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Gut Microbes
Gut Microbes
Gut Microbes
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Taylor & Francis

39305272
10.1080/19490976.2024.2404141
2404141
Version of Record
Review Article
Review
A new perspective in intestinal microecology: lifting the veil of exercise regulation of cardiometabolic diseases
C. GAO ET AL.
GUT MICROBES
Gao Can a
Wei Jinwen a
Lu Changxu a
Wang Lijie b
Dong Dan c
https://orcid.org/0009-0001-3164-2546
Sun Mingli a
a College of Exercise and Health, Shenyang Sport University , Shenyang, Liaoning, P. R. China
b Department of Cardiology, The Fourth Affiliated Hospital of China Medical University , Shenyang, Liaoning, P. R. China
c College of Basic Medical Science, China Medical University , Shenyang, Liaoning, P. R. China
CONTACT Mingli Sun sun18940103126@163.com College of Exercise and Health, Shenyang Sport University, No.36 Jinqiansong East Road, Shenyang, Liaoning 110102, P. R. China
21 9 2024
2024
21 9 2024
16 1 2404141Integra21 9 2024
Integra21 9 2024
21 3 2024
02 9 2024
09 9 2024
© 2024 The Author(s). Published with license by Taylor & Francis Group, LLC.
2024
The Author(s)
https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent.

ABSTRACT

Cardiometabolic diseases (CMDs), encompassing cardiovascular and metabolic dysfunctions, characterized by insulin resistance, dyslipidemia, hepatic steatosis, and inflammation, have been identified with boosting morbidity and mortality due to the dearth of efficacious therapeutic interventions. In recent years, studies have shown that variations in gut microbiota and its own metabolites can influence the occurrence of CMDs. Intriguingly, the composition and function of the gut microbiota are susceptible to exercise patterns, thus affecting inflammatory, immune, and metabolic responses within the host. In this review, we introduce the key mechanisms of intestinal microecology involved in the onset and development of CMDs, discuss the relationship between exercise and intestinal microecology, and then analyze the role of intestinal microecology in the beneficial effects of exercise on CMDs, aiming at elucidating the gut-heart axis mechanisms of exercise mediated protective effect on CMDs, building avenues for the application of exercise in the management of CMDs.

KEYWORDS

Exercise
intestinal microecology
gut microbiota
intestinal barrier function
cardiometabolic diseases
Basic Scientific Research Project of Liaoning Provincial Department of Education LJ212410176019 This work was supported by the Basic Scientific Research Project of Liaoning Provincial Department of Education, Grant No. LJ212410176019.
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pmcIntroduction

Cardiometabolic diseases (CMDs) are a spectrum of vascular and metabolism-related disorders, including obesity, diabetes mellitus, nonalcoholic fatty liver disease (NAFLD), cardiovascular diseases (CVDs), etc.1 CMDs cover a wide range of conditions, which all stem from metabolic disorders and ultimately lead to CVDs. In recent years, as people’s lifestyles have been changing, CMDs have become globally prevalent, with rising morbidity and mortality, thus constituting an unprecedented worldwide health crisis.2 Consequently, it is paramount to find valid tools to manage this type of disease.

Intestinal microecology, long undervalued, has been widely concern in recent years.3 According to present data, the gut microbiome contains over three million genes, which determine the extreme diversity of gut microbiome and vary from one another.4,5 Recent studies have indicated that gut microbiome influences not only the gut itself but also the host’s health via metabolic, nutritional, and immune pathways.6,7 Under usual circumstances, the intestinal microecology maintains an intricate equilibrium with the host. Nevertheless, disruption of the gut microbiota composition, often referred to as “dysbiotic”, may influence the integrity of the gut mucosa as well as the release of neurotransmitters and gastrointestinal hormones, accompanied by the excretion of bioactive molecules, thereby impacting neurological, muscle, bone, and cardiometabolic health, etc.8,9 It should be noted that intestinal microecology is not static but can be affected by various factors (Figure 1), including but not limited to exercise, diet, age, and gender.10–12 Figure 1. External and internal factors regulating the composition of intestinal microecology. The figure was created with BioRender software, ©biorender.com.

Exercise is explained as a subset of physical activity and aids in improving or maintaining physical fitness.13 Regular exercise has tremendous benefits on human physiology, and a plethora of studies have also manifested that moderate exercise can ameliorate metabolic disorders, degrade fat accumulation, and enhance the body’s cardiorespiratory function, thus effectively preventing the development of obesity, type 2 diabetes mellitus (T2DM), and other CMDs.14–16 Notably, current insights suggest exercise is likely a significant “stimulator” for intestinal microecology, proposing a novel perspective that moderate exercise can manipulate the composition and metabolic function of the gut microbiota by driving an overall increase in microbial diversity, beneficial metabolites, and other health associated microbiota.17–19

In summary, owing to the intricate connection among exercise, intestinal microecology, and CMDs, extensive investigations have been conducted in this field. Nevertheless, a comprehensive review of this field remains unreported. Therefore, the review attempts to describe key regulatory mechanisms that link intestinal microecology to CMDs-related pathological characteristics, shed light on the relationship between exercise and intestinal microecology, and highlight the role of exercise on intestinal microecology in CMDs, aiming to elucidate the gut-heart axis mechanisms of exercise mediated protective effect on CMDs, building avenues for the application of exercise in the management of CMDs.

Relationship between intestinal microecology and CMDs-related pathological characteristics

Studies have indicated that changes in intestinal microecology are closely linked to host health.20 Generally, gut microbiota exists as three subtypes, namely commensal, conditionally pathogenic, and pathogenic bacteria, based on their symbiotic relationship with the host, maintaining a state of mutual equilibrium and stability. However, this balance can be perturbed in CMDs, which in turn induces dysbiosis of gut microbiota, facilitating colonization and translocation of pathogenic microbiota, eliciting their detrimental metabolites into systemic circulation, and eventually resulting in the development of several pathological characteristics of CMDs, including insulin resistance, lipid metabolism disorders, inflammation and secondary cardiovascular dysfunctions.21–24 Figure 2 shows the process of imbalance of intestinal microecology in CMDs. Figure 2. The unbalanced process of intestinal microecology in CMDs. The unbalanced intestinal microecology includes the increased pathogenic bacteria and the decreased commensal bacteria, as well as reduced secretion of mucus and AMPs by goblet cells and Paneth cells, thereby promoting gut microbiota and harmful metabolites into the circulation. These alterations ultimately result in the development of several pathological characteristics of CMDs, including insulin resistance, lipid metabolism disorders, inflammation, and secondary cardiovascular dysfunctions. Abbreviation: TMA, Trimethylamine; LPS, Lipopolysaccharide; SCFAs, short-chain fatty acids; BCAA, branched chain amino acid; AMPs, antimicrobial peptides. The figure was created with BioRender software, ©biorender.com.

Intestinal microecology and insulin resistance

Insulin resistance is a crucial pathological characteristic of CMDs.25,26 In recent years, evidence has shown an inextricable link between abnormal gut bacterial composition and insulin resistance in CMDs. In this regard, the administration of commensal bacteria, such as gavage of T2DM rats with parabacteroides distasonis is protected from insulin resistance.27 In contrast, isolating gut pathogenic bacteria from patients with obesity induced healthy mice to the development of insulin resistance.28 These studies emphasized a strong connection between gut microbiota composition and insulin resistance.

Further research suggests changes in gut microbiota-related metabolites are an important factor in the development of insulin resistance. In this regard, Bile acids (BAs), a microbial metabolite, hold promise in improving insulin resistance. Primary BAs are released into the intestine and then modified by gut microbiota, forming secondary BAs in the distal ileum, whereas 95% of these BAs are reabsorbed by the liver and subsequently participate in a new enterohepatic circulation.29 In this process, BAs profoundly improve insulin resistance in CMDs as they can bind with two crucial receptors, farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5).30,31 In this regard, for example, BAs can improve insulin sensitivity with concomitant elevated expression of small heterodimer partner (SHP) gene and fibroblast growth factor 15/19 (FGF15/19) by activating FXR receptor.32–34 Moreover, BAs bind with another receptor, TGR5, leading to the activation of the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway, subsequently ameliorating insulin resistance.35 Another metabolite with the role of improving insulin resistance is short-chain fatty acids (SCFAs), which exert a profound impact by binding with G-protein-coupled receptors (GPCRs) on the gut epithelium, such as GPR41, GPR43, GPR109A and GPCR olfactory receptor 51E2, also known as free fatty acid receptor 3 (FFAR3), free fatty acid receptor 2 (FFAR2), niacin receptor 1 (NIACR1) and olfactory receptor 78 (Olfr78) respectively.36 Such interactions trigger the release of peptide tyrosine tyrosine (PYY) and glucagon-like peptide-1 (GLP-1), subsequently reversing islet damage.37 Apart from this, SCFAs also reiterate the pivotal role in improving insulin resistance via activating the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway.38 Similarly, indole, a tryptophan (Trp) microbial catabolite, is involved in modulating GLP-1 secretion and, therefore, may indirectly influence host insulin levels.39

On the contrary, Branched chain amino acid (BCAA), a microbial metabolite, has been shown to be positively associated with insulin resistance.40 Further investigations have revealed that BCAA can positively regulate the mammalian target of rapamycin complex 1 (mTORC1) as well as subsequent ribosomal protein S6 kinase 1 (S6K1), thus impeding insulin signaling and causing an adverse effect on health.41 Therefore, inhibiting BCAA may be an effective strategy to improve insulin resistance in CMDs.

In conclusion, alterations in the composition of gut microbiota and their secreted metabolites are intricately associated with insulin resistance in CMDs.

Intestinal microecology and abnormal lipid metabolism

Abnormal lipid metabolism, characterized by aberrant metabolism of fatty acids, cholesterol or phospholipids, causes changes in systemic blood lipids and various CMDs.42,43 There is a significant correlation between alterations of the intestinal microecology and abnormal lipid metabolism in CMDs. Some probiotics, such as Lactobacillus curvatus HY7601 and Lactobacillus plantarum KY1032, effectively decreased the accumulation of visceral fat mass in individuals with overweight.44 The study emphasizes the importance of intervening in gut microbiota for regulating lipid metabolism.

Further research has found that some gut microbiota derived metabolites can inhibit aberrant lipid metabolism. In this regard, one of the above mentioned metabolites, SCFAs, possesses the ability to ameliorate hepatic steatosis, and its effect can be reversed in GPR41 and GPR43 receptor knockout mice.45 In addition, SCFAs can also bind to their receptors and stimulate the secretion of leptin, subsequently suppressing fat synthesis and appetite, ultimately mitigating lipid accumulation.46 Another type of metabolite, known as BAs, has been demonstrated to inhibit serum cholesterol production and ameliorate hepatic steatosis. On a level of mechanism, BAs bind with one of its receptors, FXR, to stimulate intestinal FGF15/19 transcription, resulting in the attenuation of aberrant lipid metabolism.47,48

In addition to the aforementioned beneficial metabolites, numerous studies have substantiated that certain metabolites can induce aberrant lipid metabolism. Trimethylamine N-oxide (TMAO) is a metabolite synthesized in the liver with the assistance of flavin-dependent monooxygenase 3 (FMO3), and its precursor, trimethylamine (TMA), is synthesized by gut microbiota.49 Accumulated TMAO accelerates the progression of CMDs pathology primarily via disturbance of lipid metabolism. Further insight into its mechanisms, researchers found that TMAO can activate SHP and FXR, subsequently downregulating cholesterol 7alpha-hydroxylase (CYP7A1) enzymes that are essential for BAs synthesis, manipulating the composition of BAs pool, thereby inhibiting cholesterol absorption and ultimately increasing reverse cholesterol transport (RCT).50,51 Moreover, TMAO can induce the activation of scavenger receptor A (SRA) and CD36 on the surface of macrophages, thereby enhancing lipid accumulation within these cells and subsequently promoting the formation of foam cells, the phenomenon that contributes to the development of atherosclerosis.52,53 Apart from TMAO, a Trp microbial catabolite, kynurenine, can promote the accumulation of hepatic fat and hypertrophy of adipocytes. Mechanistically, inhibition of the aryl hydrocarbon receptor (AhR), a receptor for kynurenine, can reverse hypertrophic adipose growth. Therefore, targeting the kynurenine/AhR axis may be an effective strategy to improve abnormal lipid metabolism in CMDs.54 Furthermore, another Trp microbial catabolite, 5-hydroxytryptamine (5-HT), can induce hepatic steatosis, mainly by regulating hydroxytryptamine receptor 2A (HTR2A) signaling.55

In conclusion, alterations in the composition of gut microbiota, as well as its own metabolites, are intricately linked to lipid metabolism observed in CMDs, and targeting TMAO or other related metabolites represents a pivotal therapeutic approach for aberrant lipid metabolism in CMDs.

Intestinal microecology and inflammation

Inflammation is a paramount modifier in the onset and development of CMDs.56 In recent years, emerging evidence has validated a significant association between abnormal intestinal microecology and CMDs-related inflammation.57 The intestinal mucosal barrier, above all, protects our body against inflammation by preventing the entry of detrimental substances. Additionally, the mucous and antimicrobial peptides (AMPs) secreted by goblet cells and Paneth cells are paramount for preventing the colonization and threats of pathogenic bacteria.58,59 However, dysbiosis in the intestine may result in a decline in the secretion of these substances, then disrupting intestinal integrity and ultimately inducing the migration of microbial metabolites into the circulation.60,61

Lipopolysaccharide (LPS), an endotoxin found on the outer membrane of gram-negative bacteria, is inextricably linked to CMDs-related inflammation. When shifted into the circulation, it binds to pattern recognition receptors (PRRs), including subtypes of toll-like receptors (TLRs) and nod-like receptors (NLRs).62 Most importantly, LPS is able to interact with TLR4 and activate myeloid differentiation primary response 88 (MYD88), resulting in the subsequent activation of nuclear factor-kappa B (NF-κB) pathways and the release of pro-inflammatory cytokines.63,64 On the contrary, inhibition of the LPS/TLR4/NF-κB pathway is shown to reverse LPS translocation that contributes to reducing CMDs-related inflammation.65 Furthermore, TMAO is another microbial metabolite related to inflammation signaling in CMDs. In this regard, TMAO administration exacerbates the inflammatory response in mice with atherosclerosis.66 More explicitly, TMAO can induce CMDs-related inflammation via multiple signaling pathways. Firstly, the activation of nod-like receptor protein 3 (NLRP3) by TMAO, which can be achieved by either activation of the reactive oxygen species (ROS)/thioredoxin-interacting protein (TXNIP) axis or suppression of the sirtuin 3 (SIRT3)/superoxide dismutase 2 (SOD2)/mitochondrial ROS signaling pathway, can lead to inflammation in human umbilical vein endothelial cells (HUVECs), thereby proposing likely mechanisms of TMAO involved in the development of CVDs.67,68 Secondly, TMAO may possess a potential connection with epigenetics as indicated by its regulatory act on the miR-17/92 cluster and protein arginine methyltransferase 5 (PRMT5) that contribute to causing an inflammatory response in CVDs.69,70 Moreover, the NF-κB signaling pathway has also been found to be involved in the pathogenesis of TMAO-regulated inflammation in CVDs.71,72 In summary, LPS and TMAO exert a pivotal role in CMDs via several inflammatory signaling pathways.

Fortunately, some metabolites aid in ameliorating CMDs-related inflammation. On the one hand, SCFAs elicits an anti-inflammatory response in adipose tissue by regulating the expression of several cytokines, such as interleukin-1beta (IL-1β) and tumor necrosis factor-alpha (TNF-α), and the function of some immune cells, such as Tregs and M2 macrophages.73 Meanwhile, it also activates GPR41/43 to mediate the inhibitory effect of acetate on interleukin-6 (IL-6) and interleukin-8 (IL-8) expression, as well as butyrate and propionate on IL-6 expression.74 On the other hand, the inhibitory role on the body’s inflammatory response can also be mediated by other metabolites with their receptors, such as BAs with FXR and TGR5, as well as indole with pregnane X receptor (PXR) and AhR.75–78

In conclusion, the evidence seems clear that alterations in intestinal microecology are intricately linked to inflammation observed in individuals with CMDs, and targeting abnormal intestinal microecology represents a pivotal therapeutic approach for inflammation in CMDs.

Intestinal microecology and cardiovascular dysfunction characteristics

Cardiovascular dysfunctions appear at the later stage of cardiometabolic syndromes, characterized by dysregulation of the renin-angiotensin-aldosterone system (RAAS), platelet activation, vasoconstriction, and endothelial cell dysfunction, etc., which are all risk factors that may ultimately result in severe CVDs.79–81 The change in gut microbiota profoundly impacts these pathological characteristics, as evidenced by restoring the stabilization of vascular contractility via pre-depletion of the gut microbiota.82 Further investigation into its underlying mechanism reveals that the gut microbiota exerts a crucial role in the composition of metabolites, thereby influencing cardiovascular characteristics.83

A previous study has validated that SCFAs may be responsible for normal blood pressure by inducing renin secretion.84 Nevertheless, butyric acid, a subtype of SCFAs, exhibits the contrary effect on renin production, thereby mitigating dysregulation of RAAS.85 These apparently paradoxical results have shown that SCFAs may possess a dual role in the regulation of renin. In addition, butyric acid also induces vasodilation via the activation of GPR41/43 receptors and stimulation of colon-vagus nerve pathways.86 Notably, hydrogen sulfide (H2S), another microbial metabolite, downregulates the expression of Olfr78 and upregulates the expression of Gpr41 and Gpr43, ultimately playing a crucial role in enhancing glomerular filtration rate (GFR).87 The supplementation of exogenous H2S in mice induces the attenuation of endothelial dysfunction and RAAS signaling.88

On the contrary, a number of metabolites exert a detrimental effect on cardiovascular progression. Firstly, TMAO is closely associated with cardiovascular dysfunction. TMAO promotes angiotensin (Ang) II-induced vasoconstriction via activation of the protein kinase R-like endoplasmic reticulum kinase (PERK)/ROS/calmodulin-dependent protein kinase II (CaMKII)/phospholipase C β3 (PLCβ3) axis,89 induces endothelial cell dysfunction via activation of protein kinase C (PKC) and suppression of endothelial progenitor cells (EPCs) production in circulation,90,91 and more importantly, enhances platelet reactivity to collagen by inducing the phosphorylation levels of extracellular signal-regulated kinase 1/2 (ERK1/2) and Jun N-terminal kinase (JNK) in platelets.92 Secondly, BCAA also seems to induce platelet hyperreactivity, potentially via upregulation of tropomodulin-3 propionylation.93 Moreover, phenylacetylglutamine (PAGln), another microbial metabolite, is also responsible for platelet activation by activating α2A, α2B, and β2-adrenergic receptors.94

In conclusion, it is plausible that intestinal microecology is somehow linked with various cardiometabolic characteristics. Figure 3 shows how several metabolites affect CMDs-related pathological characteristics. Notably, some of the studies mentioned above only detected serum metabolites. However, fecal metabolites are more strongly associated with gut microbiota than serum metabolites. Therefore, exploring the association among gut microbiota, fecal metabolites, and serum metabolites is crucial for a comprehensive understanding of the robust correlation between intestinal microecology and CMDs. Furthermore, the above studies did not address the causality between intestinal microecology and CMDs, and further research is essential. Moreover, from a long-term perspective, there is a lack of consensus regarding the precise identification of “healthy” gut microbes, posing challenges in correctly identifying beneficial or harmful microbial species. More importantly, it is difficult to identify which strain of bacteria affects disease or health status, given the specificity of strains and multi-strain blends as more popular probiotic interventions at present. Additionally, the roles of intestinal metabolites are not explicit, posing challenges for seeking valid targets for the prevention and therapy of CMDs. Further, it is imperative to construct a complete microbial genome database aimed at correctly identifying the gut microbiota related to diseases, given the diversity of microbial function. Finally, most studies lack sufficient verification, bringing about some uncertainties in these findings. Therefore, multiple factors still need to be taken into consideration, and multiple questions urgently need to be addressed. Figure 3. The primary metabolic pathways affecting CMDs-related pathological characteristics. Abbreviation: BCAA, branched chain amino acid; SCFAs, short-chain fatty acids; BAs, bile acids; TMA, Trimethylamine; 5-HT, 5-hydroxytryptamine; mTORC1, Mammalian target of rapamycin complex 1; S6K1, S6 kinase 1; PI3K, phosphatidylinositol 3-kinase; GPCRs, G-protein-coupled receptors; PYY, peptide tyrosine tyrosine; GLP-1, glucagon-like peptide-1; FXR, farnesoid X receptor; FGF15/19, fibroblast growth factor 15/19; SHP, small heterodimer partner; TGR5, Takeda G protein-coupled receptor 5; cAMP, cyclic adenosine monophosphate; PKA, protein kinase A; FMO3, flavin-dependent monooxygenase 3; TMAO, trimethylamine N-oxide; RCT, reverse cholesterol transport; HTR2A, hydroxytryptamine receptor 2A; AhR, aryl hydrocarbon receptor; STAT3, signal transducer and activator of transcription 3; IL-6, interleukin-6; LPS, Lipopolysaccharide; H2S, hydrogen sulfide; PAGln, Phenylacetylglutamine; PXR, pregnane X receptor; TLRs, toll-like receptors; TRIF, interferon-beta; MAPKs, mitogen-activated protein kinases; MYD88, myeloid differentiation primary response 88; TAK1, transforming growth factor beta activated kinase 1; NF-κB, nuclear factor-kappa B; NLRs, nod-like receptors; PKC, protein kinase C; NLRP3, nod-like receptor protein 3; SIRT3, sirtuin 3; TXNIP, thioredoxin-interacting protein; IL-12, interleukin 12; Nox4, Nicotinamide adenine dinucleotide phosphate oxidase 4; PRMT5, protein arginine methyltransferase 5; VCAM-1, vascular cell adhesion molecule-1; EPCs, endothelial progenitor cells; Olfr78, olfactory receptor 78; ERK1/2, extracellular signal-regulated kinase 1/2; JNK, Jun N-terminal kinase; PERK, protein kinase R-like endoplasmic reticulum kinase; ROS, reactive oxygen species; CaMKII, calmodulin-dependent protein kinase II; PLCβ3, phospholipase C β3. The figure was created with BioRender software, ©biorender.com.

How does exercise modulate the intestinal microecology?

As mentioned above, there is compelling evidence regarding the correlation between intestinal microecology and cardiometabolic disorders. Of all microbiome-directed therapies, exercise is a paramount modifier of the balance of intestinal microecology, subsequently impacting the physiological and pathological functions of the organism.

Proper exercise prescription is a potential modifier of host health and links with the various changes in intestinal microecology. As to exploring the role of exercise prescription on intestinal microecology, researchers focus on intensities, types, and durations. Firstly, the composition of intestinal microecology is variable based on exercise intensities. In one study, moderate-intensity exercise markedly optimizes exercise performance in mice, and this effect is largely attributed to changes in the composition of gut microbiota.95 In another study, high-intensity exercise has shown promising results in enhancing skeletal muscle performance in mice, accompanied by changes in the composition of gut microbiota, specifically elevated abundance of Akkermansia, Allobaculum, and Lactobacillus. However, the beneficial effects disappeared after the pre-depletion of gut microbiota.96 In summary, diverse exercise intensities possess the potential to exert a positive influence on the gut microbiota and, consequently, the organisms. Apart from exercise intensities, different types and durations of exercise also have divergent impacts on intestinal microecology. A study has found significant disparities in the gut microbiota composition of healthy elderly women following trunk muscle and aerobic exercise (AE) training. In the AE training group, the elevated abundance of Bacteroides induced by exercise is strongly associated with cardiopulmonary fitness.97 In another study, healthy people who experienced endurance training exhibited significant enhancements in physiological parameters, including reduction in body fat, improvements in bone mineral density, and enhancement in cardiorespiratory fitness, along with alterations in the composition of the gut microbiota as well as elevated level of the beneficial metabolite SCFAs. By contrast, alterations in gut microbiota and physiological parameters were largely reversed once exercise training cessation.98 Moreover, exercise elicited the alteration of intestinal microecology composition is varied in different populations. There was a marked increase in the fecal metabolite SCFAs of rugby players compared with sedentary control, along with augmented muscle turnover and exercise performance.99

In addition, exercise-mediated mechanisms may, in part, be responsible for the observed variation in intestinal microecology. Firstly, IL-6, one typical myokine induced by exercise, enhances the secretion of GLP-1 from intestinal L cells, thereby contributing to maintaining health.100 Secondly, the intestinal transit time, which refers to the duration of intestinal contents passing through the gastrointestinal tract, may be another fundamental mechanism mediating the profound effect of exercise on intestinal microecology, as evidenced by the duration of high-intensity physical activity positively linked to transit time in both the colon and entire bowel.101 Thirdly, BAs, which can be affected by exercise, could regulate intestinal homeostasis by carrying out antimicrobial properties to effectively impede the colonization of pathogenic bacteria.102 Therefore, proper exercise exerts an impact on the intestinal microecology through multiple mechanisms.

On the contrary, excessive exercise, caused by unplausible exercise prescriptions and exceeding the body’s capacity, is a primary inducer of health impairment.103 Such negative effects of excessive exercise have also been testified to be related to intestinal microecology. Insights from animal studies have shown that acute high-intensity exercise-induced gastrointestinal distress symptoms are strongly correlated to the disruption of intestinal barrier integrity.104 Moreover, a single bout of acute physical exercise, very intense even reaching exhaustion for amateur athletes, triggers changes in gut microbiota as well as fecal and serum metabolites.105 Apart from the evidence mentioned above, a preclinical study has shown that overtraining in mice disrupts substance and energy metabolism, as well as immunity, with concomitant reduced diversity of the gut microbiota.106

Further insight into its mechanisms, excessive exercise elicits alterations in intestinal microecology via various pathways. Firstly, exertional heat stress elicited by gradually increased exercise intensity under high temperature exerts a significant influence on intestinal microecology. As demonstrated by research, intestinal fatty acid-binding protein (IFABP), a biomarker of intestinal epithelial injury, was elevated under exertional heat stress, leading to the migration of gut microbiota.107,108 Secondly, excessive exercise-induced alterations of intestinal microecology are also related to alterations in intestinal blood flow. Studies showed that excessive exercise leads to redistributed splanchnic blood flow, causing splanchnic hypoperfusion and insufficient intestinal blood supply, ultimately resulting in gut epithelial cell hypoxia and ischemia. Furthermore, the reperfusion of blood into the intestine after physical activity has been validated to cause further damage to the intestinal barrier.109–111 Thirdly, studies have documented that the production of mitochondrial ROS is inextricably associated with alterations in intestinal microecology during excessive exercise.112 As demonstrated, an animal study has shown that exercise-induced LPS level is markedly reduced and intestinal pathological injury is ameliorated following the inhibition of mitochondrial ROS production via the application of antioxidants.113 Finally, excessive exercise activates the hypothalamic-pituitary-adrenal (HPA) axis, triggering the secretion of a range of hormones, thus inducing gut microbiota dysbiosis and increasing intestinal permeability.114 Figure 4 depicts the mechanisms of different exercise conditions on gut microbiota. Figure 4. The underlying mechanisms of different exercise conditions induce the alterations of gut microbiota. Proper exercise induces the production of BAs, diminishes intestinal transit time, and facilitates the release of myokines, thereby contributing to the formation of a healthy gut microbiota. However, excessive exercise can lead to severe heat stress, reduce gut blood flow, promote oxidative stress, and activate the HPA axis, ultimately contributing to the dysbiosis of microbiota. Abbreviation: BAs, bile acids; ROS, reactive oxygen species; HPA, hypothalamic-pituitary-adrenal. The figure was created with BioRender software, ©biorender.com.

In conclusion, diverse exercise patterns elicit distinct modifications in intestinal microecology, thus inducing both advantageous and detrimental impacts on the organism. Therefore, it is crucial to avoid gut microbiota dysbiosis by elucidating the optimal exercise prescription and determining the precise exercise threshold. Furthermore, while the review primarily focuses on elucidating the impact of exercise on intestinal microecology, it is crucial to underline that exercise performance is also influenced by gut microbiota.115,116 Table 1. Effects of exercise training on the intestinal microecology in animals with CMDs.

Disease	Animal model	Duration of
intervention	Affected gut microbiota	Metabolites and
other gutalterations	Experiment
results	Reference	
Obesity	Male C57BL/6 mice fed with
HFD	Wheel
movement
for 12/14 weeks	Bacteroidetes↑
Firmicutes↓
Actinobacteria↓
Proteobacteria↑
Clostridiaceae↑
Lachnospiraceae↑
Ruminococcaceae↑
Lactobacillaceae↓
Turicibacteraceae↓
Erysipelotrichaceae↓
S24-7↑
Bifidobacteriaceae↓
Desulfovibrionaceae↑	─	Body weight↓
Epididymal fat pad
weight↓	117	
 	Male
Sprague-Dawley rats
fed with HFD	Moderate-intensity
exercise
training
for 8 weeks	Ery-sipelotrichaceae_
UCG_003↑
Ruminiclostridium_5↑
Eisenbergiella↑
Anaeroplasma↑
Micrococcaceae↑
Peptostreptococcaceae↓
Clostridiaceae_1↓
Romboutsia↓
Clostridium_
sensu_stricto_1↓
Ruminiclostridium_1↓
Parabacteroides↓	─	Fat mass↓
Body weight↓
Fat mass percentage↓
Fat-free mass↓
Vascular endothelial function↑	118	
 	Male obesity-prone
rats fed with HFD	Wheel
movement for
14-16 weeks	Undefined genus
in the S24-7 family↓
Bacteroidetes↓
Streptococcaceae↑
Undefined genus
in the Rikenellaceae↓	─	Body weight↓
White AT mass↓
Energy expenditure↑
Fat oxidation↑
Insulin sensitivity↑
Total cholesterol↓
Low-density
lipoproteins↓
Inflammatory markers in
all AT depots
and aorta↓
Brown AT
mitochondrial activity↑	119	
 	Male C57BL/6
mice fed with
HFD	HIIT and MICT
for 10 weeks	Bacteroidetes↑
Proteobacteria↓	GLP-1↑
LPS↓
Intestinal barrier integrity↑	Body mass↓
Body fat percentage↓
Oral
glucose intolerance↓
Fasting glycemia↓
Insulin resistance↓
Brown AT
inflammation↓
Nonshivering
thermogenesis↑	120	
 	Male Wistar rat fed with HFD	HIIT and HFD/HIIT and HPD for 10 weeks	HIIT＋HFD compared
with HFD:
Bacteroidetes↑
Bacteroides↑
Prevotella↑
Roseburia↑
Firmicutes↓
Bifidobacterium↓
Alistipes↓
Bilophila↓
Lactobacillus↓
HIIT＋HPD compared
with HPD:
Bacteroidetes↑
Bacteroides↑
Blautia↑
Lactobacillus↑
Prevotella↑
Ruminococcus↑
Firmicutes↓
Alistipes↓
Roseburia↓	─	Body weight↓
Lee index↓	121	
 	Male C57BL/6
mice
fed with HFD	Low-to-moderate
aerobic exercise
for 8 weeks	Proteus↓
Vagococcus↑	─	Body weight↓	122	
 	Male C57BL/6
mice
fed with HFD	HIIT for 6 weeks	Bacteroidetes/Firmicutes↑
Actinobacteria in
duodenum/jejunum↑
Lactobacillus in ileum↑
Bacteroidales in cecum
and colon↑
Clostridiaceae in cecum↓
Dorea in cecum and
colon↑
Bacilli in colon↑
F.Clostridium in colon↓
Lachnospiraceae in
colon↓	─	Insulin tolerance↑	123	
 	Male C57BL/6 mice fed with
HFD	Treadmill training for
12 weeks	Firmicutes/Bacteroidetes↓
Verrucomicrobia↑
Akkermansia↑
Ruminococcaceae
_UCG-014↑	Colonic Barrier Integrity↑
Colonic ZO-1↑
Colonic Occludin↑	Body weight↓
Fasting blood glucose↓
Epididymal AT↓
Lee index↓	124	
 	Male
C57BL/6 mice fed with
HFD	High- to moderate-intensity treadmill training and/or diet for 9 weeks	EX:
Helicobacter↓
Ligilactobacillus↓
Parasutterella↓
Desulfovibrio↑
Clostridium methylpentosum↑
EX＋Diet:
Helicobacter↓
Ligilactobacillus↓
Roseburia↓
Desulfovibrio↑ Muribaculum↑ Prevotellaceae UGR001↑
Unidentified genera
belonging to the families
Atopobiaceae and
Ruminococcaceae↑
Deferibacteriaceae↓
Akkermansia↑
EX/EX＋Diet:
Prevotellaceae↑
Lactobacillaceae↑
Desulfobacterota↓
Deferribacterota↓
Cyanobacteria↓
Verrucomicrobiota↑
Bacteroidota↑ Proteobacteria↑
Firmicutes/Bacteroidetes↓	─	EX＋Diet:
Kidney and heart weights↓
EX/EX＋Diet:
Liver, spleen, epididymal, and abdominal fat weight↓
Plasma insulin level↓
Inflammation↓
Antioxidant capacity↑	125	
 	Male whole-body
low-density
lipoprotein receptor
knockout mice
fed with WD	Wheel movement for 16 weeks	Actinobacteria↑	─	Exercise capacity↑
Clear glucose ability↑
Maintain
euglycemia ability↑
Lipid levels within
the liver↓
Skeletal muscle
mitochondrial
abundance↑
Inguinal white AT and gonadal white AT↓	126	
 	C57BL/6 mice fed with
HFD	Moderate-intensity exercise or/and supplement of Gen for 12 weeks	Ex＋Gen:
Ruminococcus↑	Ex＋Gen:
BAs↑	Ex/Ex＋Gen:
Body weight↓
Inflammation↓	127	
 	Male Wistar rat fed with HFD	HIIT or/and supplement of TOTUM-63 for 12 weeks	Ex/Ex＋TOTUM-63:
Tenericutes↑
Anaeroplasmaceae↑
Anaeroplasma↑
Christensenellaceae↑
Ex＋TOTUM-63:
Oscillospira↑	─	Ex/Ex＋TOTUM-63:
Body weight↓
Fat mass↓
Muscle oxidative metabolism capacity↑
Oxidative stress↓
Ex＋TOTUM-63:
Blood glucose↓	128	
Diabetes
mellitus	Male C57BL/6 J wild-type mice fed with
HFD and then injected with streptozocin	Aerobic
exercise
for 8 weeks	Bacteroidetes↑
Bacteroides↑
Proteobacteria↓	SCFAs↑	Body weight↑
Blood glucose↓
Insulin↓
Glucose tolerance↓
Insulin tolerance↓	129	
Male C57BL/KsJ-leprdb/leprdb mice	Low-intensity
treadmill
training
for 6 weeks	Enterobacteriaceae↓
Bifidobacterium spp. ↓
Bacteroides/Prevotella
spp.↓
Methanobrevibacter
spp.↓
Lactobacillus spp.↑
Clostridium leptum↑
Clostridium cluster I↑	─	─	130	
Pregnant F0
Wistar-Kyoto rats fed with HFD	Exercise
4 weeks before
conception and
continued during
pregnancy	Mucispirillum spp.↑
Helicobacter spp.↑
Acetanaerobacterium↑	─	Fetal weight↑
The exacerbation of GDM↓
Pancreatic β-cell↑
Islet mass↑	131	
Male Wistar rats fed with HFD	HIIT and CET for 10 weeks	Akkermansia muciniphila↑
Butyrivibrio fibrisolvens↑
Prevotella copri↓	Propionic acid↑
Butyric acid↑	Inflammation↓	132	
Male
C57BL/6 mice fed with HFD	Voluntary
wheel running
training during 3 weeks before
mating and
throughout
pregnancy	Mothers at weaning:
Saccharibacteria_genera_incertae_sedis↑
Odoricbacter↑
Alloprevotella↑
Barnesiella↑
Male offspring at 8
weeks of age:
Odoricbacter↑
Adult male offspring:
Helicobacter↑
Odoricbacter↑
Clostridium XIVb↑	─	Mothers at weaning:
Male offspring at 8 weeks of age and adult male offspring:
Blood glucose↓
Insulin resistance↓
Improve lipid metabolism	133	
NAFLD	LCR rats
fed with
acute HFD	─	Unassigned
Desulfovibrionaceae↓
Sutterella↑
Alcaligenaceae↑
Cyanobacteria↓
Proteobacteria↓
Unassigned
families within
the Bacteroidetes phylum↓
Christensenellaceae↑
Family S-247↓
Mogibacteriaceae↑
Dorea↑
Coprococcus↓
Phascolarctobacterium↓	Intestinal tight
junction proteins↓	Liver TG↑
Body weight↑
Retroperitoneal, epididymal, and
mesenteric fat pad
masses↑	134	
Male C57BL/6 mice fed with
HFD	Treadmill
training for
6 weeks	Firmicutes↑
Bacteroidota↑
Dubosiella↑	─	Insulin sensitivity↑
Liver lipid
accumulation↓
Liver weight↓
TG↓
Free fatty acids↓	135	
Male Wistar
rats fed with
HFD	Aerobic combined with
resistance training for 5 weeks	Firmicutes↓
Bacteroidetes↑
Firmicutes/Bacteroidetes↓
Proteobacteria↑
Deltaproteobacteria↑
Betaproteobacteria↑
Alkaliphilus↑
Desulfovibrio↑
Prevotella↑	Intestinal barrier
function↑
Enterohepatic circulation
capacity↑
LPS↓	Inflammation↓
Body weight↓
Fasting plasma
insulin↓
Liver damage↓
Intrahepatic lipid
accumulation↓
Oxidative metabolism capacity↑
Insulin resistance↓
Plasma leptin↓
Appetite↓
Oxidative stress↓	136	
Male Sprague–Dawley
rats fed with
HFD	Aerobic exercise
and/or
combined with
LBP for
8 weeks	AE:
Bacteroidetes↑
Verrucomicrobia↓
Deferribacteres↑
Firmicutes/Bacteroidetes↓
Prevotellaceae↑
Enterococcaceae↓
LBP＋AE:
Firmicutes/Bacteroidetes↓
Deferribacteres↑
Deferribacteracea↑
Dehalobacteriaceae↑
Micrococcaceae↓
Butyricicoccus↑
Butyricimonas↑	AE/LBP＋AE:
Acetic acid↑
Butyric acid↑
Valeric acid↑
Intestinal pathological
damage↓
Intestinal tight
junctions↑
LPS↓
D-Lactate↓	AE/LBP＋AE:
Inflammation↓
Hepatocytes neatly
arranged↑
Steatosis↓
Hepatic fat
accumulation↓
Liver fibrosis↓
Lipid metabolic
indices↓
Body weight↓
Insulin resistance↓
Impaired glucose
tolerance↓	137	
Hypertension	Male SHRs	Moderate-intensity
exercise for
12 weeks (Ex)/Moderate-intensity
exercise for
8 weeks and detraining for 4 weeks (Det)	Ex:
Acetate- producing
bacterial communities↑
Lactate-producing
bacterial communities↓
Firmicutes/Bacteroidetes↓
Ex/Det:
Butyrate-producing bacterial communities↑	Ex/Det:
Intestinal pathology↓
Intestinal permeability↓	Ex:
Heart weight/body
weight↓
Left ventricle
weight/tibia length↓
Cross-sectional
area of
cardiomyocytes↓
Perivascular fibrosis↓
Ex/Det:
Systolic blood
pressure↓
Inflammation↓
Heart weight/
tibia length↓	138	
SHRs	Treadmill training
or/and food
supplement
of VC for 4
weeks	Ex/Ex＋VC:
Firmicutes↑
Bacteroidetes↓
Firmicutes/Bacteroidetes↑
Turicibacter↑
Helicobacteraceae↓
Ex＋VC:
Romboutsia↑	Ex/Ex＋VC:
Intestinal pathology↓
Intestinal permeability↓
Intestinal inflammation↓	Ex/Ex＋VC:
Inflammation↓
Blood pressure↓
Oxidative stress↓	139	
MI	Male C57BL/6 mice with a coronary artery ligation	Treadmill training
for 8 weeks	Bacteroidota↑
Firmicutes↓
Alistipes↑
Lachnospiraceae
_UCG-001↓
Ruminococcus↑
Allobaculum↑
Oscillospiraceae
UCG-005↑	3-HPA↑
4-HBA↑	Cardiomyocyte
cross-sectional area↓
Apoptosis↓
Cardiac function↑
Endurance capacity↑
Cardiac fibrosis↓
Ultrastructure of
myocardium↑	140	
Male C57BL/6 mice with a coronary artery ligation	Treadmill running
for 4 weeks	Phenylobacterium↑
Roseateles↑	─	Cardiac functions↑	141	
Atherosclerosis	Male C57BL/6-Apoeem1Narl/Narl mice fed with HFD	Endurance exercise
for 3 months	Rikenellaceae↑
Erysipelotrichaceae↑
Rikenella↑
Rikenellaceae RC9↑
Dubosiella↑
Faecalibaculum↑
Desulfovibrio↓
Parabacteroides↓
Bacteroides↓
Lactococcus↓
Peptococcaceae↓
Tyzzerella↓
Lachnospiraceae↓	Total SCFAs↑
Propionate↑
Butyrate↑	Obesity↓
HDL cholesterol↓
Inflammation↓
Vascular thickening↓
Atherosclerotic plaques↓	142	
Female APOE*3-Leiden.CETP mice fed with WD	Treadmill running
for 4 weeks in early or late phase	Late exercise:
Firmicutes↑
Ruminococcaceae↑
Lachnospiraceae↑
Uncultured
Ruminococcus species↑
Uncultured
Lachnospiraceae species↑
Lachnospiracea
bacterium 28–4↑
Uncultured
Clostridiales species↑
Anaerotruncus G3↑	─	Late exercise:
Body fat mass↓
Atherosclerotic
lesions ↓
Pro-inflammatory markers↓	143	
AT Adipose tissue, HIIT High-intensity interval training, MICT Moderate-intensity continuous training, GDM Gestational diabetes mellitus, LCR Low capacity for running, HFD High-fat diet, HPD High-protein diet, LBP Lyceum barbarum polysaccharide, SHRs Spontaneously hypertensive rats, TG Triglycerides, 3-HPA 3-Hydroxyphenylacetic acid, 4-HBA 4-Hydroxybenzoic acid, WD Western diet, T2DM Type 2 diabetes mellitus, GLP-1 Glucagon-like peptide-1, LPS Lipopolysaccharide, SCFAs Short-chain fatty acids, BAs Bile acids, HDL High-density lipoprotein, NAFLD Nonalcoholic fatty liver disease, MI Myocardial infarction, ZO-1 Zonula occludens-1, VC Vitamin C, CET Continuous endurance training, Gen Genistein.

Is the intestinal microecology the missing link between exercise and CMDs?

The intestinal microecology has been validated to exert an impact on several pathological characteristics of CMDs, ranging from insulin resistance, lipid metabolism disorders, and inflammation to secondary cardiovascular dysfunctions. In addition, exercise is a potential modifier of the composition of gut microbiota and metabolites. Follow-up investigations have revealed that intestinal microecology may play a crucial role in the process of exercise-induced beneficial effects on CMDs. Therefore, the remainder of this paper will focus on discussing this topic, with summaries shown in Tables 1, 2, and Figure 5. Figure 5. Exercise induces the formation of healthy gut microbiota, protects the integrity of the intestinal barrier, and induces changes in metabolites, which are strongly associated with improving the pathology of obesity, diabetes mellitus, NAFLD, hypertension, and CHD.Abbreviation: LPS, Lipopolysaccharide; BAs, bile acids; SCFAs, short-chain fatty acids; AA, amino acid; TMAO, trimethylamine N-oxide; 3-HPA, 3-hydroxyphenylacetic acid; 4-HBA, 4-hydroxybenzoic acid; NAFLD, nonalcoholic fatty liver disease; CHD, coronary heart disease. The figure was created with BioRender software, ©biorender.com.

Table 2. Effects of exercise training on the intestinal microecology in patients with CMDs.

Disease	Subjects’
characteristics	Duration of
intervention	Affected gut microbiota	Metabolites and
other gut alterations	Experiment
results	Reference	
Obesity	Adolescents with
obesity	Program
of endurance and
strength exercises
along with
dietary
restriction for 6 weeks	Firmicutes↓
Bacteroidetes↑
Firmicutes/
Bacteroidetes↓
Lactobacillales↓
Bacilli↓
Streptococcaceae↓
Streptococcus↓
Veillonella↓
Lentisphaeria↑
Victivallales↑
Victivallaceae↑
Victivallis↑
Christensenellaceae↑
Christensenellaceae
R-7 group↑
Butyricimonas↑	─	Waist-to-hip ratio↓
Fasting blood glucose↓
Serum TGs↓
LDL-C↓
Subendocardial viability
ratio↑
AIx75↓
Rest heart rate↓
Body weight↓
BMI↓
Body fat↓	144	
 	Participants with
obesity	Aerobic
training for 8 weeks	Ruminococcus gauvreauii↑
Lachnospiraceae
FCS020↑
Anaerostipes↑	─	Cardiorespiratory fitness levels↑
Insulin sensitivity↑
Cholesterol↓
Body weight↓
BMI↓
Visceral AT mass/volume↓
DBP↓	145	
 	Children with
obesity	Strength
combined with endurance
training
for 12 weeks	Proteobacteria↓
Roseburia↑
Clostridia↑
Dialister↑
Actinobacteria↑
Gammaproteobacteria↓
Bacteroidia↓
Betaproteobacteria↓
Flavobacteriia↓
Blautia↑	BCAA↓	Glucose levels↓
Dynamic strength↑
Inflammation↓	146	
 	Adults with obesity	Eucaloric/hypocaloric diet combined with exercise training for 12 weeks	─	Hypocaloric diet＋Ex:
TMAO trend toward a reduction
Eucaloric diet＋Ex:
TMAO trend toward an increase	Eucaloric diet＋Ex:
Triglycerides↓
Visceral abdominal fat depot↓
Hypocaloric diet＋Ex:
Fasting glucose↓
Cholesterol↓
Eucaloric/hypocaloric diet＋Ex:
Body weight↓
BMI↓
Peripheral
insulin sensitivity↑
Subcutaneous abdominal fat depot↓
VO2max↑	147	
 	Men with overweight	HIIT for 3 weeks	Not greatly impact the
overall composition of
the gut microbiome	─	Insulin sensitivity↑	148	
 	Adults with obesity	Aerobic
exercise for 6 weeks	─	Fecal metabolites: 3-methylxanthine↑

Caffeine↑
Arachidonic acid↑ 2-hydroxybenzoic acid↓

3-methylglutaric acid↓

2-hydroxyphenylalanine↓

4-hydroxybenzoic acid↓
4-pyridoxic acid↓
Jasmonic acid↓
Pimelic acid↓
Suberic acid↓
Uridine↓
Serum metabolites:
Adenosine↑
Caffeine↑
Methionine↑ 1-methyluric acid↑

Quinic acid↑
Creatinine↑
3-hydroxybutyric acid↓
Palmitic acid↓
4-hydroxyphenyllactic acid↑
Indole-3-lactic acid↑	─	149	
 	Participants with
metabolic
abnormalities	Low-saturated-fat diet, reduced energy intake, with
functional foods and physical activity
for 75 days	Bacteroides↑
Faecalibacterium↑
Prevotella↓
Roseburia↓
Prevotella/Bacteroides↓
Oscillospira↑	LPS↓
BCAA↓	TG↓
Circumference↓
BMI↓
Blood pressure↓
Body fat↓
Insulin resistance↓
Glycosylated
hemoglobin↓
Glucose and insulin↓
Total LDL↓	150	
 	Young sedentary
adults with
overweight or
obesity	Resistance training
for 6 weeks	Roseburia↑	─	Fat mass％↓
Waist circumference↓
Diastolic BP↓
Fasting glucose↓
Insulin resistance↓	151	
 	Men with overweight or
Obesity	HIIT for 12 weeks	Rikenellaceae↑
Clostridiaceae↑
Actinymyocetaceae↑	─	Body weight↓
Abdominal and visceral fat mass↓
Waist circumference↓
Glycemia↓	152	
Diabetes
mellitus	Older adults with prediabetes	Continuous
or interval
exercise for
2 weeks	─	Fasting GIP
of continuous exercise↑
Fasting GIP
of interval exercise↓	Insulin↓
Glucose↓
AIx75↓
Prandial blood pressure↓
Weight↓
VO2peak↑	153	
 	Men with
prediabetes	High intensity training for 12 weeks	Anaerotruncus
colihominis↑
Bilophila wadsworthia↑
Phascolarctobacterium
succinatutens↓
Bacteroides
xylanisolvens↓
Alistipes putredinis↑
Streptococcus
mitis group↑
Akkermansia muciniphila↓
Alistipes shahii↓	GABA↑
BCAA↓
Aromatic amino acids↓
SCFAs↑	Fasting glucose level↓
Body weight↓
Fasting insulin↓
Insulin resistance↓	154	
 	Participants with T2DM	C-MICT or

C-HIIT
for 8 weeks	Compared with
C-HIIT, C-MICT resulted
in higher abundance of
species from
Verrucomicrobia phyla,
Actinobacteria phyla,
Desulfobacterota phyla,
Bifidobacterium genus,
unknown species from
Escherichia genus,
Lachnospira eligens,
unknown species from
genera Enterococcus,
Agathobaculum,
Anaeromassilibacillus,
Massimaliae, and
Clostridium leptum.
Compared with
C-MICT, C-HIIT showed
higher abundance of
species from
Erysipelotrichales order,
Methanobrevibacter smithii, other
Lachnospirales and
Oscillospirales including
Ruminococcus bromi
and unknown species
from Nagativibacillus.	─	─	155	
 	Participants with prediabetes
or T2DM	SIT/MICT for
2 weeks	SIT and MICT:
Firmicutes/Bacteroidetes↓
Blautia spp.↓
Clostridium spp.↓
SIT:
Lachnospira genus↑
MICT:
Veillonella dispar↑
Faecalibacterium genus↑
Veillonella dispar↑	─	SIT and MICT:
Whole-body
fat percentage↓
Abdominal visceral
fat mass↓
HBA1c↑
Inflammation↓
SIT:
VO2peak↑
MICT:
Fasting fatty
acid uptake↓	156	
 	Participants with a high risk of T2DM	Light
physical
activity/
MVPA	─	MVPA:
TMAO↓	─	157	
 	Participants with T2DM	Intensive lifestyle
intervention (five to six times per week aerobic sessions and
hypocaloric diet) combined
with standard care for 12
months	There are no
statistical differences
in the change of
gut microbiota
composition between
treatments after
12 months, except
minor and transient
differences at month 3	─	HbA1c↓
Physical fitness↑
Fat mass↓
Lean mass↑	158	
 	Adults with
obesity and
prediabetes	Calorie
restriction
alone/calorie
restriction combined with
exercise training until 10% weight loss was achieved	Both interventions
caused similar changes
in the gut microbiome	─	Diet+Exercise:
Plasma insulin↓
Fasting plasma
nonesterified
fatty acid↑
Plasma insulin
concentration↓
Insulin clearance rate↑
Insulin sensitivity↑
Mitochondrial
biogenesis↑
Angiogenesis↑
Energy metabolism↑
Muscle strength↑
Cardiorespiratory fitness↑	159	
 	Participants with T2DM	Endurance,
resistance and
flexibility training for 6 months	Mycetes↓
Candida albicans↓	Zonulin↓	Body weight↓
BMI↓
Fat mass↓
Waist circumference↓
Lean mass↑
Glycemia↓
Insulin resistance↓
Total cholesterol↓
Oxygen consumption↑
Inflammation↓	160	
NAFLD	Participants with
NAFLD	Aerobic
exercise for 7 days	─	Dynamic PYY
response↑
Fasting GLP-1↓
Dynamic GLP-1
response↓	Fasting glucose↓
Fasting insulin↓
Insulin sensitivity↑	161	
 	Participants with NASH	Moderate-intensity
aerobic
training for 20 weeks	Parabacteroides
distasonis↑	─	Body weight↓
Magnetic resonance
imaging proton density fat fraction↓	162	
 	Participants with
NAFLD	Aerobic
training and/or diet for 8.6 months	EX/EX＋Diet:
ASV2077 belonged
to Bacteroides↑
ASV2513 belongs to
Bacteroides↑
ASV3942 belongs to
Ruminococcus↑
ASV5361 belongs to
Lachnospiraceae↑
EX＋Diet:
ASV2440 belongs to
Bacteroides↑
ASV4432 belongs to
Lachnospiraceae↑	─	EX/EX＋Diet:
HFC↓	163	
 	Participants with
NAFLD	Endurance combined with strength
training for 8 weeks	Bacteroidia↑
Flavobacteriia↑
Actinobacteria↓
Deltaproteobacteria↑
Bacteroidetes↑
Euryarchaeota↑
Betaproteobacteria↑	─	Inflammation↓
Health‐related quality
of life↑
Hepatic steatosis↓
Hepatic fibrosis↓
VO2peak↑
Weight loss↑
Body fat↓
Systolic blood pressure↓	164	
 	Participants with NAFLD	HIIT exercise for 12 weeks	─	Leucine containing
peptides and other
glycine and histidine
derivatives↓
Xanthurenic acid↑
Amino acids
and derivatives↓
Glycerophospholipids↓
Sterols↑
Acylcarnitines↓	Fasting plasma
glucose↓
Cardiorespiratory fitness↑
Waist circumference↓	165	
 	Participants with
NAFLD	Aerobic activity
and/or LGIMD for 90 days	Aerobic activity combined with LGIMD:
Ruminococcus↑
Oscillospiraceae-UCG002↑
Oscillospiraceae-UCG005↑
Dialister↑
Alistipes↑
Eubacterium eligens↑
Collinsella↓
Lachnospiraceae
_GCA900066575↑
Clostridia VadinBB60
group↑
Enterorabdus↑
Coprobacter↑
Intestinimonas↑
Ruminococcaceae_g
_UBA1819↑
Coprococcus↓
UCG002 (Oscillospiraceae)↑
Akkermansia↑
Tyzzerella↑
Uncultured_
Peptococcaceae↑
Ruminococcus↑	─	─	166	
 	Participants with
NAFLD	Aerobic activity combined with
resistance
or anaerobic activity
(ATFIS)/
LGIMD combined with ATFIS for 90 days	─	LGIMD combined with ATFIS:
Methyl valerate↓
Butanoic acid
methyl ester↓
2-piperidinone↓
Pentanoic acid
ethyl ester↓
Levomenthol↓
Butanoic acid
butyl ester↓
Butanoic acid
propyl ester↓
Pentanoic acid
butyl ester↓
Heptanoic acid
ethyl ester↓
ATFIS:
5-hepten-2-
one_6-methyl-↓
Cetene↓
Perillene↓
1-pentadecene↓
Dimethyl_trisulfide↓
159 decatriene
2358-tetr↓
Anethole↓
1-butanol_3-methyl-↓
Tridecane↓	─	167	
 	Participants with
NAFLD	HIIT for 12 weeks	Alistipes putredinis↑
Bacteroides
cellulosilyticus↑
Lactococcus lactis↑
Roseburia sp CAG 309↑
Coprococcus eutactus↑
Dorea formicigenerans↑
Eisenbergiella
massiliensis↑
Lactobacillus
acidophilus↓
Clostridium sp CAG 58↑	─	Glucose
concentration↓
Waist circumference↓
VO2max↑
Maximum
achieved workload↑
Body weight↓
TG↓
BMI↓
Fat mass↓
Visceral fat area↓
Monounsaturated
fat↑	168	
CHD	Participants with
CHD	MICT for 12 weeks	─	FABP2↓	Cardiorespiratory
fitness↑	169	
 	Participants with
CHD;
Male Sprague-Dawley rats fed with HFD	Moderate-intensity aerobic exercise;
Swimming for 6 weeks	Rats fed with HFD:
Verrucomicrobiaceae↑
Akkermansia↑
Akkermansia
muciniphila↑
Ruminococcus↑
Prevotella↑
Verrucomicrobia↑	─	Participants with
CHD:
The incidence of cardiovascular events↓
Improve glucose and lipid metabolism
Rats fed with HFD:
Fasting plasma
glucose↓
Serum lipids↓	170	
TG Triglycerides, LDL-C Low-density lipoprotein cholesterol, Alx75 Heart rate of 75/min, BMI Body mass index, AT Adipose tissue, HIIT High-intensity interval training, HbA1c HemoglobinA1c, GIP Glucose-dependent insulinotropic polypeptide, VO2peak Peak oxygen consumption, VO2max Maximal oxygen consumption, MICT Moderate-intensity continuous training, SIT Sprint interval training, MVPA Moderate to vigorous physical activity, DBP Diastolic blood pressure, PYY Peptide tyrosine tyrosine, HFC Hepatic fat content, LGIMD Low glycemic index Mediterranean diet, FABP2 Fatty acid-binding protein 2, CHD Coronary heart disease, PCI Percutaneous coronary intervention, BP Blood pressure, BCAA Branched chain amino acids, GABA γ-aminobutyric acid, LPS Lipopolysaccharide, TMAO Trimethylamine N-oxide, SCFAs Short-chain fatty acids, GLP-1 Glucagon-like peptide-1, NASH Nonalcoholic steatohepatitis, BAs Bile acids, T2DM Type 2 diabetes mellitus, NAFLD Nonalcoholic fatty liver disease, C-MICT Combined aerobic and resistance moderate intensity continuous training, C-HIIT Combined aerobic and resistance high-intensity interval training, HFD High-fat diet.

Exercise regulates abnormal intestinal microecology in obesity

As one of the most common CMDs, obesity, is attributed to an excessive intake of calories that surpasses the body’s energy consumption, leading to fat accumulation.171 Meanwhile, research indicates that more than two-thirds of deaths related to obesity are thought to be a result of CVDs.172 In recent years, studies have consistently demonstrated a robust correlation between intestinal microecology and obesity via the “gut-fat axis”.173–175 Therefore, it is crucial to find a therapeutic target contributing to obesity management based on intestinal microecology.176,177 Existing evidence has indicated that exercise is a viable fuel for shaping intestinal microecology, which is strongly linked to the progression of obesity.

Firstly, studies have shown that exercise can potentially alleviate obesity and associated symptoms by regulating gut microbiota. In this regard, Firmicutes to Bacteroidetes ratio (F/B), a ratio of two dominant bacteria in the gut, is associated with body weight and is higher in patients with obesity.178 In several studies, this ratio is significantly reduced following exercise, resulting in a beneficial effect on obesity.117,124,125,144 Therefore, reducing the Firmicutes to Bacteroidetes ratio through various interventions, such as the supplementation of probiotics and prebiotics, may mimic some of the benefits of exercise for patients with obesity. In fact, the abundance of gut microbiota, such as Roseburia, may vary with exercise intensity in improving the progression of obesity.121,126,146,150,151 Therefore, it is critical to regulate the abundance of Roseburia to restore normal levels in patients with obesity by tailored exercise regimens. Collectively, exercise can attenuate the colonization of pathogenic microbiota and foster the proliferation of beneficial microbiota, which is linked with its beneficial effect on obesity.118,119,145,152,179 Notably, several studies indicated exercise combined with diet is a more effective strategy to resist obesity in mice, which is partly attributed to more complex alterations in gut microbiota.125,127,128 Therefore, combination therapy may have more benefits for the management of obesity.

Next, researchers explore the effects of exercise on the function of gut microbiota in obesity. In one study, exercise can markedly increase metabolism pathways pertinent to glycan biosynthesis and metabolism, carbon fixation, and the citrate cycle by predicting the function of gut microbiota, which is inextricably linked to the progress of obesity in mice.123 Furthermore, a clinical study found that resistance training can affect obesity-associated clinicopathologic features. More importantly, metabolism and cell motility pathways are altered during this process by assessing microbial functions.151 Collectively, the above results offer a more comprehensive reference of how exercise affects the gut microbiome and, consequently, obesity.

Furthermore, several studies have shown the connection among exercise, gut metabolites, and obesity. In one study, exercise training results in the downregulation of plasma glucose levels and enhances dynamic strength in children with obesity, accompanied by changes in the metabolites, including BCAA and SCFAs.146 Therefore, the emphasizes the important role of exercise as a non-pharmacological therapy in early obesity via modulating levels of metabolites. Notably, exercise combined with diet intervention can also reduce obesity-associated clinicopathologic features in patients with metabolic abnormalities. More importantly, the microbial diversity is increased, and metabolites, such as LPS and BCAA, are decreased during this process.150 Similarly, a hypocaloric diet combined with exercise training results in overall improvement of the pathologic hallmarks in adults with obesity, accompanied by reduced TMAO.147 Therefore, the studies reiterated the important role of combination therapy in managing obesity.

It is worth noting that intestinal microecology varies with different exercise intensities in obesity. In this regard, high-intensity interval training (HIIT) has the advantage of anti-inflammatory response in mice with obesity by improving intestinal tight junction protein expression compared with moderate-intensity continuous training (MICT).120 More intriguingly, exercise-induced alterations in gut microbiota, as well as their metabolites, such as aromatic amino acid (ArAA) and SCFAs, are vulnerable to the degree of obesity.98,149 Another piece of evidence that bolsters this hypothesis is that exercise in normal participants shows a greater abundance of commensal bacteria compared with participants with overweight.180 Therefore, the gut-fat axis is likely to be a bidirectional communication that contributes to the interaction between exercise and obesity.

Above all, it is possible to conclude that exercise is a paramount “modifier” of metabolic health in obesity, which is associated with the rebalance of intestinal microecology. Furthermore, exercise-induced changes in the intestinal microecology are linked with the degree of obesity. Nonetheless, clinical evidence has shown that short-term HIIT does not significantly alter the gut microbiota in men with overweight.148 Apart from that, animal studies validate no significant alterations in the overall gut microbiota following two months of low-to-moderate exercise in mice fed with HFD.122 These results might be disrupted by various factors, such as the intensity and duration of exercise, as well as individual variations in initial gut microbial composition, etc. Therefore, it is imperative to reveal the mechanisms underlying exercise-induced rebalance of intestinal microecology in obesity via controlling multiple confounding factors.

Exercise regulates abnormal intestinal microecology in diabetes mellitus

Diabetes mellitus is characterized by the presence of hyperglycemia, resulting from either defective insulin secretion or impaired biological action of insulin, or both.181 It has long been proven to increase cardiovascular burden.182 Recent research has validated that the changes in intestinal microecology play an indispensable role in diabetes mellitus.183,184 Therefore, targeting gut microbiota and its associated metabolites represents a paramount therapeutic approach in managing patients with diabetes mellitus.185,186 More importantly, exercise training can modulate intestinal microecology, thereby exerting a beneficial impact on diabetes mellitus.

Firstly, the intestinal barrier serves as an essential mediator in the beneficial effects of exercise on diabetes mellitus. Clinical experiments have revealed that chronic exercise reduces leaky gut, as evidenced by a significant downregulation of zonulin protein levels following exercise, thereby contributing to attenuating the development of T2DM.160 Moreover, the intestine also influences the progression of diabetes mellitus via secreting hormones.187 However, exercise may induce interaction between intestinal hormones and insulin, thereby improving the progression of diabetes mellitus.153 Therefore, it is essential to elucidate the gut-pancreas axis mechanisms of exercise on the progression of diabetes mellitus. Furthermore, exercise induces significant alteration in the composition of the gut microbiota in mice with diabetes mellitus compared with sedentary control, indicating that the gut microbiota is an important mediator in the regulation of diabetes mellitus following exercise.130 In this regard, gut microbiota comes to its effects via various mechanisms, including interactions with pancreatic β cells and attenuation of the release of pro-inflammatory factors.131,156 Notably, the abundance of SCFAs-producing bacteria varies with exercise intensity.132,155 Therefore, it is essential to elucidate the reasons for alterations in gut microbiota under different exercise intensities and to formulate appropriate exercise strategies. More interestingly, exercise-induced maternal gut microbiota characteristics can be transmitted to offspring in mice fed with HFD.133 Nevertheless, further investigations are imperative to validate and elucidate this concept.

Next, researchers explore the effects of exercise on the function of gut microbiota in diabetes mellitus. As evidenced by clinical research, exercise can improve the capacity for carbohydrate fermentation and amino acid catabolism by predicting the gut microbiome function and, ultimately, might contribute to ameliorating insulin resistance in patients with prediabetes.154 The results offer a more comprehensive understanding of how exercise affects the gut microbiome and, consequently, the progression of diabetes mellitus.

Moreover, metabolites have a pivotal role in exercise-mediated effects on diabetes mellitus. In this regard, exercise can induce up-regulation of SCFAs and down-regulation of BCAA in feces and circulation, which contribute to increased insulin sensitivity in patients with prediabetes.154 Furthermore, exercise can increase autophagy of skeletal muscle cells through the SCFAs/GPR43 axis, and thereby ameliorating insulin resistance in mice with diabetes mellitus. Interestingly, in the process, the expression of GPR43 following exercise is elevated in skeletal muscle, while it remains unaffected in the intestine. Therefore, it is reasonable to speculate that gut-muscle communication may be an important mechanism of exercise-mediated protective effect on diabetes mellitus.129 In addition, SCFAs can also induce GLP-1 secretion.188 More importantly, exenatide (a GLP-1 receptor agonist) induces an increase in irisin, which is important in improving hyperglycemia and hyperlipidemia in patients with T2DM.189 Therefore, exercise ameliorates the progression of diabetes mellitus may be due to the activation of the SCFAs/GLP-1/irisin signaling pathway. In conclusion, the elucidation of the above hypotheses will facilitate our comprehension of the exercise-gut-muscle axis in affecting diabetes mellitus. However, the existing research presents inconsistent findings regarding the potential impact of exercise on irisin levels,190,191 and there is also no experimental evidence on the correlation between SCFAs and irisin. Therefore, future studies are needed to determine the precise molecular mechanisms. In addition to the aforementioned metabolites, the level of TMAO is also found to be reduced in adults with a high risk of T2DM following moderate to vigorous exercise compared with sedentary and light physical activity, suggesting the importance of exercise intensity and a possible new mechanism in the management of T2DM.157

Therefore, it can be speculated that, at least in part, some of the positive effects of exercise on diabetes mellitus may be attributed to a beneficial shift in abnormal intestinal microecology toward a “healthier” composition. Notably, the degree of improvement in abnormal intestinal microecology is associated with alterations in exercise patterns in rats with diabetes mellitus.132 Therefore, the combination therapy of multiple exercise patterns may be more effective in the management of diabetes mellitus. However, some research indicates that lifestyle interventions induce an improved effect on diabetes mellitus is unlikely attributed to the observed alteration of the gut microbiota, given the limitations in assessing microbial functionality.158,159 Hence, future studies should enlarge the sample size and improve detecting techniques to comprehensively investigate the involvement of intestinal microecology in the beneficial effects of exercise on diabetes mellitus.

Exercise regulates abnormal intestinal microecology in NAFLD

NAFLD is a series of pathological syndromes involving severe fat accumulation in hepatocytes, usually associated with obesity, diabetes mellitus, dyslipidemia, and other metabolic disorders.192 Notably, the disease was renamed to metabolic-associated steatotic liver disease (MASLD) in 2023 to provide a more precise characterization, aligning with the requirements of academic rigor and scientific accuracy.193 In the review, the terminology “NAFLD” will be employed. Investigations have validated that gut microbiota and derived metabolites play a crucial role in the development of NAFLD via the “gut-liver axis”.194 Therefore, targeting the gut microbiota and its associated metabolites represents a crucial therapeutic approach in managing patients with NAFLD.195,196 More importantly, exercise may be an “initiator” of the interactions between intestinal microecology and NAFLD.

Exercise can potentially alleviate NAFLD and associated symptoms by regulating gut microbiota. In this regard, several studies have validated that exercise ameliorates the pathological features of NAFLD, as well as altering gut microbiota composition, including Actinobacteria, Euryarchaeota, SCFAs-producing bacteria, and various other well-established beneficial bacterial species in patients with NAFLD.162–164,166 Furthermore, another study has demonstrated the decisive role of gut microbiota in the beneficial effects of exercise-induced NAFLD through pre-depletion of gut microbiota and fecal microbial transplantation (FMT) of the exercise training group. Further investigation found that Dubosiella is elevated after exercise in mice with NAFLD, and supplementing Dubosiella is an effective strategy to resist NAFLD. Mechanistically, exercise improves the progression of NAFLD through fibroblast growth factor 21 (FGF21)-Dubosiella axis.135 More intriguingly, FGF21 has been identified as an important exerkines.197 Therefore, supplementation of FGF21 or Dubosiella may mimic some of the benefits of exercise for patients with NAFLD.

Moreover, intestinal barrier function is also involved in the beneficial effects of exercise on NAFLD. A study showed that Lycium barbarum polysaccharides (LBPs) combined with aerobic exercise exert beneficial effects on rats with NAFLD, while this protective effect is associated with improved intestinal barrier integrity by upregulating the expression of zonula occludens-1 (ZO-1) and occludin.137 Moreover, researchers have found that exercise improves obesity and hepatic steatosis in rats, partly attributed to preserving intestinal barrier integrity and subsequently preventing gut-liver axis deregulation.136 Apart from the intestinal barrier, gut hormones are involved in the beneficial effects of exercise on NAFLD. In one study, researchers found that aerobic exercise restores the dynamic PYY and GLP-1 responses in NAFLD, indicating that exercise positively modulates gut hormones in patients with NAFLD.161

Next, researchers explore the effects of exercise on the function of gut microbiota in NAFLD and found that energy and carbohydrate metabolism capacity is decreased in rats with low exercise capacity via assessing microbial functions, which is inextricably linked to the decrease in SCFAs-producing bacteria and development of hepatic steatosis.134 Furthermore, clinical studies have predicted gut microbiome function and revealed that exercise can significantly alter various metabolism pathways and gene expression associated with the gut microbiome and, ultimately, might contribute to alleviating NAFLD-associated clinicopathologic features.162,163 Collectively, the above research will aid in a more comprehensive understanding of the underlying mechanisms of exercise and NAFLD from a metabolic perspective.

Moreover, metabolites have a pivotal role in exercise-mediated effects on NAFLD. In one study, a HIIT intervention improves the overall condition of patients with NAFLD, meanwhile inducing alterations in metabolites, including decreases of amino acids and their derivatives as well as certain lipids in the stool.165 In another study, researchers found that the combination of diet with aerobic exercise is considered to be an effective therapy to modulate microbiota dysbiosis in patients with NAFLD, the volatile organic compounds (VOCs) detected by fecal metabolomics have significantly changed in this process.167

Above all, these findings underscore the importance of intestinal microecology in the beneficial effects of exercise on NAFLD. However, in the above studies, different exercise pattern-induced changes in the composition of gut microbiota are varied. Therefore, it is challenging to identify specific bacteria associated with NAFLD. The paramount limitation lies in the fact that the molecular mechanism of exercise-induced alterations in gut microbiota in NAFLD remains unclear, and further research is essential. Furthermore, a study indicated that exercise does not significantly impact the alpha and beta diversity of gut microbiota in patients with NAFLD. Nonetheless, it induces the interaction of the gut microbiota, which helps to improve intrahepatic lipid content.168 Therefore, it is crucial to explore the interaction among gut microbiota, rather than only focusing on changes in the abundance of gut microbiota, for a comprehensive understanding of the robust correlation between intestinal microecology and NAFLD following exercise.

Exercise regulates abnormal intestinal microecology in hypertension

Hypertension is a clinical syndrome diagnosed by increased arterial blood pressure with systolic blood pressure (SBP) ≥140 mmHg and/or diastolic blood pressure (DBP) ≥90 mmHg.198 Its risk factors encompass a range of elements, such as insufficient physical activity, unhealthy dietary patterns, and imbalanced sodium-potassium intake, and there is also an approximately linear correlation between body mass index (BMI) and blood pressure.199 Moreover, elevated blood pressure is significant in relation to an augmented susceptibility to cardiovascular events.200 Therefore, hypertension plays a pivotal role as an interconnection between metabolic disorders and CVDs. A plethora of studies have shown marked correlations between hypertension and gut microbiota dysbiosis.201–203 Therefore, targeting modulation of intestinal microecology dysfunction may emerge as a pivotal therapeutic to hypertension management.204,205 Furthermore, emerging evidence highlights the contribution of exercise in this intricate process (Figure 6). Figure 6. The intestinal microecology is involved in the process of exercise induced beneficial effects on hypertension and CHD. Abbreviation: Ocln, Occludin; Tjp1, tight junction protein-1; Cldn4, Claudin 4; ZO-1, zonula occludens-1; Muc2, mucin 2; TNF-α, tumor necrosis factor-alpha; IL-6, interleukin-6; IL-1β, interleukin-1beta; TLR4, toll-like receptor 4; I-FABP, intestinal fatty acid-binding protein; 3-HPA, 3-hydroxyphenylacetic acid; 4-HBA, 4-hydroxybenzoic acid; NRF2, nuclear factor erythroid 2-related factor 2; SCFAs, short-chain fatty acids; Olfr78, olfactory receptor 78; VCAM-1, vascular cell adhesion molecule-1; MCP-1, monocyte chemoattractant protein 1; CHD, coronary heart disease. The figure was created with BioRender software, ©biorender.com.

In spontaneously hypertensive rats (SHRs), exercise intervention results in a sustained reduction in SBP, with concomitant the diversity of the gut microbiota and the abundance of SCFAs-producing bacteria elevated, suggesting gut microbiota is involved in the beneficial effects of exercise on hypertension. Subsequently, the investigators further found that FMT from exercised SHRs into sedentary SHRs induces attenuation of SBP, microglial activation, and neuroinflammation, confirming the crucial role of gut-brain axis communication in the beneficial effect of exercise on hypertension.138 In addition, a study has demonstrated that exercise combined with food supplements of vitamin C (VC) is a more effective strategy to alleviate blood pressure in SHRs, which may result from more complex changes in gut microbiota and its function, indicating combination therapy may play a multiplier effect on ameliorating hypertension.139 Notably, clinical research revealed that the dysbiosis of gut microbiota is markedly correlated with reduced exercise capacity in individuals with hypertension,206 suggesting that researchers should adopt an exercise-gut-hypertension interaction perspective as a starting point to comprehensively understand the underlying mechanisms.

In conclusion, some studies have examined the role of intestinal microecology in the impact of exercise on hypertension. However, there are scarce studies in the field, which has been partly attributed to the mechanism underlying the exercise-induced alterations in the intestinal microecology in hypertension remains unclear. Furthermore, most of the data stems from preclinical research. Therefore, it is crucial to carry out a large number of clinical studies to promote the management of hypertension.

Exercise regulates abnormal intestinal microecology in coronary heart disease

Coronary heart disease (CHD) is a prevalent cardiovascular disorder characterized by atherosclerosis in the coronary arteries, leading to stenosis and occlusion, and more severely, cardiac ischemia and myocardial infarction (MI), and the etiology of it probably lies in the disorder of lipid and glucose metabolism.207,208 Numerous studies have revealed a close relationship between CHD and abnormal intestinal microecology through the “gut-heart axis” way,209,210 which offers novel insights for CHD management. Notably, existing evidence has indicated that exercise is a viable fuel for shaping intestinal microecology, thereby ameliorating the progression of CHD (Figure 6).

Firstly, exercise can affect the integrity of the intestinal barrier and thus may exert beneficial effects on CHD. More specifically, research has shown that exercise intervention combining aerobic and resistance training results in significant improvements in zonulin and fatty acid-binding protein 2 (FABP2), the biomarkers of intestinal barrier integrity, in patients with CHD.169 In addition, changes in the composition of gut microbiota perhaps play a crucial role in exercise-induced beneficial effects on CHD. A study found that exercise inhibits downregulation of cardiac output and stroke volume in mice with MI, with concomitant alterations in gut microbial composition.141 Another study demonstrated that physical activity can aid in altering the composition of gut microbiota, particularly the abundance of Prevotella and Oligella, which are significantly related to clinicopathologic features of atherosclerosis.211 Furthermore, moderate-intensity exercise improves glucose and lipid metabolism levels in rats fed with HFD, and the underlying mechanism is closely linked to the increased abundance of Akkermansia muciniphila.170 Notably, antibiotic therapy and FMT are carried out in a study to confirm the decisive role of gut microbiota in the beneficial effect of exercise on MI.140 However, similar research, based on the methods of harnessing antibiotics and FMT, is still scarce in this field, so it is necessary to carry out more studies to explicit the role of the gut microbiota in exercise-mediating beneficial effects on CHD.

Meanwhile, microbial metabolites serve as “communicators” between exercise and CHD. A study found that endurance exercise exerts an anti-atherosclerotic effect in mice by modulating the expression of inflammatory factors and chemokines, while increased SCFAs play a crucial role in this process.142 In addition, another study has found that late, but not early time of day, exercise can reduce the levels of pro-inflammatory markers and atherosclerotic lesions, which was probably related to the increase of SCFAs-producing bacteria. The result emphasizes that exercise at different times of the day may affect the regulation of gut microbiota in mice with atherosclerosis. In addition, the study also found that late exercise induces elevated expression of the SCFAs receptor Olfr78 in the soleus muscle, which may be contributing to attenuating the development of atherosclerosis. Therefore, it is essential to elucidate the gut microbiota-metabolite-muscle axis mechanisms of exercise on the progression of atherosclerosis.143 Apart from SCFAs, another two metabolites induced by exercise training, 3-Hydroxyphenylacetic acid (3-HPA) and 4-Hydroxybenzoic acid (4-HBA), have also been shown to mitigate apoptosis and cardiac dysfunction of mice with MI via activating nuclear factor erythroid 2-related factor 2 (NRF2).140 Therefore, supplementation of 3-HPA or 4-HBA may mimic some of the benefits of exercise for patients with MI.

In summary, the fact that exercise ameliorates the progress of CHD may, in part, be attributed to the alterations in intestinal microecology. However, in fact, the above studies were limited to interventions with a single exercise intensity. Therefore, it is crucial to elucidate the optimal exercise prescription for improving gut microbiota composition and, subsequently, CHD progression through designing different exercise intensities.

Conclusions

In summary, CMDs, a series of diseases with high global mortality and morbidity, pose a substantial risk to human well-being. Therefore, there is an imperative need for a scientifically comprehensive approach to address this issue effectively. Extensive research has given certain clues on the role of intestinal microecology in the beneficial impact of exercise on CMDs. Moderate physical activities can effectively regulate the composition and function of gut microbiota, thereby improving the cardiometabolic processes via metabolic regulation, immune modulation, and release of signaling molecules. From a popular perspective, exercise has the advantage of being cost-effective and easily implementable with a wide range of applicability. Therefore, this underscores the importance of unraveling the connection among exercise, intestinal microecology, and the CMDs.

However, although extensive research has been implemented in this field, numerous unanswered concerns still remain. (1) Experimental verification in vitro is lacking for the observed alterations of metabolites in vivo. Nevertheless, it is surprising that therapeutic effects of exercise can be mimicked by the administration of their mimetics, such as 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR) and metformin,212,213 which provides a method to verify how metabolites exert influence on the improvement of CMDs through exercise in vitro. (2) A plethora of exercise regimens are “snapshots” in the above research. The paramount limitation lies in the fact that adherence to exercise regimens can be challenging for many individuals, particularly serious patients with CMDs, which may limit the potential benefits. Therefore, tailored exercise regimens are essential for taking advantage of the complex interactions between intestinal microecology and CMDs, as well as considering the patient’s own condition, such as age, gender, and disease progression. (3) In fact, apart from age and gender, other considerations, such as diet and medication, may disturb intestinal microecology in patients with CMDs. Therefore, in the presence of various confounding factors, elucidating how exercise modulates intestinal microecology in patients with CMDs is crucial via utilizing multiple statistical analysis methods155 and improving experimental design. Moreover, given the advantages of a single intervention could be limited, the research on jointly analyzing the effects of multiple factors on intestinal microecology in CMDs has also opened a new scenario for future clinical studies. As evidenced by research, integrating exercise with diet can more complexly alter the gut microbiota composition of patients with CMDs compared with exercise alone.127,128 In line with the above finding, exercise combined with statins can reverse the side effects and provide more significant health benefits than medication alone in patients with CMDs, which may be related to more complex alterations in gut microbiota following combination therapy.170 However, the clinical investigation of jointly analyzing exercise and various factors, especially medication, remains scarce in this field. What’s more, it is reasonable to speculate that therapeutic strategies involving the use of “exercise capsules” to mimic the effects of medications on intestinal microecology would be beneficial for CMDs management, given the challenge of engaging in physical activity in patients with severe CMDs. (4) In addition to the confounding factors mentioned above, it must be recognized that the composition of gut microbiota may also be affected by the analysis method.214 Therefore, it is crucial to ensure the robustness of the gut microbiota results following exercise in CMDs through joint application of analysis tools. In fact, it is limited to understanding the relationship among exercise, intestinal microecology, and CMDs through single microbiomics research. Therefore, integrating microbiomics with other omics, such as transcriptomics and metabolomics, is crucial for a more comprehensive understanding of the robust correlation among exercise, intestinal microecology, and CMDs. (5) Notably, the human gut microbiome includes not only bacteria but also viruses/phages and fungi. Therefore, lifting the veil within the gut microbiome through conjoint analysis of gut bacteriome, virome, phageome, and mycobiome holds promise in providing a reference for managing CMDs via exercise. (6) From a broader perspective, the relationship among exercise, intestinal microecology, and CMDs is extremely complicated. In other words, apart from the research mentioned in this review, alterations in intestinal microecology also impact exercise performance, and the progression of CMDs further exacerbates imbalances in intestinal microecology. Therefore, future investigations should adopt an exercise-intestinal microecology-CMDs bidirectional communication framework to offer enhanced insights and perspectives for the better management of CMDs. (7) Lastly, disparities may arise in the application of findings obtained from the experimental rodents to humans. Therefore, a cautious inference is essential until robust evidence is presented by enhancing both the sample size and quality of preclinical and clinical studies.

Currently, the management of CMDs continues to predominantly rely on drugs, which may have some financial constraints and adverse effects for certain individuals. Fortunately, exercise, as a low-cost and effective intervention, has validated promising potential in the prevention and treatment of CMDs, accompanied by improved composition of gut microbiota and increased production of beneficial metabolites. However, there are still many gaps in understanding specific mechanisms of how exercise influences intestinal microecology and, consequently, CMDs. Therefore, it is imperative for experts and researchers in this field to collaborate and facilitate the implementation of exercise interventions for CMDs in a more feasible way.

Abbreviations

3-HPA 3-Hydroxyphenylacetic acid

4-HBA 4-Hydroxybenzoic acid

5-HT 5-hydroxytryptamine

AhR Aryl hydrocarbon receptor

AICAR 5-Aminoimidazole-4-carboxamide ribonucleotide

AMPs Antimicrobial peptides

Ang Angiotensin

ArAA Aromatic amino acid

BAs Bile acids

BCAA Branched chain amino acid

BMI Body mass index

CaMKII Calmodulin-dependent protein kinase II

cAMP Cyclic adenosine monophosphate

CHD Coronary heart disease

CMDs Cardiometabolic diseases

CVDs Cardiovascular diseases

CYP7A1 Cholesterol 7alpha-hydroxylase

DBP Diastolic blood pressure

EPCs Endothelial progenitor cells

ERK1/2 Extracellular signal-regulated kinase 1/2

F/B Firmicutes to Bacteroidetes ratio

FFAR2 Free fatty acid receptor 2

FFAR3 Free fatty acid receptor 3

FGF15/19 Fibroblast growth factor 15/19

FGF21 Fibroblast growth factor 21

FMO3 Flavin-dependent monooxygenase 3

FMT Fecal microbiota transplantation

FXR Farnesoid X receptor

GFR Glomerular filtration rate

GLP-1 Glucagon-like peptide-1

GPCRs G-protein-coupled receptors

H2S Hydrogen sulfide

HFD High-fat diet

HIIT High-intensity interval training

HPA Hypothalamic-pituitary-adrenal

HTR2A Hydroxytryptamine receptor 2A

HUVECs Human umbilical vein endothelial cells

IL-1β Interleukin-1beta

IL-6 Interleukin-6

IL-8 Interleukin-8

JNK Jun N-terminal kinase

LBPs Lycium barbarum polysaccharides

LPS Lipopolysaccharide

MASLD Metabolic associated steatotic liver disease

MI Myocardial infarction

MICT Moderate-intensity continuous training

mTORC1 Mammalian target of rapamycin complex 1

MYD88 Myeloid differentiation primary response 88

NAFLD Nonalcoholic fatty liver disease

NF-κB Nuclear factor-kappa B

NIACR1 Niacin receptor 1

NLRs Nod-like receptors

NLRP3 Nod-like receptor protein 3

NRF2 Nuclear factor erythroid 2-related factor 2

Olfr78 Olfactory receptor 78

PAGln Phenylacetylglutamine

PERK Protein kinase R-like endoplasmic reticulum kinase

PI3K Phosphatidylinositol 3-kinase

PKA Protein kinase A

PKC Protein kinase C

PLCβ3 Phospholipase C β3

PRMT5 Protein arginine methyltransferase 5

PRRs Pattern recognition receptors

PXR Pregnane X receptor

PYY Peptide tyrosine tyrosine

RAAS Renin-angiotensin-aldosterone system

RCT Reverse cholesterol transport

ROS Reactive oxygen species

S6K1 S6 kinase 1

SBP Systolic blood pressure

SCFAs Short-chain fatty acids

SHP Small heterodimer partner

SHRs Spontaneously hypertensive rats

SIRT3 Sirtuin 3

SOD2 Superoxide dismutase 2

SRA Scavenger receptor A

T2DM Type 2 diabetes mellitus

TGR5 Takeda G protein-coupled receptor 5

TLRs Toll-like receptors

TMA Trimethylamine

TMAO Trimethylamine N-oxide

TNF-α Tumor necrosis factor-alpha

Trp Tryptophan

TXNIP Thioredoxin-interacting protein

VC Vitamin C

VOCs Volatile organic compounds

ZO-1 Zonula occludens-1

Acknowledgments

We would like to thank Qingya Zhang for English language editing.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Author contribution

Mingli Sun, Dan Dong, and Lijie Wang: Conceived the concept and gave direction. Can Gao: Wrote the initial draft. Mingli Sun, Dan Dong, Can Gao, Jinwen Wei, and Changxu Lu: Supported the initial draft and revision. The final version of the manuscript has received the unanimous approval of all authors.

Data availability statement

All relevant data are within the paper.
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