Abstract
ulating sensations of fatigue and discomfort while performing maximal endurance exercise becomes essential for making informed decisions about persistence and/or failure during intense exercise. Athletes with a higher effort capacity have compet- itive advantages over those with a lower one. The microbiota–brain axis is a considered the sixth sense and a modulator of the host’s emotional stability and physical well-being. Objectives:This narrative review aims to explore and evaluate the potential mechanisms involved in regulating perceptions during endurance exercise, with a focus on the possible relationship between the gut microbiota balance and the neural system as an adaptive response to high fatigue chronic exposure.Methods:Electronic databases (PubMed, Web of Science, Google Scholar, and Scopus) were used to identify studies and hypotheses that had documented predefined search terms related to endurance exercise, gut microbiota, the central nervous system, pain, discomfort, fatigue, and tolerance to effort.Results:This narrative review shifts the focus concerning the symbiotic relationship between the
system as an adaptive response to high fatigue chronic exposure.Methods:Electronic databases (PubMed, Web of Science, Google Scholar, and Scopus) were used to identify studies and hypotheses that had documented predefined search terms related to endurance exercise, gut microbiota, the central nervous system, pain, discomfort, fatigue, and tolerance to effort.Results:This narrative review shifts the focus concerning the symbiotic relationship between the gut microbiota, the vagus nerve, the central/enteric nervous system, and the regulation of afferences from different organs and systems to manage discomfort and fatigue perceptions during maximal physical effort. Consequently, the chronicity supporting fatigued exercise and nutritional stimuli could specifically adapt the microbiota–brain connection through chronic efferences and afferences. The present hypothesis could represent a new focus to be considered, analysing individual differences in tolerating fatigue and discomfort in athletes supporting conditions of intense endurance exercise.Conclusions:A growing body of evidence suggests that the gut microbiota has rapid adaptations to afferences from the brain axis, with a possible relationship to the management of fatigue, pain, and discomfort. Therefore, the host–microbiota relationship could determine predisposition to endurance performance by increasing thresholds of sensitive afferences perceived and tolerated. A richer and more diverse GM of athletes in comparison with sedentary subjects can improve the bacteria-producing metabolites connected to brain activity related with fatigue. The increase in fatigue thresholds directly improves exercise performance, and the gut–brain axis may contribute through the equilibrium of metabolites produced for the microbiota. Keywords:microbiota; exercise; pain; effort perception; nutrition; endurance exercise Nutrients2025,17, 2836 https://doi.org/10.3390/nu17172836
Nutrients2025,17, 2836 2 of 27 1. Introduction In recent years, research on the connection between the gut microbiota (GM) and the central nervous system (CNS) has been growing exponentially [1,2], particularly in its relation to health, physical performance, and cognitive processes related to perception, emotions, and pain [3–5]. Until now, only a limited number of studies have reported the interaction between the GM and the brain’s emotions, perceptions, and sensations. Thus, no previous studies have hypothesised on the possible bidirectional influence existing between endurance exercise and the GM-CNS axis, which modulates fatigue and unpleas- ant sensations [1,6]. The primary communication networks between the gut and brain involve neural, endocrine, and immune pathways, encompassing the central, enteric, and autonomic nervous systems, as well as the hypothalamic–pituitary–adrenal axis. The GM can modulate the enteric nervous system response through the excitability of the nervous system, as well as the production of metabolites that enable signals to reach the CNS via the vagus nerve [7]. The GM, composed of a complex community of microorganisms, interact with the vagus nerve in the passage of digestive material [8] and in the regulation of gut hormones, neurotransmitters, and short-chain fatty acids (SCFAs) [8–10]. Therefore, individual differences and chronic changes in the GM profile may influence the cognition, perceptions, and sensations of the host. Some investigations have described that exercise in humans also increases neurogenesis and alters the microbiota profile [11]. Endurance exercise involves the ability to sustain a specific type of physical activity, such as running, cycling, or swimming, for a prolonged period, where intensity and duration increase, perceived effort rises, and fatigue levels become limiting to continue the activity. The physiological changes that occur during long endurance activities, affecting different systems such as cardiovascular and respiratory, metabolism, thermoregulation, and acid–base balance, contribute to altered perceptions. For this reason, training routines contribute to elevating sensitisation, the neuronal plasticity that occurs in response to prolonged fatigue, pain, and discomfort stimuli during intense efforts, even over several days [8]. Therefore, the globality of training stimulus, supported by endurance athletes, focuses on improving, on the one hand, physiological performance, and,
metabolism, thermoregulation, and acid–base balance, contribute to altered perceptions. For this reason, training routines contribute to elevating sensitisation, the neuronal plasticity that occurs in response to prolonged fatigue, pain, and discomfort stimuli during intense efforts, even over several days [8]. Therefore, the globality of training stimulus, supported by endurance athletes, focuses on improving, on the one hand, physiological performance, and, on the other, enhancing sensitivity to tolerating discomfort and unpleasant sensations. The hardness perceived during endurance exercise may contribute to increased sensi- tisation for peripheral tissues, as well as GM adaptation in athletes. The present hypothesis describes how promoting a higher effort sensitisation from peripheral and central tissues adaptively changes the abundance of specific gut bacteria related to brain perceptions (see Figure). Overall, in response to physical and cognitive stress, two different regulatory systems are activated: (1) the sympathetic–adrenomedullary and hypothalamic–pituitary– adrenal axes [8,12], and (2) the autonomic nervous system (ANS) [13]. Throughout these processes, the intestine is particularly important due to its direct influence on the regu- lation of the CNS, among other factors. Not surprisingly, there is increasing interest in research on GM and the brain axis, as well as their various connections with health, physi- cal performance, and cognitive processes related to perception, emotions, and pain [3–5]. Recently, several publications have reported on the implications of GM on physiological and cognitive functions [1,6]. Still, data are largely lacking on how gut health can directly influence endurance performance through regulated emotions and tolerance to discomfort and fatigue.
Nutrients2025,17, 2836 3 of 27 Figure 1.Endurance exercise (EE) is the essential stimulus for promoting effort tolerance in athletes and GM phenotypic adaptive changes. EE promotes gastrointestinal (GI) ischemia, gastrointestinal damage, and intestinal permeability, which are aggravated by inadequate nutrition and hydration during EE. EE stimulates the redistribution of blood flow (BF) to the active muscles, promoting hyperthermia and systemic hypoxemia. The gut microbiota (GM) plays a crucial role in producing neurotransmitters (NTs) in the gut, primarily through bacteria such asBifidobacterium, Lactobacillus, Anaerostipes caccae, andEubacterium hallii. Thus, some bacteria, such asAkkermansia muciniphilaand Faecalibacterium prausnitzii, specifically produce SCFAs. NTs produced in the gut may contribute to altering physiological perceptions directly through neural signals from the gut to the brain, and perceptual thresholds (perceptual E) related to EE are supported during daily activities. EE would be a necessary stimulus to increase the NT threshold production from the gut, thereby modulating exertion tolerance. Notably, it has been suggested that interventions enhancing GM diversity could pos- itively impact endurance performance [14] and, in parallel, stimulate the production of metabolites such as NTs and other molecules involved in modulating perceptions and, consequently, tolerance to fatigue [15–17]. Instead, a GM imbalance may lead to poor well-being from leaky gut syndrome, which includes chronic low-grade inflammatory con- ditions, emotional instability, dysregulation of neurotransmitters, chronic fatigue, and even depression, all of which may impair athletic performance and tolerance to fatigue [18,19]. In this article, we reviewed the current scientific evidence on the relationship between endurance exercise and GM modulation in CNS perceptions. In addition, we discussed whether there exists a possible GM profile that improves higher effort tolerance. The main goal of the present article was to explore the hypothesis based on how hardness training in athletes could influence the GM ecosystem, alter sensory control through the autonomic nervous system, and influence additional gut metabolites in the blood and achieving the brain. The current work aimed to broaden perspectives in the field of sports science by suggesting that GM composition plays an important role in modulating perceptions during endurance performance. 2. The Relationship Between Endurance Exercise, Fatigue Perceptions,
influence the GM ecosystem, alter sensory control through the autonomic nervous system, and influence additional gut metabolites in the blood and achieving the brain. The current work aimed to broaden perspectives in the field of sports science by suggesting that GM composition plays an important role in modulating perceptions during endurance performance. 2. The Relationship Between Endurance Exercise, Fatigue Perceptions, and Gut Microbiota Adaptations The factors limiting endurance performance have traditionally focused on under- standing how cardiovascular, metabolic, and muscular adaptations are produced [20]. The
Nutrients2025,17, 2836 4 of 27 central (mental) regulation and the control of peripheral afferences from specific locomotor and visceral tissues that limit endurance performance through perceptions remain less studied. Human feeling includes the expression of body perceptions, emotions, and the modulation of systemic afferences. In the complex interplay of all these influences, the gastrointestinal tract and the GM, particularly, are relevant components influencing higher cerebral functions and behaviour [21–23]. In this regard, the gut metabolomic dialogue with the brain is essential for regulating perceptions and sensations [24], acting as both an autocrine, paracrine, and endocrine organ. In addition, the relationship between en- durance exercise and this malleable organ, composed of the GM, could be very important to modulate physiological perceptions related to physical effort tolerance. In such a case, discomfort and fatigue represent an individual and subjective per- ception involving nociception and nociplasticity [25,26]. In some cases, a higher capacity for tolerating discomfort during endurance exercise or other activities can explain why some individuals achieve better physical performances than others [27–29]. Hence, pain and discomfort coping is an integral part of athletic preparation that develops athletic character [30–38] in endurance athletes [33,39–47] or combat fighters [48], compared to power athletes [49]. The “individual limit of sensory tolerance” [28,29,50–52] has been proposed to describe the point at which individuals recognise their limit based on fatigue, pain, or effort [53], and can be improved following several weeks of intense training [44,54]. Pain, defined as the unpleasant, noxious perception that affects mood, social life, and overall quality of life, is a significant limiter of physical activity and quality of life. The individual threshold of pain is subjective, involving not only nociception but also emotional, cognitive, and social components [25]. During maximal endurance activities, athletes feel unpleasant sensations described with comments such as the following: “I cannot continue the race at this pace”, “exercise was hard”, “I never feel good”, “legs do not work”, etc. This effort fatigue is initiated by the activation of nociceptors that populate peripheral organs, such as skin, muscles, bones, joints, and deep visceral tissues [25,55]. Acute pain can contribute
athletes feel unpleasant sensations described with comments such as the following: “I cannot continue the race at this pace”, “exercise was hard”, “I never feel good”, “legs do not work”, etc. This effort fatigue is initiated by the activation of nociceptors that populate peripheral organs, such as skin, muscles, bones, joints, and deep visceral tissues [25,55]. Acute pain can contribute to modulating immune responses and protect organisms; however, chronic and sensitive thresholds in the nervous system can lead to elevated nociceptive activation, making organisms more sensitive to minimal immune reactions. Previous studies in clinical medicine have linked the composition of the gut microbiota to a higher incidence and progression of hyperalgesia and pain in certain chronic pathologies and treatments, such as chemotherapy [56]. Adaptive mechanisms for increasing pain and discomfort tolerance primarily depend on the stimulation of the interoceptive system, which is interconnected with the brain and integrated into the interoceptive consciousness [57–59]. The interoceptive system is an essential peripheral governor, constantly sensing physiological changes that trigger homeostatic thresholds for internal perceptions, emotions, pain, temperature, oxygen, sensory touch, muscle tension, discomfort, and intestinal sensations. These sensations are processed in the brain as an integrated interoceptive conscience [57–59]. As depicted in Figure, physiological afferences processed by the brain from peripheral organs and tissues transfer a consciousness of the internal body state during physical activities [60]. Thus, the operation of the interoceptive system is a highly relevant topic of research interest for manipulating perceptions and cognitive responses in conditions of effort, pain, or discomfort [61].
Nutrients2025,17, 2836 5 of 27 Figure 2.Relationship between maximal endurance performance, the interoceptive system, and regulatory feedback. During maximal effort, athletes feel sensations of pain and discomfort which are derived from different peripheral systems and processed by the brain. Everyone has a different set point of tolerance for stress, pain, and exertion, according to their systemic allostatic thresholds. The interoceptive system has the important function of regulating perceptions from afferent inputs, including specialised cells, organs, and active tissues such as muscles. The gut and microbiota also produce afferences from the neurons, metabolites, and enterocytes during endurance exercise and recovery processes. The intensity and duration of endurance exercise imply metabolic alterations that modify the neural response in the motor cortex, resulting in an increase in exertion from a perceptual perspective of sensations [62,63]. Previous studies have suggested that GM can modulate the neural system originating from the intestines and may influence pain thresholds in the brain, which are related to various systemic conditions [3,64,65]. The GM is capable of activating nociceptors [66], altering mediators of inflammation, and inducing phosphorylation in certain receptors and ion channels of sensory neurons, which can result in peripheral sensitisation [65]. Under this premise, the chronic stimulus of endurance exercise and other specific routines, such as nutrition and hydration, changes the GM profile individually. Therefore, the individual sensitive perceptions in a complex system of the body include the afferences derived from the gut through neural, chemical, and molecular signals. 3. The Hypothesis: Connection Between the GM and Tolerance to Effort, Pain, or Discomfort Sensations During maximal endurance exercise, the physiological demands increase proportion- ally. The brain acts mainly in two protective ways: (1) monitoring biological vital signals from specialised cells for oxygen, temperature, vascular pressure, etc., and (2) producing neural perceptions according to the individual thresholds (set-points) that are derived from afferent discharges from organs and tissues to optimize the intensity of exercise. In addition, gut–brain communication is crucial in regulating afferent responses related to all stimuli arising from immune responses, inflammatory pathways, and metabolic efficiency [67], as well as systemic organs (see Figure). With regular endurance
(2) producing neural perceptions according to the individual thresholds (set-points) that are derived from afferent discharges from organs and tissues to optimize the intensity of exercise. In addition, gut–brain communication is crucial in regulating afferent responses related to all stimuli arising from immune responses, inflammatory pathways, and metabolic efficiency [67], as well as systemic organs (see Figure). With regular endurance training, the different systemic thresholds can alter their grade of tolerance as an adaptive vital mechanism; if it is positive, athletes can perform at higher exercise intensities because their physiological and perceptual limits are increased based on their brain perception tolerance.
Nutrients2025,17, 2836 6 of 27 Concomitant changes that occur during exercise alter oxygenation, temperature, and metabolic activity, which directly affect gut microenvironments and thereby impact the gut microbiota [68]. The important role of the GM during physical failure is considered due to its modulatory effect on metabolic digestion, the immune system, systemic inflam- mation, and endocrine function, which involves regulating NTs and hormones related to perceptions, emotions, and sensations [1,6,69]. Here, we hypothesise that tolerance to pain, fatigue, and discomfort may be linked, in part, to intestinal barrier health, damage, and its biological function of permeability. This premise is based on the concept that the gut microbiota can directly or indirectly modulate peripheral sensitisation underlying chronic afferent pain or unpleasant sensations through multiple mediators, including the microbial by-products (e.g., PAMPs), metabolites (e.g., SCFAs, Bile Acids), and neurotransmitters (e.g., GABA) that are released. In this regard, athletes who are more sensitive to pain and effort sensations may be more susceptible to dysregulation of neurotransmitters and may experience GM dysbiosis [70]. In this case, in response to exercise demands, the GM may be unable to produce and maintain a certain threshold of SCFAs and NTs in the brain [70,71] to counteract the cognitive demands of discomfort [72] (Figure). Hence, in this regard, it can be hypothesised that improved intestinal health derived from a positive GM profile might positively impact the higher tolerance of sensory limits and effort perceptions in the long term. Therefore, the metabolite dialogue between bacteria and host neural path- ways would be crucial in stimulating synaptic plasticity, an essential component of the microbiota–gut–brain axis, and in modifying the neural thresholds of tolerance to fatigue or discomfort [73]. To modify neuronal perception and sensitivity, it is hypothesised that physical and functional changes at the level of individual connections between neurons have occurred [74]. Figure 3.Hypothesis from interactions between GM and CNS afferences related to perceptive tolerance. The GM acts as a key neuroendocrine organ, directly connected to the CNS through neural afferences, NT production, and hormone levels. As a premise of the present hypothesis, it has been postulated that the
functional changes at the level of individual connections between neurons have occurred [74]. Figure 3.Hypothesis from interactions between GM and CNS afferences related to perceptive tolerance. The GM acts as a key neuroendocrine organ, directly connected to the CNS through neural afferences, NT production, and hormone levels. As a premise of the present hypothesis, it has been postulated that the GM profile in each individual may differ depending on the perceptions that evolve from acute to chronic neuropathic injuries, accompanied by pain and impairments in functional performance in athletes [75,76]. Regarding osteoarthritis pain, for example, increases inStreptococcus
Description
The review discusses the gut microbiota's role in modulating effort tolerance in endurance athletes.