauwallner, A.: Exercise, intestinal barrier dysfunction and probiotic supplementation. Med. Sport Sci. 59, 47–56 (2012). https://doi.org/10.1159/000342169
26. PETERS, H.P.F., DE VRIES, W.R., VANBERGE-HENEGOUWEN, G.P., AKKERMANS, L.M.A.: Potential benefits and hazards of physical activity and exercise on the gastrointestinal tract. Gut. 48, 435–439 (2001). https://doi.org/10.1136/gut.48.3.435
27. Cinca-Morros, S., Álvarez-Herms, J.: The Importance of Maintaining and Improving a Healthy Gut Microbiota in Athletes as a Preventive Strategy to Improve Heat Tolerance and Acclimatization. Microorganisms. 12, 1160 (2024). https://doi.org/10.3390/microorganisms12061160
28. Beiter, T., Erz, G., Würden, A., Nieß, A.M.: Impact of moderate environmental heat stress during running exercise on circulating markers of gastrointestinal integrity in endurance athletes. Physiol. Rep. 13, (2025). https://doi.org/10.14814/phy2.70305
29. Camus, G., Nys, M., Poortmans, J.-R., Venneman, I., Monfils, T., Deby-Dupont, G., Juchm�s-Ferir, A., Deby, C., Lamy, M., Duchateau, J.: Endotoxaemia, production of tumour necrosis factor ? and polymorphonuclear neutrophil activation following strenuous exercise in humans. Eur. J. Appl. Physiol. 79, 62–68 (1998). https://doi.org/10.1007/s004210050474
30. Lefevre, C., Bindels, L.B.: Role of the Gut Microbiome in Skeletal Muscle Physiology and Pathophysiology. Curr. Osteoporos. Rep. 20, 422–432 (2022). https://doi.org/10.1007/s11914-022-00752-9
31. Kamada, N., Seo, S.-U., Chen, G.Y., Núñez, G.: Role of the gut microbiota in immunity and inflammatory disease. Nat. Rev. Immunol. 13, 321–335 (2013). https://doi.org/10.1038/nri3430
32. Ducharme, J.B., McKenna, Z.J., Deyhle, M.R.: Exercise mitigates the Toll of muscle atrophy: a narrative review of the effects of exercise on Toll-like receptor-4 in leukocytes and skeletal muscle. American Journal of Physiology-Cell Physiology. 322, C581–C589 (2022). https://doi.org/10.1152/ajpcell.00005.2022
33. JEUKENDRUP, A.E., VET-JOOP, K., STURK, A., STEGEN, J.H.J.C., SENDEN, J., SARIS, W.H.M., WAGENMAKERS, A.J.M.: Relationship between gastro-intestinal complaints and endotoxaemia, cytokine release and the acute-phase reaction during and after a long-distance triathlon in highly trained men. Clin. Sci. 98, 47–55 (2000). https://doi.org/10.1042/cs0980047
34. Jeukendrup, A.E., Vet-Joop, K., Sturk, A., Stegen, J.H., Senden, J., Saris, W.H., Wagenmakers, A.J.: Relationship between gastro-intestinal complaints and endotoxaemia, cytokine release and the acute-phase reaction during and after a long-distance triathlon in highly trained men. Clin. Sci. (Lond). 98, 47–55 (2000)
35. Bruunsgaard, H., Galbo, H., Halkjaer-Kristensen, J., Johansen, T.L., MacLean, D.A., Pedersen, B.K.: Exercise‐induced increase in serum interleukin‐6 in humans is related to muscle damage. J. Physiol. 499, 833–841 (1997). https://doi.org/10.1113/jphysiol.1997.sp021972
36. Peake, J.M., Neubauer, O., Walsh, N.P., Simpson, R.J.: Recovery of the immune system after exercise. J. Appl. Physiol. 122, 1077–1087 (2017). https://doi.org/10.1152/japplphysiol.00622.2016
37. Schwellnus, M., Soligard, T., Alonso, J.-M., Bahr, R., Clarsen, B., Dijkstra, H.P., Gabbett, T.J., Gleeson, M., Hägglund, M., Hutchinson, M.R., Janse Van Rensburg, C., Meeusen, R., Orchard, J.W., Pluim, B.M., Raftery, M., Budgett, R., Engebretsen, L.: How much is too much? (Part 2) International Olympic Committee consensus statement on load in sport and risk of illness. Br. J. Sports Med. 50, 1043–1052 (2016). https://doi.org/10.1136/bjsports-2016-096572
38. Carrard, J., Rigort, A.-C., Appenzeller-Herzog, C., Colledge, F., Königstein, K., Hinrichs, T., Schmidt-Trucksäss, A.: Diagnosing Overtraining Syndrome: A Scoping Review. Sports Health: A Multidisciplinary Approach. 14, 665–673 (2022). https://doi.org/10.1177/19417381211044739
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