- Open Access
A narrative review of the moderating effects and repercussion of exercise intervention on osteoporosis: ingenious involvement of gut microbiota and its metabolites
Journal of Translational Medicine volume 20, Article number: 490 (2022)
Osteoporosis (OP) is a systemic bone disease characterized by the decreased bone mass and destruction of bone microstructure, which tends to result in the enhanced bone fragility and related fractures, as well as high disability rate and mortality. Exercise is one of the most common, reliable and cost-effective interventions for the prevention and treatment of OP currently, and numerous studies have revealed the close association between gut microbiota (GM) and bone metabolism recently. Moreover, exercise can alter the structure, composition and abundance of GM, and further influence the body health via GM and its metabolites, and the changes of GM also depend on the choice of exercise modes. Herein, combined with relevant studies and based on the inseparable relationship between exercise intervention-GM-OP, this review is aimed to discuss the moderating effects and potential mechanisms of exercise intervention on GM and bone metabolism, as well as the interaction between them.
Osteoporosis (OP) is a kind of systemic metabolic bone disease characterized by descending bone mass and destruction of bone microarchitecture, predisposing to the enhanced bone fragility and associated fractures, as well as the high disability rate and mortality [1,2,3]. According to previous reports, 1/3 of female and 1/5 of male over the age of 50 are likely to experience the osteoporotic fractures at least once in their whole lifetime. Meanwhile, the number of the osteoporotic fractures worldwide exceeds 8.9 million every year, and an average of one case of osteoporotic fracture occurs every 3 s, which becomes a major challenge for the patients themselves, their families and social medical security system [4, 5].
Currently, a variety of drugs with different mechanisms of action have been applied in preventing and treating OP. Nevertheless, in the process of integrated management of OP, the pivotal contribution of exercise intervention still cannot be ignored [6, 7]. In the context of current global aging, the middle-aged and elderly individuals, as a special group, are mostly combined with one or more chronic diseases (including OP, diabetes, cardiovascular diseases, osteoarthritis, and so on) [8, 9]. Cardiovascular diseases and OP together account for most of the morbidity and mortality in aging population despite significant improvements in treatment. Recently, converging lines of evidence suggest that these 2 diseases share an etiologic factor, that hyperlipidemia contributes not only to atherosclerotic plaque formation, but also to bone loss, following a similar biologic mechanism involving the lipid oxidation . Meanwhile, dyslipidemia is also a major cause of non-alcoholic fatty liver disease (NAFLD). NAFLD and OP are strictly linked, as more recently it has been evidenced that NAFLD is related to an increased incidence of OP and bone fractures . Although the mechanisms remain poorly understood, it is reasonable to conclude that low levels of physical activity may lead to a decrease in bone mineral density (BMD), development of insulin resistance, and as a consequence to the presence of NAFLD . However, moderate exercise has vital benefits for the middle-aged and elderly individuals to manage several kinds of chronic diseases [13, 14]. Moreover, exercise is also one of the most common, reliable and cost-effective interventions for the prevention and treatment of OP . Especially in the case that the activities of elderly individuals are reduced due to various reasons, how to conduct the exercise intervention that adapted to their own physical health and surrounding environment, and how to ensure the sufficient exercise amount are of great significance.
In addition, as the largest and most complicated micro-ecosystem in human body, the gut microbiota (GM) and its metabolites play a critical role in the regulation of host metabolism, nutrition, immunity, and so on . Meanwhile, more and more researches have showed that the abnormal physiological metabolism of body is not only modulated by its own genes, but also inseparable from the maintenance of GM homeostasis . Changes in the internal and external environment of the body could disrupt the balance between GM and body, resulting in a variety of inflammatory or metabolic diseases, such as inflammatory bowel disease, colon cancer, obesity, diabetes, OP and so on [18,19,20,21]. With regard to this, in our previous critical reviews, based on the concept of “brain-gut-bone” axis, we have summarized the modulatory effects and implication of GM to OP , as well as the regulative effects and repercussion of the probiotics and prebiotics on OP . In view of the close association between GM and bone metabolism, it is acknowledged that GM might be regarded as a potential target for the prevention and treatment of OP.
Importantly, exercise is of great significance for the maintenance of whole-body health. On one hand, exercise can directly act on various tissues and organs of the body to regulate different functions. On the other hand, exercise could significantly alter the structure, composition and abundance of GM, and further affect the body health through GM and its metabolites . Meanwhile, exercise is able to alter the composition and function of GM, and the changes of GM also depend on the choice of exercise modes . Herein, combined with relevant researches and based on inseparable relationship between exercise intervention-GM-OP, this review is aimed to discuss the moderating effects and potential mechanisms of exercise intervention on GM and bone metabolism, as well as the interaction between them.
The inseparable association between OP and GM
As the largest micro-ecosystem in human body, more than 1014 orders of magnitude bacteria are colonized in the intestine, and the number of genes in the genome of GM is about 150 times that of the total number of genes in human genome . The GM is interdependent with human body, influencing multiple systems (including enteric nervous system, enteroendocrine system, immune system and so on), and playing an indelible role in food digestion, nutrients intake, resistance to the invasion of foreign pathogenic microorganisms, and so on . Currently, the correlation between intestinal microecology and bone metabolism has gradually become a research hotspot all over the world . Especially in the recent years, it has been observed that the changes of GM are closely related to the reduction of bone mass and the incidence of OP in middle-aged and elderly individuals [5, 28]. Meanwhile, more and more human and animal studies reveal that GM may alter the relative activities of osteoblasts and osteoclasts by modulating metabolites, host metabolism, inflammatory reaction, immune response, and other mechanisms, so as to participate in the regulation of bone metabolism.
Specifically, in terms of the clinical studies, Wang et al.  conducted the 16 S ribosomal RNA (16 S rRNA) sequencing analysis of the feces from patients with OP, patients with osteopenia and the individuals in the control group, and observed that the composition and diversity of GM in OP group and control group were significantly different, mainly reflected in the proportion of Firmicutes and Bacteroidetes. Fuhrman et al.  examined 60 randomly selected healthy postmenopausal women and revealed that the fecal microbial diversity and relative abundance of Clostridium and Bacillus were positively related to urinary estrogen metabolites, and the diversity of GM also increased with the enhancement of proportion of hydroxylated estrogen metabolites in urine. Meanwhile, the use of probiotics and prebiotics could change the composition, structure and abundance of GM, indicating the benefits of probiotics and prebiotics for bone metabolism. Regarding this, a previous randomized controlled trial conducted by Nilsson et al.  suggested that the postmenopausal women aged 75–80 years old who received a daily dose of 1⊆1010 CFU of Lactobacillus reuteri ATCCPTA 6475 had a significantly lower reduction in BMD than individuals in control group after 12 months of treatment. Lei et al.  observed in a prospective randomized controlled trial that the elderly patients with distal radius fractures can also accelerate the process of fracture healing by ingesting Lactobacillus casei Shirota for a period of 6 months. Moreover, van den Heuvel et al.  showed in a randomized crossover study that the supplementation of Transgalactooligosaccharides was able to enhance the intestinal calcium absorption in postmenopausal women, thus enhancing the bone mass and preventing OP.
As for the animals’ studies, by constructing the mice model of postmenopausal OP induced by ovariectomy (OVX), Tu et al.  revealed that the estrogen-deficiency was related to the imbalance of GM, impaired intestinal mucosal barrier function, and enhanced inflammatory and immune reactivity. On the basis of this, the metabolites of intestinal pathogenic bacteria could enter into the body circulation through impaired intestinal mucosal barrier, induce the immune reaction mediated by CD4 + T cells, generate a variety of pro-osteoclastogenic cytokines, and mediate the activation of osteoclasts and accelerate the bone resorption. Additionally, Sjögren et al.  observed in an animal experiment study that compared with the normal mice in control group, the germ-free (GF) mice had enhanced bone mass and lower levels of CD4 + T cells and tumor necrosis factor-α (TNF-α) in bone marrow. However, after the transplantation of GM from normal mice to GF mice, the bone mass, levels of CD4 + T cells and TNF-α of GF mice returned to normal. Goto et al.  indicated that transplanting segmental filamentous bacteria (SFB) into GF mice could increase the number of T helper cell 17 (Th17) cells, resulting in the enhancement of the levels of TNF-α, interleukin 1β (IL-1β), and IL-17, and inducing the expression of receptor activator of nuclear factor-κ B ligand (RANKL), thereby playing a vital role in promoting the formation of osteoclasts. Interestingly, IL-17 also plays a key role in atherosclerosis following obesity-related NAFLD . Yan et al.  also reported that the colonization of GM in mice increased the rate of bone formation and length of femur, and detected the enhancement of serum insulin-like growth factor-1 (IGF-1) and bone formation marker (procollagen type I N-terminal propeptide (P1NP)), suggesting that the stimulation of bone formation through GM may be mediated by IGF-1. Zhang et al.  showed that fecal microbiota transplantation (FMT) plays an active role in remodeling the GM and improving the bone loss in OVX-induced mice with OP. In details, by correcting imbalance of GM, improving the level of SCFAs, optimizing the intestinal permeability and inhibiting the release of pro-inflammatory cytokines, FMT may inhibit the excessive generation of osteoclasts and obtain the balance between bone formation and bone absorption, thus ameliorating the bone loss in OVX-induced mice with OP.
Taken together, there is a close link between GM and OP, and a healthy intestinal microenvironment state has a significant protective effect on the bone. Importantly, GM mainly affects the balance between osteoblast-mediated bone formation and osteoclast-mediated bone resorption, which plays a vital role in the regulation of bone metabolism and provides a novel target of intervention for the prevention and treatment of OP. Nevertheless, the relevant studies on the association between GM and OP are still in the initial stage, and more researches are needed to further clarify its deep-level mechanisms and explore more effective conditioning measures.
The moderating effects of exercise intervention on the human and experimental animals’ GM
As a kind of homeostatic stimulus, exercise intervention may diversify the GM and increase the number of beneficial microbial communities in gut. Exercise intervention contributes to enhancing the gastrointestinal peristalsis of body and promotes the timely excretion of feces, so as to reduce the contact time of intestinal mucosa with pathogens and harmful substances, further affect the characteristics of the intestinal contents and alter the composition of GM [40, 41]. Meanwhile, when participating in different types of exercise, different qualitative and quantitative changes may occur in GM, thereby influencing multiple body functions, such as the nutrient absorption, energy distribution, immune and inflammatory regulation . Moreover, a variety of previous studies have also showed that the exercise intervention might modulate the occurrence and progression of OP and other skeletal diseases by altering intestinal mucosal barrier function and the composition, structure and abundance of GM [43,44,45,46]. Accordingly, different kinds of physical activities may also have different influence on the GM . The relationship between exercise intervention and GM is complicated, which depends on several factors, such as the types of exercise, intensities of exercise, duration of exercise, frequency of exercise, surrounding environment during exercise, and so on [48, 49]. Understanding the various functions of GM in exercise performance is of great significance to both ordinary individuals and athletes seeking to improve the exercise effects and reduce the training recovery time. Herein, the moderating effects of exercise intervention on the human and experimental animals’ GM are summarized as follow, and Fig. 1 exhibits the close interaction relationship between the GM and exercise intervention.
As for human
Long-term chronic moderate-to-low intensity exercise
The dynamic balance between GM and host physiological function determines the possibility of host morbidity caused by GM imbalance. However, several previous studies have revealed that long-term chronic moderate-to-low intensity exercise has beneficial effects on body [50, 51]. Moreover, the World Health Organization (WHO) has previously established the guidelines of 150 min of moderate intensity exercise per week as the recommended minimum level of exercise, which seems to be sufficient to alter the composition and abundance of GM and promote the health . Balducci et al.  showed that long-term sustained aerobic exercise and resistance exercise with moderate-to-low intensity could reduce the expression of inflammatory cytokines (such as IL-1β and TNF-α), while increase the expression of anti-inflammatory cytokines (such as IL-4 and IL-10) in the body. Meanwhile, according to previous reports, especially in partial professional athletes, the acute and vigorous exercise might induce the transient gastrointestinal symptoms (such as nausea, diarrhea, gastrointestinal bleeding, and so on) [54,55,56]. However, the participation in normal moderate intensity exercise is considered to resist intestinal inflammatory diseases, and the gastrointestinal disorders usually do not occur after the moderate intensity exercise, which might be associated with the involvement of GM in regulation . Furthermore, the stimulation of sustained moderate intensity exercise also has an indelible effect on maintaining the abundance of GM that can generate the short chain fatty acids (SCFAs) and regulating the expression levels of related genes . Allen et al.  observed in a population-based study that after 6 weeks of aerobic endurance training, the contents of propionic acid and butyric acid in the feces, the abundance of butyric acid-producing bacteria, and the relative contents of butyric acid-producing genes, returned to the baseline level after 6 weeks of returning to sedentary life.
In addition, compared with the sedentary women, the premenopausal women who exercise continuously at the low intensity are equipped with the increased abundance of Akhmann mucophilus and Clostridium praevia, and these bacteria have been verified to be anti-inflammatory bacterial species . Moreover, previous population-based research conducted by Munukka et al.  also indicated that the relative abundance of Verrucomicrobia, Verrucomicrobiaceae, Akkermansia and Dorea in the feces of the sedentary and overweight women increased after 6 weeks of moderate-to-low intensity power cycling training. Therein, Akkermansia and Dorea were verified to be able to ferment with dietary fiber as the substrate to generate the butyric acid. Besides, Hamasaki et al.  also concluded that as a moderate intensity exercise involving deep breathing and meditation, Tai Chi might induce the beneficial changes in GM and its metabolites by modulating the hypothalamic-pituitary-adrenal (HPA) axis. Similarly, the Chinese traditional martial arts are also a common moderate intensity exercise that is suitable for the physical exercise of middle-aged and elderly individuals. A number of previous studies have revealed that martial arts can effectively optimize the structure and abundance of GM in the middle-aged and elderly individuals [63, 64]. For the middle-aged and elderly individuals who have been practicing the martial arts for a long time, the abundance of Enteric acidophilus, Bifidobacteria and Lactobacillus in their intestines increases, resulting in a decrease of the content of malondialdehyde and an increase of the activity of antioxidant enzyme, so as to improve a variety of metabolic processes in the body and then promote health [65, 66]. Hence, it is acknowledged that appropriate (mainly moderate-to-low intensity) exercise is able to produce the benign changes to the health of human body by regulating the GM and its metabolites.
Nevertheless, different from the moderate-to-low intensity exercise, in the case of acute/vigorous exercise, the ischemic effects of intestinal mucosa and the enhancement of intestinal permeability resulting in the intake of bacteria and toxins could induce the inflammatory response of body . According to previous reports, 20–50% of athletes might experience multiple gastrointestinal symptoms that increase with the exercise intensity [68, 69]. In a triathlon competition, Jeukendrup et al.  observed 29 well-trained male athletes, and the results suggested that 93% of the participants reported gastrointestinal dysfunction, and two participants abandoned the competition due to the severe vomiting and diarrhea. Hence, it is recognized that gastrointestinal symptoms are more common in athletes, because the body temperature rises during vigorous exercise and blood flows from the gastrointestinal tract to the surrounding muscles and organs (such as heart, liver and lungs) [71, 72]. The redistribution of blood flows away from the intestine and the thermal injury to intestinal mucosa can result in the destruction of intestinal mucosal barrier and then trigger the inflammatory response .
With regard to this, Zouhal et al.  suggested that the individuals who exercise at the condition of 70% VO2max might reduce the visceral blood flow by 60–70%, and when the blood flow was reduced by 50%, the exercise-induced ischemia may result in the increased intestinal permeability. On the basis of this, the blood flows from the gastrointestinal tract via surrounding organs may also result in the loosening of tight junction proteins (mainly expressed by zonula occludens-1 (ZO-1) and Occludin), so as to further damage the intestinal mucosal barrier . Moreover, in a study of healthy young adult male cyclists who engaged in 4–10 h of endurance exercise per week, Duijghuijsen et al.,  observed that if they conducted the exercise for one hour with only 70% of maximum workload, they would have insufficient visceral perfusion, which resulted in the decline of gastrointestinal circulation, the increase of intestinal permeability and the damage of accessory organs. Therefore, it is recognized that the acute/vigorous exercise may cause the partial negative effects on human body (mainly gastrointestinal symptoms), which especially needs to be paid enough attention in the future researches.
As for experimental animals
Autonomous exercise is a significant part of the structure of exercise modes. With regard to this, Matsumoto et al.  first observed in a study that the composition and abundance of GM were significantly different between the rats in autonomic exercise group and sedentary group. Moreover, other researchers tested the concentration of butyric acid in the cecum of rats, and results revealed that compared with the rats in sedentary group, the concentration of butyric acid in autonomic exercise group was twice that of the former [78, 79]. As one kind of significant SCFAs, the butyric acid provides the energy for colonic epithelial cells and has been verified to have multiple benefits to host. Moreover, wheeled running is one of the most convenient approaches to simulate the autonomous exercise in animal models, and the exercise amount can be calculated by the rotation distance of wheel. Aoki et al.  revealed that daily wheeled running can affect the composition of GM in mice, and ameliorate high-fat diet (HFD)-induced obesity by altering the ratio between Firmicutes and Bacteroidetes. Li et al.  also suggested that compared with the HFD-induced osteoarthritis mice in sedentary group, level of lipopolysaccharide (LPS) in circulation of mice (autonomous exercise group) decreased, and the diversity of GM increased, which alleviated the process of chronic inflammation and osteoarthritis in body. These studies have revealed that the composition and diversity of GM could be optimized to varying degrees after the continuous autonomic exercise in the animal models, and the conditions of obesity and metabolic skeletal diseases could be effectively alleviated. The benign changes of GM induced by autonomic exercise might be another effective approach to alleviate or treat the metabolic diseases, but the interaction between autonomic exercise and GM, control parameters of exercise volume, and participation of dietary factors still need to be further explored in the future.
In animal models, the most common type of forced exercise is the forced treadmill exercise. Compared with the autonomous exercise, the forced exercise has significantly different influence on the GM of experimental animals. With regard to this, in the mice model of colitis, Cook et al.  observed that the autonomic exercise could attenuate the intestinal inflammation, while the forced exercise exacerbated research outcomes, indicating that different exercise modes might have different influences on the clinical outcomes and composition and abundance of GM during the process of inflammatory injury. Based on this, Allen et al.  collected the feces of mice in the autonomous exercise group and forced treadmill exercise group for analysis, and the results showed that both autonomous exercise and forced treadmill exercise altered various individual bacterial taxa, and the level of Agrobacterium (closely related to immune function and intestinal diseases) reduced significantly in autonomous exercise group, suggesting that exercise intensity and exercise amount might be the variables influencing the function of GM. In addition, the changes in GM caused by exercise also seem to depend on the physiological state of individuals. A previous study conducted by Gordon et al.  indicated that whether the obese-hypertensive rats or normal rats, regular forced exercise may have different influence on the composition and abundance of respective GM. Collectively, there are certain differences in the effects of different exercise intensities and amounts on the changes of GM, and the changes of GM induced by exercise are different in various phenotypic animal models. Further exploration of appropriate exercise modes and the load in different kinds of phenotypic animal models might provide a relatively complete theoretical basis for the establishment of exercise strategies and formulation of exercise prescriptions to a certain extent.
Current researches and evidence on exercise intervention-GM-OP
The musculoskeletal system plays an indelible role and significance in the human health. In addition to acting as a scaffold for body, it also continuously communicates with other organs through the biochemical signals, and has basic neural, immune and endocrine regulatory functions [85, 86]. The GM and its metabolites are associated with a variety of diseases in musculoskeletal system, including the sarcopenia, osteoarthritis, ankylosing spondylitis, OP, and rheumatoid arthritis [87,88,89,90,91]. The GM is involved in regulating the balance of musculoskeletal development and homeostasis, and related researches have also shifted from describing simple correlations to seeking intervention mechanisms through the basic researches and clinical trials, which has made this field develop rapidly in recent years [92, 93]. Additionally, the role of exercise in promoting the bone health, improving the bone metabolism and preventing and treating OP has been widely verified, and the studies on the mechanisms of exercise in preventing and treating OP has also been a research hotspot in academic circle [94, 95]. Previous studies have showed that the alterations of exercise-induced hormones, cytokines, bone metabolic signaling pathways and mechanical stress are the main mechanisms of exercise in prevention and treatment of OP, while the interaction between exercise intervention, GM and OP has a pivotal position and still cannot be ignored [96,97,98].
Recently, there have been research reports that the promoting effects of exercise on the bone is closely associated with GM. In a previous study, McCabe et al.  focused on how exercise affects the regulation of HFD on the bone of mice. The researchers intervened the mice with HFD or low-fat diet (LFD), and divided mice into autonomous exercise group and sedentary group for a 14-week experimental period. The results of this study indicated that HFD resulted in the decrease of vertebral and tibial trabeculae, the increase of fat in bone marrow, and the disorder of GM in mice. Nevertheless, exercise can improve the adverse symptoms caused by HFD. Specifically, exercise can reduce the disorder of GM caused by HFD, which was conducive to remodeling the structure and abundance of GM. On the basis of this, the researchers observed that exercise can reduce the ratio of Firmicutes and Bacteroides. Moreover, in terms of the clinical practice, Ilesanmi-Oyelere et al.  conducted a randomized controlled trial of the effects of synbiotic supplements (acting by modulating GM) and exercise on the postmenopausal OP in New Zealand. The researchers expected that the combination modes of synbiotic supplements and exercise may be a promising non-invasive method to manage and/or improve the bone health in postmenopausal women. Shimizu et al.  concluded that the moderate exercise and proper dietary intake are of great significance for the prevention and treatment of OP. Moreover, by integrating various interventions that modulate the composition and/or diversity of GM, it should be a promising strategy for maintaining personal health status and activities of daily living. Collectively, these results suggested that the improvement of GM by exercise may be a novel mechanism for the exercise to promote bone health, and provided a new direction for the mechanism-related studies of exercise intervention in prevention and treatment of OP. However, to date, there are still few studies on the interaction between exercise intervention-GM-OP, and its in-depth mechanisms and possible intervention strategies need to be further clarified in future. Furthermore, the literatures exhibiting outcomes and involved mechanisms with the application of exercise intervention to bone-related diseases in population-based studies and animals researches from the perspective of GM and its metabolites are summarized in Table 1 [99,100,101].
The potential mechanisms of exercise intervention on bone metabolism from the perspective of GM and its metabolites
The regulation of intestinal metabolites
As one of the significant metabolites of GM, SCFAs are mainly composed of the carboxylic acids and small hydrocarbon chains [102, 103]. SCFAs is mainly composed of the acetic acid, propionic acid, butyric acid, and so on. Therein, the acetic acid and propionic acid can act on the liver and surrounding organs, and are the substrates for gluconeogenesis and lipogenesis, while the butyric acid provides the energy for colonic epithelial cells [104,105,106]. Barton et al.  compared the 16 S rRNA sequencing and metabolomics results of 40 professional athletes and 46 sedentary controls, and found that the GM of professional athletes had enhanced the ability to synthesize amino acids and regulate the carbohydrate metabolic pathways, and the contents of metabolites also increased significantly. Yu et al.  revealed that increased production of metabolites after exercise can induce an increase in the genetic expression of sestrin-2 (SESN2) and CREB regulated transcription coactivator 2 (CRTC2) in the liver of mice, resulting in a decline in the expression of inflammatory factors (such as IL-1β and TNF-α), and significantly reduce the level of LPS in circulation, so as to ameliorate the inflammatory or metabolic related diseases. Mailing et al.  also showed a role of butyric acid in the intestine to prevent the degradation of intestinal mucosa. Researchers observed an increase in relative abundance of butyric acid-producing bacteria (Blautia, Roseburia, Anaerostipes, Butyricicoccus) in the intestine of athletes under high intensity exercise conditions. Butyric acid can directly supply the energy to the intestinal epithelial cells and repair injury, thereby reducing the injury to intestine of body caused by high intensity exercise training [110, 111]. Meanwhile, Xia et al.  suggested that the benefits of exercise could be transmitted between the individuals via the transplantation of GM. Specifically, after 12 weeks of moderate intensity exercise, the systolic blood pressure of hypertensive rats reduced, accompanied by the increase in diversity of GM, and this antihypertensive effect can be transmitted to non-exercise hypertensive rats by means of FMT. Scheiman et al.  transplanted the atypical Veillonella isolated from the feces of marathon athletes into experimental mice, and the exercise endurance of mice was significantly improved. Besides, several studies have also reported that the production of butyric acid is related to the production of heat shock protein 70 (HSP70) [114, 115]. HSP70 contributes to maintaining the structural and functional properties of intestinal epithelial cells in response to the damage caused by the prolonged vigorous exercise, which may provide structural and functional stability to intestinal epithelial cells under adverse conditions. Hence, these researches revealed that GM and SCFAs played a critical role in mediating the exercise benefits.
In addition to SCFAs, the metabolic disturbance of bile acids (BAs) is also involved in the occurrence and progression of OP. As a kind of signal molecule, BAs not only play a significant role in the absorption, transport and distribution of fat and fat-soluble vitamins, but also participate in the regulation of energy metabolism, thereby inhibiting the excessive proliferation of GM . Fukiya et al.  showed that Bacteroides enterica and Escherichia coli were involved in the production of secondary BAs in the colon, and exercise may increase the level of secondary BAs by increasing the contents of beneficial bacteria. Meanwhile, Meissner et al.  also revealed that compared with the mice in sedentary group, mice participating in 12-week autonomous exercise had the increased secretion of BAs and output of fecal BAs, and the fecal BAs increased with the enhancement of exercise amount and exercise intensity. On the basis of this, Clark et al.  showed that secondary BAs produced by GM could participate in the regulation of reactive oxygen species (ROS) and inflammatory responses in body by attenuating TNF-α-mediated immune responses and reducing the expression of inflammasomes (such as NOD-like receptor thermal protein domain associated protein 3 (NLRP3)). In addition, the dysbiosis of GM may also decrease the activation of BAs and reduce the levels of free BAs and secondary BAs, and the activation of farnesoid X receptor (FXR), takeda G protein-coupled receptor 5 (TGR5) and the interaction with mitochondria might also be weakened, and these receptors have been verified to be closely related to the regulation of the balance between osteoblasts and osteoclasts [120, 121]. It is recognized that the changes of GM and its metabolites under different intervention conditions, as well as the further in-depth regulatory effects, have become one of vital potential mechanisms of exercise-mediated OP benefits.
The regulation of intestinal mucosal barrier, inflammatory response and oxidative stress
Different exercise amount and exercise intensity may have different effects on the intestinal mucosal barrier and mucosal immune function, and regular moderate exercise may reduce the incidence of infection in body . Meanwhile, moderate exercise can reduce the intestinal inflammatory reaction without affecting the normal tissue structure and morphology of intestinal mucosal barrier . Both prolonged endurance exercise and high intensity exercise could result in the impaired intestinal mucosal barrier function, and mechanisms may be related to the redistribution of blood in whole body. During the process of exercise, blood is mainly concentrated in the heart and skeletal muscles, and the symptoms (such as ischemia and hypoxia) may appear in intestine for a short period of time . With the enhancement of exercise intensity and prolonged duration, the blood redistribution of body may become more apparent. Furthermore, the decrease of intestinal PH value caused by mesenteric ischemia, hypoxia and ischemia-reperfusion is the main reason to induce the intestinal oxidative stress and metabolic abnormalities. The production of excessive nitrogen and oxides caused by high intensity exercise might exacerbate the oxidative damage of intestinal biomolecules, resulting in the injury of intestinal tight junction proteins, and the structure and function of intestinal epithelial cells, thereby further resulting in “intestinal leakage” [125, 126]. Moreover, during the process of acute/vigorous exercise, core temperature in body increases continuously, and prolonged overheating (> 40 °C) can bring about the damage to intestinal epithelial cells, thereby resulting in cell shedding, intestinal villus contraction, edema or hemorrhage .
In addition, the long-term aerobic exercise can enhance the adaptability of body to exercise, and the intestinal mucosal barrier function can also be significantly improved under the long-term exercise intervention . Kang et al.  indicated that long-term round-running exercise intervention could significantly increase the expression of antioxidant enzymes, anti-inflammatory factors and anti-apoptotic proteins in intestinal lymphocytes of mice, accompanied by the decline of serum inflammatory factor levels, suggesting that long-term aerobic exercise plays a positive role in maintaining intestinal villus morphology and improving intestinal permeability. Motiani et al.  observed that after 12 weeks of HFD induction, the basal part of intestinal villi of mice could be significantly widened, and its mechanisms may be related to the infiltration of intestinal inflammatory cells and increase of adipocytes. However, the morphology of intestinal villi and proportion of intestinal inflammatory cells in mice treated with HFD combined with long-term round-running exercise intervention were significantly improved. Other researches have also proposed that the positive impact of long-term aerobic exercise on intestinal mucosal barrier function is associated with the improvement of structure and abundance of GM, the decline of serum inflammatory level and the tolerance level of intestinal ROS [131, 132]. A large number of free radicals generated during exercise are related to the damage of bone, skeletal muscle and the decline of exercise capacity. Excessive free radicals generated by long-term and high intensity exercise might result in the body to generate the exercise-induced oxidative stress damage, which is detrimental to the health and exercise capacity of athletes [133, 134]. Hsu et al.  revealed that the endurance exercise time of specific pathogen free (SPF) mice was significantly higher than that of GF mice, and levels of serum glutathione peroxidase and catalase were also higher than that of GF mice, indicating that GM might eliminate the excessive free radicals produced by exercise, alleviate the exercise fatigue and improve the exercise capacity by enhancing the level of antioxidant enzymes. As there are few relevant studies, more animal models and its potential mechanisms still need to be verified in the future. Nevertheless, as a beneficial stimulus, it is recognized that the exercise intervention can enhance the long-term elasticity of intestinal mucosal barrier, reduce the release of pro-osteoclastogenic cytokines, and increase antioxidant capacity, thus inhibiting the activation of RANKL/OPG/RANK pathway, regulating the balance of osteoblasts and osteoclasts, and further preventing or treating OP.
The involvement of immune regulation
On one hand, GM is involved in immune maturation and anti-infection protection of the body, and in this process, the microorganisms are involved in immune system to recognize and distinguish between the beneficial and harmful bacteria . On the other hand, GM can directly or indirectly influence the function of dendritic cells and macrophages, modulate the activity of T cells, and induce the maturation of B cells via epithelial cells [137, 138]. Moreover, GM can also promote the immune progress of intestinal mucosa through dialogue with the immune system, which might be a critical mechanism for body to prevent the invasion of pathogens . The innate immune system recognizes and differentiates the pathogens and harmless substances through the toll-like receptors (TLRs) and nucleotide-bonded oligomerization domain receptor mechanisms, while microorganisms regulate the expression of TLRs through microbe-associated molecular patterns (MAMPs) pathway, trigger the cascade effect, and further induce the immune response [140, 141].
In addition, the supplementation of probiotics/prebiotics also has a crucial impact and repercussion on exercise-mediated immune regulation. Athletes might also benefit from the regular probiotic supplementations, while with certain strain specificity [142, 143]. Probiotics commonly used to improve the immune function of athletes include Lactobacillus and Bifidobacterium [144, 145]. Previous studies have indicated that after the regular supplementation of probiotics, the severity of gastrointestinal diseases and incidence rate of respiratory diseases in high intensity male athletes are significantly reduced, and the immune disturbance induced by exercise is correspondingly weakened [146,147,148]. Bermon et al.  revealed that the course and severity of upper respiratory tract infection were decreased in the 20 high-level long-distance runners after the oral administration of Lactobacillus yeast, while the levels of IgA, IL-4 and IL-12 in saliva were not significantly changed. Furthermore, as a kind of indigestible polysaccharide, the prebiotics can stimulate the activation and growth of one or more beneficial bacteria in intestine. Similarly, Drakoularakou et al.  revealed in a randomized controlled study involving 159 healthy volunteers engaged in an international tourism that the incidence rate and the duration of diarrhea were reduced after the supplementation of Galactooligosaccharides (GOS). Regular supplementation of Fructooligosaccharides (FOS) is also related to increased serum intestinal peptide concentrations and decreased circulating C-reactive protein (CRP) levels . As a result, although there are still few studies on the involvement of exercise in osteoimmunology regulation via GM and its metabolites , more and more relevant researches in recent years have indicated that GM has a potential immunomodulatory function and can build a bridge between exercise and osteoimmunology, indicating a novel research direction of exercise-bone-immunology. Collectively, the potential mechanism of exercise intervention on bone metabolism from the perspective of GM and its metabolites are summarized in Fig. 2.
Conclusions and perspectives
In general, there is increasing evidence that exercise is an independent factor of external environmental stressors that affects the composition and diversity of GM, and improves the body metabolism and immune system. The imbalance of GM has a direct impact on the normal physiological function and the health status of host. Exercise can enrich the abundance and diversity of GM, improve the proportion of Firmicutes and Bacteroidetes, induce the proliferation of beneficial bacteria and metabolites, and improve the function of intestinal mucosal barrier, so as to further modulate the bone metabolism. Hence, the appropriate exercise has indelible effects on prevention and treatment of OP. However, there are still various issues need to be negotiated in the researches on relationship between exercise, bone metabolism and GM and its metabolites, specifically including: (1) The mechanisms of exercise-related GM and its metabolites directly regulating bone metabolism needs to be further improved; (2) Whether the exercise-related GM and its metabolites have the linkage effects with other important organs in body to indirectly modulate bone metabolism; (3) Paying attention to and screening out the specific GM suitable for different races around the world and the specific flora for improving the motor function may provide the novel insights for the healthy development of motor system and the improvement of motor function level. Nevertheless, with the increasing maturity of microbiome technologies and the wide application of sterile or GF animals, it is believed that further in-depth exploration might provide new perspectives for the researches on link between exercise, GM and its metabolites, and bone metabolism, and also promote the interdisciplinary and integrated researches of exercise physiology, microbiology and metabolomics.
The data used during this current study are available from the corresponding author on reasonable request.
bone mineral density
tumor necrosis factor-α
segmental filamentous bacteria
- Th 17:
T helper cell 17
receptor activator of nuclear factor-κ B ligand
insulin-like growth factor-1
procollagen type I N-terminal propeptide
World Health Organization
short chain fatty acids
fecal microbiota transplantation
heat shock protein 70
reactive oxygen species
NOD-like receptor thermal protein domain associated protein 3
specific pathogen free
farnesoid X receptor
takeda G protein-coupled receptor 5
microbe-associated molecular patterns
CREB regulated transcription coactivator 2
non-alcoholic fatty liver disease
- 16S rRNA:
16 S ribosomal RNA
Xu XM, Li N, Li K, Li XY, Zhang P, Xuan YJ, Cheng XG. Discordance in diagnosis of osteoporosis by quantitative computed tomography and dual-energy X-ray absorptiometry in Chinese elderly men. J Orthop translation. 2019;18:59–64.
Zhang YW, Cao MM, Li YJ, Dai GC, Lu PP, Zhang M, Bai LY, Chen XX, Zhang C, Shi L, et al: The regulative effect and repercussion of probiotics and prebiotics on osteoporosis: involvement of brain-gut-bone axis. Critical reviews in food science and nutrition 2022:1–19.
Zhu Y, Huang Z, Wang Y, Xu W, Chen H, Xu J, Luo S, Zhang Y, Zhao D, Hu J. The efficacy and safety of denosumab in postmenopausal women with osteoporosis previously treated with bisphosphonates: A review. J Orthop translation. 2020;22:7–13.
Kimmel DB, Vennin S, Desyatova A, Turner JA, Akhter MP, Lappe JM, Recker RR. Bone architecture, bone material properties, and bone turnover in non-osteoporotic post-menopausal women with fragility fracture. Osteoporosis international: a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA 2022, 33(5):1125–1136.
Zhang YW, Lu PP, Li YJ, Dai GC, Cao MM, Xie T, Zhang C, Shi L, Rui YF. Low dietary choline intake is associated with the risk of osteoporosis in elderly individuals: a population-based study. Food Funct. 2021;12(14):6442–51.
Brooke-Wavell K, Skelton DA, Barker KL, Clark EM, De Biase S, Arnold S, Paskins Z, Robinson KR, Lewis RM, Tobias JH, et al: Strong, steady and straight: UK consensus statement on physical activity and exercise for osteoporosis. British journal of sports medicine 2022.
Stanghelle B, Bentzen H, Giangregorio L, Pripp AH, Skelton DA, Bergland A. Effects of a resistance and balance exercise programme on physical fitness, health-related quality of life and fear of falling in older women with osteoporosis and vertebral fracture: a randomized controlled trial. Osteoporosis international: a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA 2020, 31(6):1069–1078.
Allegrante JP, Wells MT, Peterson JC. Interventions to Support Behavioral Self-Management of Chronic Diseases. Annu Rev Public Health. 2019;40:127–46.
Zhang YW, Lu PP, Li YJ, Wang H, Zhao YK, Chen H, Rui YF. Short report: relationship between self-reported sleep characteristics and falls-associated fractures in elderly individuals: a population-based study. Psychology, health & medicine 2022:1–9.
Parhami F, Garfinkel A, Demer LL. Role of lipids in osteoporosis. Arteriosclerosis, thrombosis, and vascular biology 2000, 20(11):2346–2348.
Loosen SH, Roderburg C, Demir M, Qvartskhava N, Keitel V, Kostev K, Luedde T. Non-alcoholic fatty liver disease (NAFLD) is associated with an increased incidence of osteoporosis and bone fractures. Z Gastroenterol. 2022;60(8):1221–7.
Filip R, Radzki RP, Bieńko M. Novel insights into the relationship between nonalcoholic fatty liver disease and osteoporosis. Clin Interv Aging. 2018;13:1879–91.
Alison JA, McKeough ZJ, Leung RWM, Holland AE, Hill K, Morris NR, Jenkins S, Spencer LM, Hill CJ, Lee AL, et al: Oxygen compared to air during exercise training in COPD with exercise-induced desaturation. The European respiratory journal 2019, 53(5).
Grünig E, MacKenzie A, Peacock AJ, Eichstaedt CA, Benjamin N, Nechwatal R, Ulrich S, Saxer S, Bussotti M, Sommaruga M, et al. Standardized exercise training is feasible, safe, and effective in pulmonary arterial and chronic thromboembolic pulmonary hypertension: results from a large European multicentre randomized controlled trial. Eur Heart J. 2021;42(23):2284–95.
Ng CA, McMillan LB, Humbert L, Ebeling PR, Scott D. Feasibility, safety and effectiveness of a pilot 16-week home-based, impact exercise intervention in postmenopausal women with low bone mineral density. Osteoporosis international: a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA 2021, 32(5):893–905.
Conway J, N AD. Ageing of the gut microbiome: Potential influences on immune senescence and inflammageing. Ageing Res Rev. 2021;68:101323.
Blasco T, Pérez-Burillo S, Balzerani F, Hinojosa-Nogueira D, Lerma-Aguilera A, Pastoriza S, Cendoya X, Rubio Á, Gosalbes MJ, Jiménez-Hernández N, et al. An extended reconstruction of human gut microbiota metabolism of dietary compounds. Nat Commun. 2021;12(1):4728.
Forslund K, Hildebrand F, Nielsen T, Falony G, Le Chatelier E, Sunagawa S, Prifti E, Vieira-Silva S, Gudmundsdottir V, Pedersen HK, et al. Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature. 2015;528(7581):262–6.
Franzosa EA, Sirota-Madi A, Avila-Pacheco J, Fornelos N, Haiser HJ, Reinker S, Vatanen T, Hall AB, Mallick H, McIver LJ, et al. Gut microbiome structure and metabolic activity in inflammatory bowel disease. Nat Microbiol. 2019;4(2):293–305.
Liu JH, Chen CY, Liu ZZ, Luo ZW, Rao SS, Jin L, Wan TF, Yue T, Tan YJ, Yin H, et al: Extracellular Vesicles from Child Gut Microbiota Enter into Bone to Preserve Bone Mass and Strength. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 2021, 8(9):2004831.
Yang J, Wei H, Zhou Y, Szeto CH, Li C, Lin Y, Coker OO, Lau HCH, Chan AWH, Sung JJY, et al. High-Fat Diet Promotes Colorectal Tumorigenesis Through Modulating Gut Microbiota and Metabolites. Gastroenterology. 2022;162(1):135–49.e132.
Zhang YW, Li YJ, Lu PP, Dai GC, Chen XX, Rui YF. The modulatory effect and implication of gut microbiota on osteoporosis: from the perspective of “brain-gut-bone” axis. Food Funct. 2021;12(13):5703–18.
Denou E, Marcinko K, Surette MG, Steinberg GR, Schertzer JD. High-intensity exercise training increases the diversity and metabolic capacity of the mouse distal gut microbiota during diet-induced obesity. Am J Physiol Endocrinol metabolism. 2016;310(11):E982–93.
Quiroga R, Nistal E, Estébanez B, Porras D, Juárez-Fernández M, Martínez-Flórez S, García-Mediavilla MV, de Paz JA, González-Gallego J, Sánchez-Campos S, et al. Exercise training modulates the gut microbiota profile and impairs inflammatory signaling pathways in obese children. Exp Mol Med. 2020;52(7):1048–61.
Chi L, Tu P, Ru H, Lu K. Studies of xenobiotic-induced gut microbiota dysbiosis: from correlation to mechanisms. Gut Microbes. 2021;13(1):1921912.
Wen C, Yan W, Mai C, Duan Z, Zheng J, Sun C, Yang N. Joint contributions of the gut microbiota and host genetics to feed efficiency in chickens. Microbiome. 2021;9(1):126.
Cai J, Sun L, Gonzalez FJ. Gut microbiota-derived bile acids in intestinal immunity, inflammation, and tumorigenesis. Cell Host Microbe. 2022;30(3):289–300.
Ozaki D, Kubota R, Maeno T, Abdelhakim M, Hitosugi N. Association between gut microbiota, bone metabolism, and fracture risk in postmenopausal Japanese women. Osteoporosis international: a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA 2021, 32(1):145–156.
Wang J, Wang Y, Gao W, Wang B, Zhao H, Zeng Y, Ji Y, Hao D. Diversity analysis of gut microbiota in osteoporosis and osteopenia patients. PeerJ. 2017;5:e3450.
Fuhrman BJ, Feigelson HS, Flores R, Gail MH, Xu X, Ravel J, Goedert JJ. Associations of the fecal microbiome with urinary estrogens and estrogen metabolites in postmenopausal women. J Clin Endocrinol Metab. 2014;99(12):4632–40.
Nilsson AG, Sundh D, Bäckhed F, Lorentzon M. Lactobacillus reuteri reduces bone loss in older women with low bone mineral density: a randomized, placebo-controlled, double-blind, clinical trial. J Intern Med. 2018;284(3):307–17.
Lei M, Hua LM, Wang DW. The effect of probiotic treatment on elderly patients with distal radius fracture: a prospective double-blind, placebo-controlled randomised clinical trial. Beneficial microbes. 2016;7(5):631–7.
van den Heuvel EG, Schoterman MH, Muijs T. Transgalactooligosaccharides stimulate calcium absorption in postmenopausal women. J Nutr. 2000;130(12):2938–42.
Tu MY, Han KY, Chang GR, Lai GD, Chang KY, Chen CF, Lai JC, Lai CY, Chen HL, Chen CM. Kefir Peptides Prevent Estrogen Deficiency-Induced Bone Loss and Modulate the Structure of the Gut Microbiota in Ovariectomized Mice. Nutrients 2020, 12(11).
Sjögren K, Engdahl C, Henning P, Lerner UH, Tremaroli V, Lagerquist MK, Bäckhed F, Ohlsson C. The gut microbiota regulates bone mass in mice. J bone mineral research: official J Am Soc Bone Mineral Res. 2012;27(6):1357–67.
Goto Y, Panea C, Nakato G, Cebula A, Lee C, Diez MG, Laufer TM, Ignatowicz L. Ivanov, II: Segmented filamentous bacteria antigens presented by intestinal dendritic cells drive mucosal Th17 cell differentiation. Immunity. 2014;40(4):594–607.
Tarantino G, Costantini S, Finelli C, Capone F, Guerriero E, La Sala N, Gioia S, Castello G. Is serum Interleukin-17 associated with early atherosclerosis in obese patients? J translational Med. 2014;12:214.
Yan J, Herzog JW, Tsang K, Brennan CA, Bower MA, Garrett WS, Sartor BR, Aliprantis AO, Charles JF. Gut microbiota induce IGF-1 and promote bone formation and growth. Proc Natl Acad Sci USA. 2016;113(47):E7554–63.
Zhang Y-W, Cao M-M, Li Y-J, Lu P-P, Dai G-C, Zhang M, Wang H, Rui Y-F. Fecal microbiota transplantation ameliorates bone loss in mice with ovariectomy-induced osteoporosis via modulating gut microbiota and metabolic function. J Orthop translation. 2022;37:46–60.
Kim D, Kang H. Exercise training modifies gut microbiota with attenuated host responses to sepsis in wild-type mice. FASEB journal: official publication of the Federation of American Societies for Experimental Biology. 2019;33(4):5772–81.
O’Sullivan O, Cronin O, Clarke SF, Murphy EF, Molloy MG, Shanahan F, Cotter PD. Exercise and the microbiota. Gut Microbes. 2015;6(2):131–6.
Jang LG, Choi G, Kim SW, Kim BY, Lee S, Park H. The combination of sport and sport-specific diet is associated with characteristics of gut microbiota: an observational study. J Int Soc Sports Nutr. 2019;16(1):21.
Ilesanmi-Oyelere BL, Roy NC, Kruger MC. Modulation of Bone and Joint Biomarkers, Gut Microbiota, and Inflammation Status by Synbiotic Supplementation and Weight-Bearing Exercise: Human Study Protocol for a Randomized Controlled Trial. JMIR Res protocols. 2021;10(10):e30131.
McCabe LR, Irwin R, Tekalur A, Evans C, Schepper JD, Parameswaran N, Ciancio M. Exercise prevents high fat diet-induced bone loss, marrow adiposity and dysbiosis in male mice. Bone. 2019;118:20–31.
Rizzoli R, Biver E, Brennan-Speranza TC. Nutritional intake and bone health. The lancet Diabetes & endocrinology. 2021;9(9):606–21.
Shimizu Y. Gut microbiota in common elderly diseases affecting activities of daily living. World J Gastroenterol. 2018;24(42):4750–8.
Pedersini P, Turroni S, Villafañe JH. Gut microbiota and physical activity: Is there an evidence-based link? The Science of the total environment 2020, 727:138648.
Dorelli B, Gallè F, De Vito C, Duranti G, Iachini M, Zaccarin M, Preziosi Standoli J, Ceci R, Romano F, Liguori G, et al: Can Physical Activity Influence Human Gut Microbiota Composition Independently of Diet? A Systematic Review. Nutrients 2021, 13(6).
Monda V, Villano I, Messina A, Valenzano A, Esposito T, Moscatelli F, Viggiano A, Cibelli G, Chieffi S, Monda M, et al: Exercise Modifies the Gut Microbiota with Positive Health Effects. Oxidative medicine and cellular longevity 2017, 2017:3831972.
Anderson L, Nguyen TT, Dall CH, Burgess L, Bridges C, Taylor RS. Exercise-based cardiac rehabilitation in heart transplant recipients. Cochrane Database Syst Rev. 2017;4(4):Cd012264.
Larun L, Brurberg KG, Odgaard-Jensen J, Price JR. Exercise therapy for chronic fatigue syndrome. Cochrane Database Syst Rev. 2019;10(10):Cd003200.
Mok A, Khaw KT, Luben R, Wareham N, Brage S. Physical activity trajectories and mortality: population based cohort study. BMJ (Clinical research ed). 2019;365:l2323.
Balducci S, Zanuso S, Nicolucci A, Fernando F, Cavallo S, Cardelli P, Fallucca S, Alessi E, Letizia C, Jimenez A, et al: Anti-inflammatory effect of exercise training in subjects with type 2 diabetes and the metabolic syndrome is dependent on exercise modalities and independent of weight loss. Nutrition: NMCD 2010, 20(8):pp. 608–17.
Peters HP, De Vries WR, Vanberge-Henegouwen GP, Akkermans LM. Potential benefits and hazards of physical activity and exercise on the gastrointestinal tract. Gut. 2001;48(3):435–9.
Douglas JA, King JA, Clayton DJ, Jackson AP, Sargeant JA, Thackray AE, Davies MJ, Stensel DJ: Acute effects of exercise on appetite, ad libitum energy intake and appetite-regulatory hormones in lean and overweight/obese men and women. International journal of obesity (2005) 2017, 41(12):1737–1744.
da Silva CD, de Oliveira DR, Perrone ÍT, Fonseca CH, Garcia ES. Low-fat, lactose-free and leucine-enriched chocolate cow milk prototype: A preliminary study on sensorial acceptability and gastrointestinal complaints following exhaustive exercise. J Int Soc Sports Nutr. 2021;18(1):14.
Ribeiro FM, Petriz B, Marques G, Kamilla LH, Franco OL. Is There an Exercise-Intensity Threshold Capable of Avoiding the Leaky Gut? Frontiers in nutrition 2021, 8:627289.
Frampton J, Murphy KG, Frost G, Chambers ES. Short-chain fatty acids as potential regulators of skeletal muscle metabolism and function. Nat metabolism. 2020;2(9):840–8.
Allen JM, Mailing LJ, Niemiro GM, Moore R, Cook MD, White BA, Holscher HD, Woods JA. Exercise Alters Gut Microbiota Composition and Function in Lean and Obese Humans. Med Sci Sports Exerc. 2018;50(4):747–57.
Clauss M, Gérard P, Mosca A, Leclerc M. Interplay Between Exercise and Gut Microbiome in the Context of Human Health and Performance. Front Nutr. 2021;8:637010.
Munukka E, Ahtiainen JP, Puigbó P, Jalkanen S, Pahkala K, Keskitalo A, Kujala UM, Pietilä S, Hollmén M, Elo L, et al. Six-Week Endurance Exercise Alters Gut Metagenome That Is not Reflected in Systemic Metabolism in Over-weight Women. Front Microbiol. 2018;9:2323.
Hamasaki H. Exercise and gut microbiota: clinical implications for the feasibility of Tai Chi. J Integr Med. 2017;15(4):270–81.
Cella V, Bimonte VM, Sabato C, Paoli A, Baldari C, Campanella M, Lenzi A, Ferretti E, Migliaccio S. Nutrition and Physical Activity-Induced Changes in Gut Microbiota: Possible Implications for Human Health and Athletic Performance. Foods (Basel, Switzerland) 2021, 10(12).
Liang R, Zhang S, Peng X, Yang W, Xu Y, Wu P, Chen J, Cai Y, Zhou J. Characteristics of the gut microbiota in professional martial arts athletes: A comparison between different competition levels. PLoS ONE. 2019;14(12):e0226240.
Clark A, Mach N. Exercise-induced stress behavior, gut-microbiota-brain axis and diet: a systematic review for athletes. J Int Soc Sports Nutr. 2016;13:43.
Aya V, Flórez A, Perez L, Ramírez JD. Association between physical activity and changes in intestinal microbiota composition: A systematic review. PLoS ONE. 2021;16(2):e0247039.
Camilleri M. Leaky gut: mechanisms, measurement and clinical implications in humans. Gut. 2019;68(8):1516–26.
Rao KA, Yazaki E, Evans DF, Carbon R. Objective evaluation of small bowel and colonic transit time using pH telemetry in athletes with gastrointestinal symptoms. Br J Sports Med. 2004;38(4):482–7.
Wallett A, McKune A, Pyne D, Bishop D, Girard O, Saunders P, Périard J. Repeated-Sprint Exercise in the Heat Increases Indirect Markers of Gastrointestinal Damage in Well-Trained Team-Sport Athletes. Int J Sport Nutr Exerc Metab. 2022;32(3):153–62.
Jeukendrup AE, Vet-Joop K, Sturk A, Stegen JH, Senden J, Saris WH, Wagenmakers AJ: 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. Clinical science (London, England: 1979) 2000, 98(1):47–55.
Lin L, Zhang J. Role of intestinal microbiota and metabolites on gut homeostasis and human diseases. BMC Immunol. 2017;18(1):2.
Codella R, Luzi L, Terruzzi I. Exercise has the guts: How physical activity may positively modulate gut microbiota in chronic and immune-based diseases. Digestive and liver disease: official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver 2018, 50(4):331–341.
Pedersen BK, Toft AD. Effects of exercise on lymphocytes and cytokines. Br J Sports Med. 2000;34(4):246–51.
Zouhal H, Sellami M, Saeidi A, Slimani M, Abbassi-Daloii A, Khodamoradi A, El Hage R, Hackney AC, Ben Abderrahman A. Effect of physical exercise and training on gastrointestinal hormones in populations with different weight statuses. Nutr Rev. 2019;77(7):455–77.
Pasini E, Corsetti G, Assanelli D, Testa C, Romano C, Dioguardi FS, Aquilani R. Effects of chronic exercise on gut microbiota and intestinal barrier in human with type 2 diabetes. Minerva Med. 2019;110(1):3–11.
JanssenDuijghuijsen LM, van Norren K, Grefte S, Koppelman SJ, Lenaerts K, Keijer J, Witkamp RF, Wichers HJ. Endurance Exercise Increases Intestinal Uptake of the Peanut Allergen Ara h 6 after Peanut Consumption in Humans. Nutrients 2017, 9(1).
Matsumoto M, Inoue R, Tsukahara T, Ushida K, Chiji H, Matsubara N, Hara H. Voluntary running exercise alters microbiota composition and increases n-butyrate concentration in the rat cecum. Biosci Biotechnol Biochem. 2008;72(2):572–6.
Kramer JM, Plowey ED, Beatty JA, Little HR, Waldrop TG. Hypothalamus, hypertension, and exercise. Brain Res Bull. 2000;53(1):77–85.
Chen CY, Bonham AC. Postexercise hypotension: central mechanisms. Exerc Sport Sci Rev. 2010;38(3):122–7.
Aoki T, Oyanagi E, Watanabe C, Kobiki N, Miura S, Yokogawa Y, Kitamura H, Teramoto F, Kremenik MJ, Yano H. The Effect of Voluntary Exercise on Gut Microbiota in Partially Hydrolyzed Guar Gum Intake Mice under High-Fat Diet Feeding. Nutrients 2020, 12(9).
Li K, Liu A, Zong W, Dai L, Liu Y, Luo R, Ge S, Dong G. Moderate exercise ameliorates osteoarthritis by reducing lipopolysaccharides from gut microbiota in mice. Saudi J Biol Sci. 2021;28(1):40–9.
Cook MD, Martin SA, Williams C, Whitlock K, Wallig MA, Pence BD, Woods JA. Forced treadmill exercise training exacerbates inflammation and causes mortality while voluntary wheel training is protective in a mouse model of colitis. Brain Behav Immun. 2013;33:46–56.
Allen JM, Berg Miller ME, Pence BD, Whitlock K, Nehra V, Gaskins HR, White BA, Fryer JD, Woods JA: Voluntary and forced exercise differentially alters the gut microbiome in C57BL/6J mice. Journal of applied physiology (Bethesda, Md: 1985) 2015, 118(8):1059–1066.
Gordon CJ, Phillips PM, Johnstone AF. Impact of genetic strain on body fat loss, food consumption, metabolism, ventilation, and motor activity in free running female rats. Physiol Behav. 2016;153:56–63.
Mahmoodzadeh S, Koch K, Schriever C, Xu J, Steinecker M, Leber J, Dworatzek E, Purfürst B, Kunz S, Recchia D, et al. Age-related decline in murine heart and skeletal muscle performance is attenuated by reduced Ahnak1 expression. J cachexia sarcopenia muscle. 2021;12(5):1249–65.
Wang Z, Chen K, Wu C, Chen J, Pan H, Liu Y, Wu P, Yuan J, Huang F, Lang J, et al. An emerging role of Prevotella histicola on estrogen deficiency-induced bone loss through the gut microbiota-bone axis in postmenopausal women and in ovariectomized mice. Am J Clin Nutr. 2021;114(4):1304–13.
Wei J, Zhang C, Zhang Y, Zhang W, Doherty M, Yang T, Zhai G, Obotiba AD, Lyu H, Zeng C, et al: Association Between Gut Microbiota and Symptomatic Hand Osteoarthritis: Data From the Xiangya Osteoarthritis Study. Arthritis & rheumatology (Hoboken, NJ) 2021, 73(9):1656–1662.
Yuan Y, Yang J, Zhuge A, Li L, Ni S. Gut microbiota modulates osteoclast glutathione synthesis and mitochondrial biogenesis in mice subjected to ovariectomy. Cell Prolif. 2022;55(3):e13194.
Zhou C, Zhao H, Xiao XY, Chen BD, Guo RJ, Wang Q, Chen H, Zhao LD, Zhang CC, Jiao YH, et al. Metagenomic profiling of the pro-inflammatory gut microbiota in ankylosing spondylitis. J Autoimmun. 2020;107:102360.
Liu C, Cheung WH, Li J, Chow SK, Yu J, Wong SH, Ip M, Sung JJY, Wong RMY. Understanding the gut microbiota and sarcopenia: a systematic review. J cachexia sarcopenia muscle. 2021;12(6):1393–407.
Zhang X, Zhang D, Jia H, Feng Q, Wang D, Liang D, Wu X, Li J, Tang L, Li Y, et al. The oral and gut microbiomes are perturbed in rheumatoid arthritis and partly normalized after treatment. Nat Med. 2015;21(8):895–905.
Chen YC, Greenbaum J, Shen H, Deng HW. Association Between Gut Microbiota and Bone Health: Potential Mechanisms and Prospective. J Clin Endocrinol Metab. 2017;102(10):3635–46.
Lahiri S, Kim H, Garcia-Perez I, Reza MM, Martin KA, Kundu P, Cox LM, Selkrig J, Posma JM, Zhang H, et al: The gut microbiota influences skeletal muscle mass and function in mice. Science translational medicine 2019, 11(502).
Behera J, Ison J, Tyagi SC, Tyagi N. The role of gut microbiota in bone homeostasis. Bone. 2020;135:115317.
Li J, Ho WTP, Liu C, Chow SK, Ip M, Yu J, Wong HS, Cheung WH, Sung JJY, Wong RMY. The role of gut microbiota in bone homeostasis. Bone & joint research. 2021;10(1):51–9.
Abdelfattah Abulfadle K, Refaat Abdelkader Atia R, Osama Mohammed H, Saad Ramadan R, Mohammed NA. The potential anti-osteoporotic effect of exercise-induced increased preptin level in ovariectomized rats. Anatomical science international 2022.
Tong X, Chen X, Zhang S, Huang M, Shen X, Xu J, Zou J: The Effect of Exercise on the Prevention of Osteoporosis and Bone Angiogenesis. BioMed research international 2019, 2019:8171897.
Park JH, Park KH, Cho S, Choi YS, Seo SK, Lee BS, Park HS. Concomitant increase in muscle strength and bone mineral density with decreasing IL-6 levels after combination therapy with alendronate and calcitriol in postmenopausal women. Menopause (New York NY). 2013;20(7):747–53.
Wu J, Oka J, Higuchi M, Tabata I, Toda T, Fujioka M, Fuku N, Teramoto T, Okuhira T, Ueno T, et al. Cooperative effects of isoflavones and exercise on bone and lipid metabolism in postmenopausal Japanese women: a randomized placebo-controlled trial. Metab Clin Exp. 2006;55(4):423–33.
Rios JL, Bomhof MR, Reimer RA, Hart DA, Collins KH, Herzog W. Protective effect of prebiotic and exercise intervention on knee health in a rat model of diet-induced obesity. Sci Rep. 2019;9(1):3893.
Hao X, Zhang J, Shang X, Sun K, Zhou J, Liu J, Chi R, Xu T. Exercise modifies the disease-relevant gut microbial shifts in post-traumatic osteoarthritis rats. Bone & joint research. 2022;11(4):214–25.
Pang B, Jin H, Liao N, Li J, Jiang C, Shao D, Shi J. Lactobacillus rhamnosus from human breast milk ameliorates ulcerative colitis in mice via gut microbiota modulation. Food Funct. 2021;12(11):5171–86.
Vicentini FA, Keenan CM, Wallace LE, Woods C, Cavin JB, Flockton AR, Macklin WB, Belkind-Gerson J, Hirota SA, Sharkey KA. Intestinal microbiota shapes gut physiology and regulates enteric neurons and glia. Microbiome. 2021;9(1):210.
Portincasa P, Bonfrate L, Vacca M, De Angelis M, Farella I, Lanza E, Khalil M, Wang DQ, Sperandio M, Di Ciaula A. Gut Microbiota and Short Chain Fatty Acids: Implications in Glucose Homeostasis. International journal of molecular sciences 2022, 23(3).
Boets E, Gomand SV, Deroover L, Preston T, Vermeulen K, De Preter V, Hamer HM, Van den Mooter G, De Vuyst L, Courtin CM, et al. Systemic availability and metabolism of colonic-derived short-chain fatty acids in healthy subjects: a stable isotope study. J Physiol. 2017;595(2):541–55.
Fava F, Rizzetto L, Tuohy KM: Gut microbiota and health: connecting actors across the metabolic system. The Proceedings of the Nutrition Society 2019, 78(2):177–188.
Barton W, Penney NC, Cronin O, Garcia-Perez I, Molloy MG, Holmes E, Shanahan F, Cotter PD, 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. 2018;67(4):625–33.
Yu C, Liu S, Chen L, Shen J, Niu Y, Wang T, Zhang W, Fu L. Effect of exercise and butyrate supplementation on microbiota composition and lipid metabolism. J Endocrinol. 2019;243(2):125–35.
Mailing LJ, Allen JM, Buford TW, Fields CJ, Woods JA. Exercise and the Gut Microbiome: A Review of the Evidence, Potential Mechanisms, and Implications for Human Health. Exerc Sport Sci Rev. 2019;47(2):75–85.
Silva JPB, Navegantes-Lima KC, Oliveira ALB, Rodrigues DVS, Gaspar SLF, Monteiro VVS, Moura DP, Monteiro MC. Protective Mechanisms of Butyrate on Inflammatory Bowel Disease. Curr Pharm Design. 2018;24(35):4154–66.
Lenoir M, Martín R, Torres-Maravilla E, Chadi S, González-Dávila P, Sokol H, Langella P, Chain F. Bermúdez-Humarán LG: Butyrate mediates anti-inflammatory effects of Faecalibacterium prausnitzii in intestinal epithelial cells through Dact3. Gut Microbes. 2020;12(1):1–16.
Xia WJ, Xu ML, Yu XJ, Du MM, Li XH, Yang T, Li L, Li Y, Kang KB, Su Q, et al. Antihypertensive effects of exercise involve reshaping of gut microbiota and improvement of gut-brain axis in spontaneously hypertensive rat. Gut Microbes. 2021;13(1):1–24.
Scheiman J, Luber JM, Chavkin TA, MacDonald T, Tung A, Pham LD, Wibowo MC, Wurth RC, Punthambaker S, Tierney BT, et al. Meta-omics analysis of elite athletes identifies a performance-enhancing microbe that functions via lactate metabolism. Nat Med. 2019;25(7):1104–9.
Venkatraman A, Ramakrishna BS, Shaji RV, Kumar NS, Pulimood A, Patra S. Amelioration of dextran sulfate colitis by butyrate: role of heat shock protein 70 and NF-kappaB. Am J Physiol Gastrointest liver Physiol. 2003;285(1):G177–84.
Malago JJ, Koninkx JF, Tooten PC, van Liere EA, van Dijk JE. Anti-inflammatory properties of heat shock protein 70 and butyrate on Salmonella-induced interleukin-8 secretion in enterocyte-like Caco-2 cells. Clin Exp Immunol. 2005;141(1):62–71.
Lin H, An Y, Tang H, Wang Y. Alterations of Bile Acids and Gut Microbiota in Obesity Induced by High Fat Diet in Rat Model. J Agric Food Chem. 2019;67(13):3624–32.
Fukiya S, Arata M, Kawashima H, Yoshida D, Kaneko M, Minamida K, Watanabe J, Ogura Y, Uchida K, Itoh K, et al. Conversion of cholic acid and chenodeoxycholic acid into their 7-oxo derivatives by Bacteroides intestinalis AM-1 isolated from human feces. FEMS Microbiol Lett. 2009;293(2):263–70.
Meissner M, Lombardo E, Havinga R, Tietge UJ, Kuipers F, Groen AK. Voluntary wheel running increases bile acid as well as cholesterol excretion and decreases atherosclerosis in hypercholesterolemic mice. Atherosclerosis. 2011;218(2):323–9.
Clark A, Mach N. The Crosstalk between the Gut Microbiota and Mitochondria during Exercise. Front Physiol. 2017;8:319.
Mosińska P, Szczepaniak A, Fichna J. Bile acids and FXR in functional gastrointestinal disorders. Digestive and liver disease: official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver 2018, 50(8):795–803.
Sorrentino G, Perino A, Yildiz E, El Alam G, Bou Sleiman M, Gioiello A, Pellicciari R, Schoonjans K. Bile Acids Signal via TGR5 to Activate Intestinal Stem Cells and Epithelial Regeneration. Gastroenterology. 2020;159(3):956–68.e958.
Pires W, Veneroso CE, Wanner SP, Pacheco DAS, Vaz GC, Amorim FT, Tonoli C, Soares DD, Coimbra CC. Association Between Exercise-Induced Hyperthermia and Intestinal Permeability: A Systematic Review. Sports medicine (Auckland, NZ) 2017, 47(7):1389–1403.
Luo B, Xiang D, Nieman DC, Chen P. The effects of moderate exercise on chronic stress-induced intestinal barrier dysfunction and antimicrobial defense. Brain Behav Immun. 2014;39:99–106.
Wang J, Zhang Q, Xia J, Sun H. Moderate Treadmill Exercise Modulates Gut Microbiota and Improves Intestinal Barrier in High-Fat-Diet-Induced Obese Mice via the AMPK/CDX2 Signaling Pathway. Diabetes, metabolic syndrome and obesity: targets and therapy 2022, 15:209–223.
Zuhl M, Schneider S, Lanphere K, Conn C, Dokladny K, Moseley P. Exercise regulation of intestinal tight junction proteins. Br J Sports Med. 2014;48(12):980–6.
Dokladny K, Zuhl MN, Moseley PL: Intestinal epithelial barrier function and tight junction proteins with heat and exercise. Journal of applied physiology (Bethesda, Md: 1985) 2016, 120(6):692–701.
King MA, Rollo I, Baker LB: Nutritional considerations to counteract gastrointestinal permeability during exertional heat stress. Journal of applied physiology (Bethesda, Md: 1985) 2021, 130(6):1754–1765.
Keirns BH, Koemel NA, Sciarrillo CM, Anderson KL, Emerson SR. Exercise and intestinal permeability: another form of exercise-induced hormesis? Am J Physiol Gastrointest liver Physiol. 2020;319(4):G512-g518.
Kang SS, Jeraldo PR, Kurti A, Miller ME, Cook MD, Whitlock K, Goldenfeld N, Woods JA, White BA, Chia N, et al. Diet and exercise orthogonally alter the gut microbiome and reveal independent associations with anxiety and cognition. Mol neurodegeneration. 2014;9:36.
Motiani KK, Collado MC, Eskelinen JJ, Virtanen KA, Löyttyniemi E, Salminen S, Nuutila P, Kalliokoski KK, Hannukainen JC. Exercise Training Modulates Gut Microbiota Profile and Improves Endotoxemia. Med Sci Sports Exerc. 2020;52(1):94–104.
Pilmark NS, Oberholzer L, Halling JF, Kristensen JM, Bønding CP, Elkjær I, Lyngbæk M, Elster G, Siebenmann C, Holm NFR, et al: Skeletal muscle adaptations to exercise are not influenced by metformin treatment in humans: secondary analyses of 2 randomized, clinical trials. Applied physiology, nutrition, and metabolism = Physiologie appliquee, nutrition et metabolisme 2022, 47(3):309–320.
Li Y, Zafar S, Salih Ibrahim RM, Chi HL, Xiao T, Xia WJ, Li HB, Kang YM. Exercise and food supplement of vitamin C ameliorate hypertension through improvement of gut microflora in the spontaneously hypertensive rats. Life Sci. 2021;269:119097.
Tobore TO. Towards a comprehensive theory of obesity and a healthy diet: The causal role of oxidative stress in food addiction and obesity. Behav Brain Res. 2020;384:112560.
Przewłócka K, Folwarski M, Kaźmierczak-Siedlecka K, Skonieczna-Żydecka K, Kaczor JJ. Gut-Muscle AxisExists and May Affect Skeletal Muscle Adaptation to Training. Nutrients 2020, 12(5).
Hsu YJ, Chiu CC, Li YP, Huang WC, Huang YT, Huang CC, Chuang HL. Effect of intestinal microbiota on exercise performance in mice. J strength conditioning Res. 2015;29(2):552–8.
Yang W, Cong Y. Gut microbiota-derived metabolites in the regulation of host immune responses and immune-related inflammatory diseases. Cell Mol Immunol. 2021;18(4):866–77.
de Oliveira GLV, Leite AZ, Higuchi BS, Gonzaga MI, Mariano VS. Intestinal dysbiosis and probiotic applications in autoimmune diseases. Immunology. 2017;152(1):1–12.
Shulzhenko N, Morgun A, Hsiao W, Battle M, Yao M, Gavrilova O, Orandle M, Mayer L, Macpherson AJ, McCoy KD, et al. Crosstalk between B lymphocytes, microbiota and the intestinal epithelium governs immunity versus metabolism in the gut. Nat Med. 2011;17(12):1585–93.
Littman DR. Do the Microbiota Influence Vaccines and Protective Immunity to Pathogens? If So, Is There Potential for Efficacious Microbiota-Based Vaccines? Cold Spring Harbor perspectives in biology 2018, 10(2).
Feldman N, Rotter-Maskowitz A, Okun E. DAMPs as mediators of sterile inflammation in aging-related pathologies. Ageing Res Rev. 2015;24(Pt A):29–39.
Sina C, Kemper C, Derer S. The intestinal complement system in inflammatory bowel disease: Shaping intestinal barrier function. Semin Immunol. 2018;37:66–73.
Hughes RL, Holscher HD. Fueling Gut Microbes: A Review of the Interaction between Diet, Exercise, and the Gut Microbiota in Athletes. Advances in nutrition (Bethesda, Md) 2021, 12(6):2190–2215.
Calero CDQ, Rincón EO, Marqueta PM. Probiotics, prebiotics and synbiotics: useful for athletes and active individuals? A systematic review. Beneficial microbes. 2020;11(2):135–49.
Gleeson M, Bishop NC, Oliveira M, Tauler P. Daily probiotic’s (Lactobacillus casei Shirota) reduction of infection incidence in athletes. Int J Sport Nutr Exerc Metab. 2011;21(1):55–64.
Axling U, Önning G, Combs MA, Bogale A, Högström M, Svensson M. The Effect of Lactobacillus plantarum 299v on Iron Status and Physical Performance in Female Iron-Deficient Athletes: A Randomized Controlled Trial. Nutrients 2020, 12(5).
Nichols AW. Probiotics and athletic performance: a systematic review. Curr Sports Med Rep. 2007;6(4):269–73.
Tavakoly R, Hadi A, Rafie N, Talaei B, Marx W, Arab A. Effect of Probiotic Consumption on Immune Response in Athletes: A Meta-analysis. Int J Sports Med. 2021;42(9):769–81.
Pyne DB, Guy JH, Edwards AM. Managing heat and immune stress in athletes with evidence-based strategies. Int J Sports Physiol Perform. 2014;9(5):744–50.
Bermon S, Petriz B, Kajėnienė A, Prestes J, Castell L, Franco OL. The microbiota: an exercise immunology perspective. Exerc Immunol Rev. 2015;21:70–9.
Drakoularakou A, Tzortzis G, Rastall RA, Gibson GR. A double-blind, placebo-controlled, randomized human study assessing the capacity of a novel galacto-oligosaccharide mixture in reducing travellers’ diarrhoea. Eur J Clin Nutr. 2010;64(2):146–52.
Velayati A, Kareem I, Sedaghat M, Sohrab G, Nikpayam O, Hedayati M, Abhari K, Hejazi E. Does symbiotic supplementation which contains Bacillus Coagulans Lactobacillus rhamnosus, Lactobacillus acidophilus and fructooligosaccharide has favourite effects in patients with type-2 diabetes? A randomised, double-blind, placebo-controlled trial. Archives of physiology and biochemistry 2021:1–8.
Tu Y, Yang R, Xu X, Zhou X. The microbiota-gut-bone axis and bone health. J Leukoc Biol. 2021;110(3):525–37.
This current work was supported by grants from Winfast Charity Foundation Project (YL20220525); Jiangsu Provincial Medical Talent, The Project of Invigorating Health Care through Science, Technology and Education (ZDRCA2016083); and Jiangsu Elderly Health Research Project, Key Project of Elderly Health Research Project (LKZ2022010).
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Zhang, YW., Cao, MM., Li, YJ. et al. A narrative review of the moderating effects and repercussion of exercise intervention on osteoporosis: ingenious involvement of gut microbiota and its metabolites. J Transl Med 20, 490 (2022). https://doi.org/10.1186/s12967-022-03700-4
- Exercise intervention
- Gut microbiota