Gut Microbiota in Exercise-Regulated Development, Progression, and Management of Type 2 Diabetes Mellitus: A Review of the Role and Mechanisms

Introduction

Over the past few decades, the prevalence of T2DM mellitus (T2DM) has increased significantly worldwide, gradually becoming one of the major diseases endangering human health. It is not only the main risk factor for cardiovascular and cerebrovascular diseases, but is also closely related to the incidence of a variety of malignant tumors, causing heavy medical and economic burdens for the patients’ families and society [1]. The onset of T2DM and its complications can be avoided or delayed through a healthy diet, increased physical activity, and regular screening. Exercise therapy is the most cost-effective method for early diabetes prevention and treatment. For patients with abnormal glucose metabolism, the benefits of exercise are mainly reflected in weight loss, as well as promoting cardiovascular health and improving glucose and lipid metabolism. Studies have shown that exercise training can improve inflammatory status, insulin sensitivity, and blood glucose control in T2DM patients [2]. In addition, weight loss via a regular exercise program can promote T2DM remission [3].

The gut microbiome is a general term for the community of microorganisms inhabiting the human gut. The gut microbiota is closely related to human health, and plays an important role in maintaining the gut mucosal barrier, participating in immune regulation, synthesizing important vitamins, and utilizing undigested carbohydrates to produce short-chain fatty acids [4]. The composition and dysfunction of gut microbiota are closely related to the incidence of metabolic diseases such as obesity and diabetes. Studies have shown that dysbiosis of the gut microbiota is a potential factor contributing to the rapid progression of insulin resistance in T2DM. Dysbiosis of the gut microbiota can reshape the gut barrier function and host metabolic and signaling pathways in patients with T2DM, which are directly or indirectly associated with insulin resistance in T2DM. At the same time, commensal fungi and opportunistic bacteria stimulate the local immune system, alter gut permeability, and lead to gut leakiness, which in turn activates systemic inflammation and results in insulin resistance [5]. It was also found that T2DM patients have low bacterial diversity, for example, a reduced abundance of short-chain fatty acid (SCFA)-producing bacteria, especially butyric acid-producing bacteria (such as Roseburia gutis and Faecalibacterium prausnitzii) [6]. Other studies have highlighted the important role of Akkermansia muciniphila as a mediator of metabolic benefits (eg, by regulating glucose homeostasis and insulin sensitivity), although this benefit is not significant in patients with pre-T2DM and newly diagnosed T2DM [7]. Another important observation was increased gut permeability in T2DM patients compared to healthy controls. This “leaky gut” can cause inflammatory molecules to enter the patient’s systemic circulation, resulting in elevated insulin resistance (IR) [8].

Recent studies have shown that a highly diverse gut microbiota is generally associated with better health, and that regular physical activity is positively correlated with the diversity of gut microbiota [9]. Studies have found that compared with sedentary people, active people have more beneficial bacteria. For example, Faecalibacterium prausnitzii produces butyrate, promotes of insulin secretion, improves insulin sensitivity, and reduces pro-inflammatory cytokine release. Roseburia hominis produces butyrate, promotes insulin secretion, and improves insulin sensitivity. By increasing the expression of tight junction proteins such as zonula occludens-1 (ZO-1), Roseburia hominis helps to enhance gut barrier function, reduces gut permeability, and thereby lowers systemic inflammation, and Akkermansia muciniphila maintains intestinal barrier function, reduces the release of pro-inflammatory cytokines, and regulates glucose homeostasis and insulin sensitivity. In addition, body fat percentage, muscle mass, and physical activity are significantly associated with gut microbial diversity. Through exercise, especially longer periods of aerobic/endurance exercise, the abundance of beneficial bacteria, including Lactobacillus and Bifidobacterium, can be increased. Lactobacillus can produce lactic acid, reduce intestinal pH, inhibit the growth of harmful bacteria, and increase the expression of tight junction proteins (such as ZO-1) in intestinal epithelial cells. Bifidobacterium can produce short-chain fatty acids (SCFAs) such as acetic acid, propionic acid, and butyric acid through the fermentation of dietary fiber, increase the expression of tight junction proteins (such as ZO-1) in intestinal epithelial cells, reduce intestinal permeability, regulate the immune system, reduce the release of pro-inflammatory cytokines, and enhance the body’s immune defense capabilities. Additionally, these beneficial bacteria can also reduce intestinal permeability, decrease the release of pro-inflammatory cytokines, and break down complex carbohydrates in food to produce SCFAs (such as acetic acid, propionic acid, and butyric acid). In addition, these beneficial bacteria (lactobacilli, bifidobacteria) can also competitively inhibit the growth of harmful bacteria, reduce the risk of intestinal infections, and increase the abundance of Akkermansia muciniphila, which can maintain intestinal barrier function. Beneficial bacteria help to maintain the acid–base balance of the gut, improve immunity, and prevent the breeding of harmful microorganisms. Proper exercise can indirectly promote the balance of the gut microbiota by promoting the reproduction of beneficial bacteria. In addition, exercise not only affects the abundance and diversity of gut microbes, but also changes their metabolic activity [10]. Studies have found that exercise can regulate the metabolic level of gut microbes and affect the survival and reproduction of specific gut microbes. This change in metabolic level may be related to the regulation of human metabolism and energy balance, and further affect overall health [11]. This paper focuses on the relationship between gut microbiota and T2DM, the impact of exercise on gut microbiota, and the role of gut microbiota in exercise-induced improvement of T2DM, aiming to review of the role and mechanisms of the gut microbiota in exercise-regulated development, progression, and management of T2DM.

Type 2 Diabetes

Diabetes is a serious chronic metabolic disease characterized by hyperglycemia. Relative or absolute lack of insulin secretion is its main feature. Chronic hyperglycemia can lead to damage or even failure of a variety of organs, including the heart, great blood vessels, retina, kidney muscles, and nerves, causing a huge social and economic burden. An international diabetes study recently found that the global prevalence of diabetes rose sharply from 3.2% in 1990 to 6.1% in 2021, an increase of more than 90%, and is not only a major problem for global public health now, but will become even more serious over the next 3 decades [12]. Systematic analysis shows that from 2021 to 2050, the global prevalence of diabetes will continue to rise sharply from 6.1% to nearly 10%, with a corresponding increase in people’s risk of developing the disease of nearly 60%. By then, the total number of people with diabetes may exceed 1.3 billion [13]. T2DM, which accounts for more than 90% of diabetes, is a chronic metabolic disease characterized by hyperglycemia, insulin resistance and low-grade inflammation, which can lead to serious complications such as cerebrovascular disease and diabetic nephropathy. T2DM is thought to be caused by poor or unhealthy diet, physical inactivity, smoking, and obesity. With economic development and improvement of quality of life, the incidence of T2DM is gradually increasing worldwide. According to data released by the International Diabetes Federation in 2021, the number of people with T2DM worldwide has reached 537 million and is expected to increase to 643 million by 2030 [14]. When the liver, muscle, and fat tissue become less sensitive to insulin, it causes relative insulin resistance (IR). Pancreatic beta cells become dysfunctional due to increased load and are unable to compensate for IR, thus inducing T2DM. Therefore, reducing IR to relieve the burden of pancreatic beta cells is the most effective way to delay the progression of T2DM. Currently, it is believed that IR runs through the natural course of T2DM, and the resulting hyperinsulinemia easily promotes high hypoadiponectin and cardiovascular diseases, but a complete treatment strategy has not yet been formed.

Gut Microbiota

The human gastrogut tract is a complex ecosystem, in which a dense and diverse bacterial community (about 1000~1150 species and about 100 trillion bacteria and archaea), also known as the gut microbiome, has co-evolved with the host, forming a symbiotic relationship and jointly maintaining the physiological balance of the host [15]. The host provides a nutritional environment for the growth of bacteria, and bacteria play an important role in providing some physiological functions for the host that the host itself cannot complete, such as maintaining the gut mucosal barrier, participating in immune regulation, synthesizing important vitamins, using undigested carbohydrates, and fermenting to produce short-chain fatty acids. The gut microbiota can also regulate the expression of host genes, which are involved in a variety of host functions, including substance metabolism, immune system development and maturation, and tissue and organ development. It is becoming increasingly clear that dysbiosis, which is the loss of balance in complex ecosystems, is associated with many human diseases [16]. The gut microbiota has a significant impact on host physiological functions, including metabolic and nutritional balance, immune system maturation and activation, and even brain activity. These effects are mediated by cell interactions and metabolites produced by microorganisms or transformed by host molecules. The gut microbiome is considered to be a true endocrine organ that produces molecules capable of interacting with the physiological functions of the host and triggering responses at both local and distant levels. Any means of interfering with the homeostatic balance of the host-gut microbiome may be an initiating or reinforcing factor in the pathogenesis of disease. Many metabolites drive homeostasis between the host and its flora, such as short-chain fatty acids produced by bacterial fermentation fibers. The bile acids produced by the liver and transformed by gut bacteria affect the host, and the gut microbiota regulates the host’s tryptophan metabolism in the gut [17]. The main components of gut microorganisms include Firmicutes, Bacteroides, Actinobacteria, Proteobacteria, and Verrucobacteria, among which the relative abundance of Firmicutes and Actinobacteria exceeds 90%. The composition of the human gut microbiota is influenced by a number of factors, including the host’s age, sex, ethnicity, region, dietary habits, sanitary conditions, and use of antibiotics, probiotics, and prebiotics. Many studies have shown that disturbance of gut microbiota composition is associated with various metabolic diseases such as obesity, T2DM, and insulin resistance [18].

The Impact of Gut Microbiota on T2DM

The microbiome is involved in the pathophysiology of most chronic diseases. T2DM is no exception. More and more evidence shows that gut microbiota dysregulation plays an important role in the pathogenesis of insulin resistance and T2DM through various mechanisms, including increased gut permeability and low degree endotoxemia, altered production of SCFA and branched-chain amino acids (BCAAs), and disrupted bile acid metabolism [19]. Changes in the composition and function of the gut microbiota have been observed in individuals with T2DM and pre-diabetes, and fecal microbiota transplantation from healthy donors to patients with metabolic syndrome can increase microbial diversity and improve glycemic control and insulin sensitivity in T2DM patients [20]. Wu et al showed that the overall composition of the gut microbiota was changed in people with impaired glucose tolerance combined with abnormal glucose tolerance and T2DM, but not in people with impaired fasting blood glucose. In addition, in both pre-diabetes and type 2 diabetes mellitus (T2DM), the abundance and function of some butyrate-producing bacteria are reduced. Multivariate analysis and machine learning microbiome models show that insulin resistance is closely associated with microbial variation [21]. Sedighi et al conducted a comparative study on gut microbiota between adults with T2DM and healthy individuals, indicating that the level of lactic acid bacteria in T2DM patients was significantly increased, while the incidence of Bifidobacterium in healthy people was significantly increased. Significant changes in dominant bacteria genera in stool of T2DM patients highlight the association between T2DM and variation in gut microbiota composition [22]. Wu et al [23] studied the molecular characteristics of fecal microbiota of patients with type II diabetes, and showed that the abundance of common Bacteroides and Bifidobacterium in the microbiota of the diabetic group was significantly reduced. Han et al [24] studied the relationship between gut microflora and T2DM and showed that the abundance of Firmicutes and Clostridium in the intestines of T2DM patients decreased significantly, while the relative proportions of Bacteroides and β-Proteobacteria increased significantly. Zhang et al [25] showed that, compared with the normal-glucose group, the level of β-Proteus was significantly higher in patients with pre-diabetes and T2DM. Karlsson et al [26] observed that 4 species of Lactobacillus were significantly increased and 5 species of Clostridium were significantly decreased in the gut tract of T2DM patients. Sato et al [27] showed that the levels of Clostridium group, Mirabile group, and Prevotella in fecal samples of diabetic patients were significantly lower than those of the control group, and the total Lactobacillus level was significantly higher than that of the control group. In addition, the detection rate of live gut bacteria in the blood of diabetic patients was significantly higher than that of the control group. Larsen et al [28] compared the gut microflora of adult type 2 diabetic patients with non-diabetic patients, and the results showed that the proportion of Firmicutes and Sometomycetes in type 2 diabetic patients was significantly lower than that in the control group, but proteobacteria microorganisms were abundant. The proportion of Bacteroidetes and Firmicutes and the proportion of Bacteroides-Prevotella group and C. coccoides-E. rectale group were positively correlated with blood glucose concentration, but were not correlated with body mass index (BMI) (body mass coefficient). Proteobacteria also had a positive correlation with blood glucose concentration. Zhong et al [29] conducted a study on the unique gut metagenomic and meta-proteomic characteristics in pre-diabetic patients and untreated type 2 diabetic patients, and showed that the abundance of metagenomic-linked groups of Clostridium was significantly lower, as well as the relative abundance of several species of butyric-producing bacteria. Studies by Martin et al [30] show that dysfunctional gut microflora can stimulate the gut cell walls to secrete a large amount of serotonin through the secretion of secondary bile acid, thereby increasing the blood glucose level and inducing chronic hyperglycemia, leading to diabetes. Sanna et al [31] applied Mendelian randomization analysis to confirm the causal relationship between gut microbiota and glucose metabolism dysfunction, and proposed that changes in gut microbiota produce SCFAs as an important mechanism. Higher content of butyrate in stool was associated with better insulin response, but higher propionic acid content in the stool was associated with an increased risk of T2DM, and these are related to genes. Gurung et al [32] systematically reviewed the role of gut microbiota in the pathogenesis of T2DM. Bifidobacterium, Bacteroides, Clostridium tenuis, Akkermansia, and Rotella were negatively correlated with T2D, while Ruminococcus, Clostridium, and Lauteria were positively correlated with T2DM. The gut microbiota can participate in the regulation of T2DM metabolism by regulating inflammatory factors, gut permeability, glucose metabolism, fatty acid oxidation, synthesis, and energy metabolism, as well as multi-bacterial cooperation. Yu et al [33] found that the β-diversity and relative abundance of gut microbiota in T2DM model mice were significantly changed. At 6 taxonomic levels, including phylum, class, order, and family, Verrucomicrobia abundance was significantly increased. Bacteroides were significantly decreased at family, genus, and species levels, and Prevotella was significantly decreased at the family and genus levels. Koh et al [34] found that T2DM patients had higher blood content of imidazole propionate (histidine-derived metabolite produced by gut microbiota). In a simulated in vitro fermentation experiment, the concentration of imidazole propionate produced by fecal bacteria in T2DM patients was higher. Forty-two strains were identified that could produce imidazole propionate, 67% of which were higher in T2DM patients. Injection of imidazole propionate reduced insulin receptor (IRS) levels and their phosphorylation levels in mice, impairing glucose tolerance.

The Impact of Exercise on T2DM

There is growing evidence that long-term, moderate physical activity, including aerobic and voluntary exercise, representing habitual exercise, helps promote glucose uptake and fat oxidation [1]. Exercise can promote the decrease of blood branched-chain amino acids, thus promoting glucose and lipid metabolism in T2DM patients [35]. Exercise also increases insulin sensitivity and decreases IR in T2DM patients by mediating the competing endogenous RNA (ceRNA) axis. Swimming training can inhibit IR induced by high-fat diet (HFD) by reducing lipid accumulation in the liver and muscles and regulating energy metabolism in skeletal muscle [19]. Studies have also shown that regular exercise can enhance glucose oxidation, improving glucose uptake and skeletal muscle IR by increasing transcription of glucose transporter 4 (GLUT4), a key glucose transporter subtype responsible for insulin and exercise-stimulated glucose transport in skeletal muscle [36]. In a review of the relationship between exercise and diabetes, Colberg et al [37] showed that exercise can improve blood glucose control in patients with T2DM, reduce risk factors of cardiovascular disease, contribute to weight loss, and improve health status. Regular exercise can prevent or delay the development of T2DM. Regular exercise also has considerable health benefits for people with type 1 diabetes (eg, improved cardiovascular health, muscle strength, insulin sensitivity). Borror et al [38] reviewed the effects of postprandial exercise on blood glucose control in T2DM, suggesting it is an effective method to improve blood glucose control in patients with T2DM. Postprandial aerobic exercise can reduce the area under the short-term glucose curve by 3.4–26.6% and the prevalence of 24-hour hyperglycemia by 11.9–65%. Resistance exercise reduced the area under the short-term glucose curve by 30% and the prevalence of 24-hour hyperglycemia by 35%. Hamasaki et al [39] conducted intermittent exercise intervention treatment for T2DM and found that, compared with continuous exercise, intermittent exercise was not only feasible and effective for blood glucose control in T2DM patients, but also more effectively improved body composition, insulin sensitivity, aerobic exercise capacity, and oxidative stress. Karstoft et al [40] showed that free intermittent walking exercise could significantly reduce body weight and fat mass (fat mass and visceral fat) as well as mean and maximum continuous blood glucose monitoring blood glucose levels in patients with T2DM. Karstoft et al [41] found that intermittent walking can significantly improve the glucose self-metabolic efficiency of patients with T2DM, which may be the main mechanism to improve their blood glucose control. Jiang et al [42] showed that aerobic exercise training at the maximum fat oxidation intensity could improve body composition, blood glucose control, and physical fitness of elderly people with T2DM. Brown et al [43] found that one-time endurance resistance training can significantly reduce the blood glucose level in patients with T2DM, improve insulin sensitivity, and reduce cardiovascular risk.

In conclusion, adopting and maintaining physical activity is key to blood glucose management and overall health in people with diabetes and pre-diabetes. According to data from the American Diabetes Association (ADA) annual meeting in 2015, up to 26% of the total population has pre-diabetes, many of which will develop T2DM. Effective intervention in pre-diabetes can significantly reduce the likelihood of its progression to diabetes [44]. According to the 30-year follow-up results of the high-profile Daqing study in China, early lifestyle intervention in people with impaired glucose tolerance can delay the onset of T2DM, reducing the incidence of cardiovascular events by 26%, microvascular complications by 35%, and cardiovascular and all-cause mortality by 33% and 26%, respectively, and extend life expectancy [45]. A prospective study presented at the 2019 ADA Annual Meeting, the largest to date in the field of diabetes prevention and weight loss maintenance, and the first randomized controlled study using total meal substitutes, conducted a 3-year lifestyle intervention in approximately 2300 overweight pre-diabetic patients. It was found that the 3-year cumulative incidence of diabetes was only 4%, much lower than the 21% reported in the literature [46]. This further confirms the effectiveness of early lifestyle interventions in the pre-diabetic population.

The Impact of Exercise on the Gut Microbiota

Environmental stimuli and behavioral habits can regulate the composition and function of the gut microbiota. For example, diet, obesity status, and mode of delivery have been shown to have important effects on the metabolic and immunomodulatory capacity of the gut microbiome throughout a person’s life cycle. Recent studies have shown that exercise has a regulatory effect on the gut microbiota and metabolites of humans and animals [5]. Early life exercise may promote lasting brain health and metabolic homeostasis by regulating gut microbiota metabolites. Barton et al [47] and Clarke et al [48] conducted metabolic phenotypic analysis and functional metagenomics analysis on the gut microbiome of international professional rugby league participants and a control group, and the results showed that the microbiome of professional athletes had higher diversity and better metabolic capacity. This is manifested by a relative increase in metabolic pathways (such as amino acids, antibiotic biosynthesis, and carbohydrate metabolism) and fecal metabolites (such as SCFAs acetic acid, propionic acid, and butyrate produced by microorganisms). Allen et al [49] conducted endurance training on lean and obese adults for 6 weeks and observed the effects on their gut microbiota composition, functional ability, and metabolic output. The analysis showed that exercise training could induce changes in the composition and function of human gut microbiota without changing dietary patterns. The results showed that the concentration of short-chain fatty acids in stool and the ability of gut microorganisms to produce short-chain fatty acids were significantly increased in lean and obese participants, and the group of bacteria regulating butyrate was significantly increased. Allen et al [50] showed that exercise improved gut microbiota. Mice transplanted with gut microbiota of exercise mice have a higher proportion of microorganisms responsible for secreting butyrate (a short-chain fatty acid that is conducive to the survival of gut cells, reducing inflammation, and providing energy for the host). In another study, Allen et al [50] found that exercise increased the levels of SCFAs, especially butyrate, in the gut, and with exercise, the number of beneficial bacteria increases significantly. Scheiman et al [51] studied the gut microbiota of top marathon runners and found that the abundance of a particular genus of bacteria in their gut increased significantly after training. When transplanted into the intestines of mice, the bacteria significantly increased exercise endurance. Munukka et al [52] showed that 6-week resistance training could improve the composition of gut microflora, reducing the numbers of microorganisms that could cause inflammation (Proteobacteria) and increasing the microorganisms that could enhance metabolism (Akermannia). These results all confirmed that different forms of exercise can cause changes in gut microbiota. However, whether and how alterations in the gut microbiome functionally contribute to the metabolic benefits of exercise remains unclear. In addition, the effects of different types of exercise, intensity, and duration on intestinal flora were not uniform. The differences in results may be due to genetics, diet, type, intensity, and duration of exercise. Future studies should consider appropriately increasing the duration of interventions and sample size, with long-term follow-up, and also need to focus on the determinants of disease, such as age, sex, and comorbidities, which are highly likely to influence the disease response to exercise.

Despite existing research indicating that exercise can significantly modulate the composition and function of the gut microbiota, thereby exerting positive effects on the host’s metabolic health [53], systematic comparative studies on different exercise intensities (such as low, moderate, and high intensity) are relatively scarce. For instance, some studies have shown that high-intensity interval training (HIIT) can significantly increase the abundance of beneficial bacteria (such as Bifidobacterium and Lactobacillus), but there is a lack of direct comparisons of the effects of different exercise intensities [54]. Research on exercise duration is also somewhat limited. Most studies have focused on the effects of short-term (eg, a few weeks) and long-term (eg, several months) exercise on the gut microbiota, but there is a lack of systematic studies comparing different durations (such as short-term, medium-term, and long-term). For example, a study found that 12 weeks of aerobic exercise can significantly improve the diversity and function of the gut microbiota, but there is a lack of systematic comparisons of the effects of different exercise durations [55]. There are also differences in the impact of different types of exercise (such as aerobic exercise, resistance training, and flexibility training) on the gut microbiota, but the published research has mostly focused on specific types of exercise, lacking comprehensive comparisons of multiple types of exercise. For example, studies have found that aerobic exercise can increase the abundance of butyrate-producing bacteria, while the impact of resistance training on the gut microbiota is relatively smaller [56]. More systematic comparative studies on the effects of different exercise intensities, durations, and types of exercise on the gut microbiota are needed. This will help to develop more precise exercise intervention plans to improve gut health and metabolic conditions.

The Role of Gut Microbiota in Exercise for T2DM

Studies have shown that regular exercise exerts a positive influence on T2DM by altering the composition of the gut microbiota, shifting it towards health-promoting bacteria [57]. Lambert et al [58] first studied the relationship between T2DM, gut microbiota, and exercise training in 2015. The results showed that exercise improved insulin resistance in diabetic db/db mice, decreased blood glucose, and increased the abundance of Firmicutes. The abundance of Bacteroides/Prevotella and Methanobacterium genera was relatively low. Yang et al [59] showed that 8-week swimming training significantly reduced the insulin resistance index of T2DM model mice, significantly reversed the decline of Enterobacteroides and the increase of Firmicutes, and significantly increased the gut and plasma total SCFAs contents (Table 1). Valder et al [60] showed that regular exercise can affect gut microbiota composition and gut barrier function, and has positive effect on T2DM. In particular, an increase in the number of SCFA-producing bacteria and an improvement in gut barrier integrity and a reduction in endotoxemia appear to be key points for positive interactions between gut health and T2DM, resulting in improved low systemic inflammatory status and glycemic control. Pasini et al [61] found that long-term exercise can significantly reduce the body weight, BMI, fat mass, and waist circumference, and significantly increase lean body mass in stable T2DM patients. Fasting blood glucose, glycosylated hemoglobin (HbA1c), and insulin resistance index (HOMA-IR), total cholesterol and C-reactive protein levels of reactive system inflammation were significantly reduced in Candida albicans and Mycetes spp. Zonulin content, a marker of gut permeability, were significantly reduced, indicating that long-term exercise can control diabetes by changing gut microbiota composition and gut barrier function (Table 1).

Torquati et al [62] explored the effects of different intensities of exercise on gut microbiome composition and function of T2DM patients who lacked exercise, and the results showed that 8 weeks of different exercise intensities significantly increased specific health-promoting and butyrate-producer species, and showed differentially abundant gut microbiome metabolic pathways. Moderate-intensity aerobic combined resistance exercise can make Bifidobacterium, A. muciniphila, and butyrate-producers Lachnospira eligens, and Enterococcus spp., and the relative abundance of Clostridium cluster IV increased significantly. However, high-intensity aerobic combined resistance exercise can stimulate butyrate-producers (from Eryspelothrichales and Oscillospirales), and the methane-producer Methanobrevibacter smithii showed a significant increase in relative abundance. Pyruvate metabolism (ko00620), COG “Cell wall membrane envelope biogenesis” and “Unknown function” can be induced by both moderate- and high-intensity aerobic combined resistance exercise. Pathways had a significant effect, but moderate-intensity aerobic combined resistance exercise had a greater effect. Differential abundance analysis in the KEGG Orthology (KO) database showed higher expression of the 2-component system in a high-intensity aerobic combined resistance exercise group. Transcription factors and “unknown metabolism”-related pathways decreased in both groups. Tian et al [63] found that 6-week high-intensity intermittent exercise can significantly reduce fasting plasma glucose (FPG), fasting insulin (FINS) and HOMA-IR in middle-aged and elderly T2DM patients, significantly increase α diversity, and create a more complex and stable microflora relationship, and its network characteristics are further enhanced after intervention, and gut microecology is more stable. It contains more dominant bacteria that can improve glucose and lipid metabolism, insulin metabolism, and gut inflammation. Motiani et al [64] analyzed the effects of sprint interval training (SIT) or moderate-intensity continuous training (MICT) on gut microbiota and gut insulin-stimulated glucose uptake in sedentary, insulin-resistant individuals. The results showed that the levels of systemic pro-inflammatory tumor necrosis factor α (TNF-α), C-reactive protein (CRP), and gut inflammatory lipopolysaccharides-binding protein (LBP) in pre-T2DM or T2DM patients were significantly reduced by both training interventions, and the number of Bacteroidetes and the Bacteroidetes/Firmicutes ratio were significantly increased. The number of bacteria genera of Clostridium and Blautia genera was significantly decreased (Table 1).

Studies have also shown that the anti-diabetic effect of exercise is also affected by the characteristics of an individual’s gut microbiome [65]. Liu et al [66] showed that after 12 weeks of high-intensity endurance/resistance combined training in a pre-T2DM population, the body weight and fat of the entire exercise group were significantly reduced, while insulin sensitivity, lipid status, cardiopulmonary function, and levels of adipokines related to insulin sensitivity were significantly improved. However, high interindividual variation in fasting glucose, insulin, and insulin resistance balance model assessment (HOMA-IR) was observed. The authors then further divided participants into exercise responders and non-responders, and explored whether the gut microbiota was involved in the heterogeneous metabolic effects of exercise in the cohort, finding that the abundance of Bacteroides xylanisolvens decreased, while that of Streptococcus mitis increased. In addition, responders showed a 3.5-fold increase in the abundance of Lachnospiraceae bacterium, a butyrate-producing bacterium, and a 43% decrease in the abundance of Alistipes shahii, a possible inflammatory promoter. In contrast, non-responders had a decrease in Ruminococcus gnavus and a 3.9-fold increase in Alistipes shahii. In terms of bacterial growth dynamics, responders showed a decreased replication rate of Copri prevotella (possibly related to the biosynthesis of BCAAs) and an increased growth rate of several species in the genus Bacteroides, most of which are propionic acid-synthesizing bacteria. In addition, increased expression of SCFA synthesis and genes associated with metabolic pathways leading to the breakdown of BCAAs were observed in the gut microbiota of responders. Transplantations of the microbiomes of 2 responders and 2 non-responders from the above experiments into antibiotic-treated mice found that mice receiving the responder microbiomes showed reduced glucose and insulin levels, as well as improved glucose clearance/disposal. In addition, mice with the gut microbiota of inoculated responders showed increased circulating SCFA levels and decreased BCAAs concentrations. In contrast, glucose regulation, insulin sensitivity, and short-chain fatty acids were unchanged, as were branched-chain amino acids, in mice colonized by unresponsive bacteria. Overall, these results suggest that changes in the gut microbiota induced by exercise training are (collectively) involved in the regulation of glycemic control/insulin sensitivity. Furthermore, gut microbiota composition appears to be a determinant of the effect of exercise training, as baseline microbiota composition also differs between responders and non-responders. Therefore, targeting the gut microbiome could help predict the beneficial effects of exercise on T2DM.

Possible Mechanism of Exercise Regulating Microbiota to Improve T2DM

IMPROVE ENERGY METABOLISM:

Studies have shown that supplementation of SCFAs can regulate energy metabolism and improve insulin sensitivity [69]. SCFAs are the main metabolic products of gut microbiota, involving bacteria such as anaerobic Bacteroides, Bifidobacterium, Akkermansia, Firmicutes, Streptococcus, and Lactobacillus. These bacteria ferment indigestible carbohydrates, such as resistant starch and non-starch polysaccharides, to produce SCFAs. SCFAs are most abundant in acetic acid, propionic acid, and butyric acid (accounting for up to 90%), and they are involved in important physiological functions such as digestion, immunity, and the nervous system in the human body. Butyric acid, in particular, has attracted attention for its unique role in gastrointestinal-related functions and its association with the prevention and treatment of various diseases, including inflammatory bowel disease, obesity, T2DM, and cardiovascular diseases [70]. SCFAs directly act on pancreatic β-cells to promote insulin secretion and act on intestinal L-cells to enhance the secretion of glucagon-like peptide-1 (GLP-1), thereby regulating blood glucose levels. SCFAs are absorbed by intestinal epithelial cells and eventually reach the bloodstream, affecting the glycogen storage in muscles, liver, and fat. Acetic acid can reach the brain, reducing appetite, and thus decreasing food intake [71]. G protein-coupled receptors GPR41/43 are specific receptors for SCFAs. GPR41/43 can induce the synthesis and secretion of GLP-1 and peptide tyrosine (PYY) by enteroendocrine cells, which can induce satiety in the host and promote insulin secretion [72]. Studies have shown that SCFAs can increase glucose uptake by fat cells and C2C12 muscle cells by activating GPR41 [73]. In addition, studies have shown that SCFAs can activate adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK) – peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) pathway in skeletal muscle, up-regulate PGC-1α mRNA and protein expression, promote mitochondrial biosynthesis, enhance glucose uptake and fatty acid oxidation, and thus improve blood glucose homeostasis and insulin sensitivity [73]. In addition, intestinal flora can also promote the synthesis of bile acids, promote the production of fibroblast growth factor 15/19 and the secretion of GLP-1 through Farnesoid derivative X receptor and G protein-coupled receptor 5, respectively, improving insulin sensitivity and regulating glucose metabolism. Farnesoid derivative X receptor can increase the expression of PGC-1α to promote fatty acid metabolism, and can induce G protein-coupled receptor 5 to activate cAMP, promote fat consumption, and indirectly affect the homeostasis of blood glucose [74].

BILE ACID METABOLIC PATHWAY:

The metabolic pathway of bile acids has been extensively studied. Research by Zhanga et al [75] has shown that in mice, voluntary wheel running significantly improved glucose metabolism and offset the adverse effects of high-fat feeding on body weight and glucose tolerance. Voluntary wheel running can program changes in gut microbiota composition and fecal metabolites, and plays a role in regulating bile acid metabolism and the biosynthesis of secondary bile acids in high-fat-fed mice. Bile acids (BAs) are amphipathic molecules derived from cholesterol metabolism in the liver. They are primarily secreted into the intestine via bile and are essential for the emulsification and absorption of lipids. Recent studies have identified BAs as key endogenous steroids that play critical roles in regulating lipid, glucose, and energy metabolism, and are closely associated with T2DM and gut microbiota [76]. Bile acids regulate glucose metabolism by activating their receptors, such as the farnesoid X receptor (FXR) and the G protein-coupled receptor TGR5. FXR is mainly expressed in the liver and intestine, and its activation can promote insulin sensitivity and improve glucose tolerance [1]. The gut microbiota can also promote bile acid synthesis, fibroblast growth factor 15/19 production, and GLP-1 secretion via FXR and TGR5, thereby improving insulin sensitivity and regulating glucose metabolism. FXR can promote fatty acid metabolism by increasing the expression of PGC-1α and induce TGR5 to activate cAMP, promoting fat consumption and indirectly affecting glucose homeostasis [77]. TGR5, expressed in various tissues, can increase GLP-1 secretion upon activation, thereby enhancing insulin secretion and improving glucose control [3].The gut microbiota plays a significant role in bile acid metabolism. Primary bile acids (such as cholic acid and chenodeoxycholic acid) are converted into secondary bile acids (such as deoxycholic acid and lithocholic acid) by the gut microbiota in the intestine. These secondary bile acids have stronger biological activity and can regulate the host’s metabolic processes [7].

IMPROVEMENT OF LOW-GRADE CHRONIC INFLAMMATION:

Low-grade inflammation is the cause of insulin resistance. Studies have shown that intestinal mucosal permeability is increased in T2DM patients and model animals, tight junctions between epithelial cells are decreased, and inflammation is intensified [68]. Animal studies have shown that long-term moderate physical activity increases the presence of intestinal immunoglobulin A (IgA) and decreases the effect of lymphocyte B and CD4+T cells on gene expression of cytokines, such as IL-6, IL-4, IL-10, and TGF-β, which are involved in IgA production [75]. These modifications increase mucosal immunity and can resist colonization by intestinal pathogens. It is also interesting to consider the possible indirect effects of exercise on gut microbiota and intestinal permeability. Previous data have shown that exercise stimulates the release of muscle myokines, increases muscle glucose metabolism through AMPK activity, and reduces inflammation in the body [76]. The study also found that 6 months of chronic exercise (endurance, resistance, and flexibility training) reduced intestinal pathogen colonization and fecal ZO-1, lipopolysaccharide (LPS), and C-reactive protein (CPR) concentrations in T2DM patients [59]. When stool from free-wheel trained mice was transplanted into germ-free mice for 6 weeks, it was found that the thickness of the colon mucus layer increased and the infiltration of immune cells decreased [77].

REDUCE OXIDATIVE DAMAGE:

Oxidative stress is closely related to the development of T2DM. Studies have shown that LPS can bind to inflammatory factors and activate the pattern recognition receptor Toll-like receptor 4 (TLR4), thereby initiating the nuclear factor-kappa B (NF-κB) signaling pathway and the protein kinase-1 signaling pathway, leading to production of large amounts of reactive oxygen species (ROS). These ROS can damage pancreatic β-cells and induce insulin resistance [78]. The gut microbiota plays a significant role in the body’s antioxidant defense system. The intake of probiotics has been proven to effectively enhance the body’s antioxidant capacity. The antioxidant mechanisms of probiotics may involve chelation of metal ions and reduction of the activity of superoxide anions and hydrogen peroxide [79]. Animal experiment results have shown that the intake of Lactobacillus acidophilus NL41 can significantly increase the activity of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), thereby improving glucose metabolism [80]. In addition, it has been reported that SCFAs can regulate oxidative stress by inhibiting GPR43 and histone deacetylase (HDAC) [81]. However, there is currently no direct evidence that exercise can improve oxidative stress by regulating the gut microbiota, thereby improving T2DM. Further research is needed in this area to clarify its potential mechanisms and clinical application value.

REPAIRING THE INTESTINAL MUCOSAL BARRIER:

Intestinal mucosal damage refers to disruption of the structural integrity of the intestinal mucosal layer, leading to impaired mucosal barrier function. Such damage can be triggered by a variety of factors, including infection, inflammation, physical or chemical irritation, and immune responses [82]. The intestinal mucosa is a key component of the human digestive system, primarily composed of a single layer of epithelial cells and covered by a layer of mucus, whose main function is to protect the intestine from harmful substances. The main characteristics of intestinal mucosal damage are increased intestinal permeability and a reduction in the number of tight junction proteins (TJs) between epithelial cells. This can lead to increased leakage of LPS. LPS can exacerbate inflammatory responses by interfering with the phosphorylation and dephosphorylation processes of TJs and reducing the expression levels of ZO-1 in epithelial cells [83].

Studies have shown that in patients with T2DM, the overgrowth of pathogenic bacteria in the gut microbiota is often accompanied by a significant increase in D-lactate and zonulin levels, indicating that the intestinal barrier function has been compromised and has triggered low-grade systemic inflammation that affects glucose metabolism, leading to a vicious cycle of gut fungal overgrowth [84]. Zhang et al (2024) found that after 6 months of Baduanjin (a traditional Chinese exercise), the abundance of intestinal pathogenic bacteria and systemic inflammatory status in T2DM patients were significantly reduced, and gut barrier function was improved, ultimately maintaining glucose homeostasis and insulin sensitivity [85]. Another study found that 6 months of exercise (including endurance, resistance, and flexibility training) could reduce the colonization of intestinal pathogens in T2DM patients, as well as decrease the concentrations of ZO-1, LPS, and tight junction proteins (TJ proteins, CPR) in feces. In addition, when feces from free-wheel trained mice were transplanted into germ-free mice for 6 weeks, it was found that the thickness of the colon mucus layer in germ-free mice increased and immune cell infiltration decreased [86]. Long-term exercise training can also increase the abundance of butyrate-producing bacterial groups in the gut, such as Lachnospiraceae and Faecalibacterium prausnitzii. Butyrate can modulate the function and migration of neutrophils, increase the expression of TJ genes, and inhibit the release of pro-inflammatory cytokines, thereby playing a role in maintaining intestinal epithelial barrier integrity [87]. In summary, the composition and function of the gut microbiota are closely related to T2DM. By modulating the gut microbiota, exercise can improve insulin resistance, increase insulin content, and regulate blood glucose levels in patients with T2DM. The mechanisms may involve exercise increasing the abundance of beneficial gut bacteria in T2DM patients, thereby regulating bile acid metabolism, enhancing intestinal barrier function, improving energy metabolism and low-grade chronic inflammation, and reducing oxidative damage.

Limitations and Future Research Directions

Despite existing research indicating that exercise can significantly modulate the composition and function of the gut microbiota, thereby improving host metabolic health, the published studies have some limitations, mainly involving sample size, research methods, and potential biases. 1) Most of the studies cited in this article used animal models or were small-scale human trials. These studies typically have small sample sizes, which limits the generalizability and statistical power of the results. For example, some studies involved only a few participants, which may lead to greater variability in the results and make it difficult to extrapolate the findings to a broader population. Studies with small sample sizes may not accurately reflect the differences in individual responses to exercise interventions, thereby affecting the reliability of the study conclusions. 2) The diversity of research methods also increases the complexity of the results. Different studies have employed varying exercise intensities, durations, and types, making it difficult to compare and synthesize the results. For example, some studies used high-intensity interval training (HIIT), while others use moderate-intensity continuous exercise, which may have led to different outcomes. The lack of standardized research methods makes it difficult to determine which type of exercise has the best regulatory effect on the gut microbiota, thereby limiting the guiding significance for clinical applications. 3) Many studies have potential biases, such as selection bias, measurement bias, and confounding factors. Selection bias may occur in the selection of participants, leading to unrepresentative results. Measurement bias can arise from different detection methods and analytical techniques, while confounding factors (such as diet, lifestyle, and initial health status) can affect interpretation of the results. These biases can lead to inaccurate study results, thereby affecting the understanding of the mechanisms by which exercise regulates the gut microbiota.

To overcome these limitations, there is a need for larger-scale, longer-term clinical trials to verify the regulatory effects of exercise on the gut microbiota and its long-term impact on metabolic health. This will help improve the reliability and generalizability of research findings. Future research should use standardized exercise intervention protocols, including uniform exercise intensity, duration, and type, to facilitate comparison and synthesis of results from different studies. Studies should also combine multi-omics technologies such as metabolomics, transcriptomics, and proteomics to comprehensively analyze the impact of exercise on the gut microbiota and its metabolic functions, revealing its underlying mechanisms. Considering individual differences, future research should focus more on the design of personalized exercise intervention plans to enhance the regulatory effects of exercise on the gut microbiota.

Conclusions

The gut microbiota is closely related to T2DM, and exercise can significantly improve insulin resistance, increase insulin content, and regulate blood glucose levels in individuals with T2DM by modulating the gut microbiota. The mechanisms may include increasing the abundance of beneficial gut bacteria, thereby regulating bile acid metabolism, enhancing intestinal barrier function, improving energy metabolism, and reducing low-grade chronic inflammation and oxidative damage. Given the limitations of traditional anti-diabetic therapies, exercise, as a safe and effective non-pharmacological intervention, holds great potential for developing personalized treatment strategies and offers innovative solutions for the management of T2DM.