Targeting gut microbiota: Potential mechanisms in the pathogenesis of type 2 diabetes mellitus and emerging translational intervention strategies

Abstract

Type 2 diabetes mellitus (T2DM) is a common metabolic disorder characterized by insulin resistance and progressive impairment of β-cell function, accounting for the vast majority of diabetes cases worldwide. Beyond classic mechanisms such as ectopic fat deposition and chronic inflammation, increasing evidence indicates that the gut microbiota serves as a critical system regulating glucose homeostasis and plays a key role in the pathogenesis and progression of T2DM. T2DM is frequently accompanied by gut dysbiosis, characterized by an enrichment of pro-inflammatory and endotoxin-producing bacteria alongside a reduction in short-chain fatty acid-producing and barrier-maintaining microbes. This dysbiosis induces metabolic inflammation, disrupts the bile acid-farnesoid X receptor/Takeda G protein-coupled receptor 5 signaling pathway, weakens the incretin response, and exacerbates insulin resistance. Conversely, restoring specific microbial functional modules can improve hyperglycemia, suggesting that functional dysregulation rather than mere compositional shifts lies at the disease core. This review examines primary mechanisms by which gut microbes promote or suppress T2DM. Crucially, we describe microbe-targeted intervention strategies, including dietary modulation, prebiotics/probiotics, fecal microbiota transplantation, pharmacotherapy, and traditional Chinese medicine approaches.

Key Words: Type 2 diabetes mellitus; Gut microbiota; Traditional Chinese medicine; Treatment; Metabolic diseases

Core Tip: Increasing evidence indicates that gut microbiota plays a critical role in the development of type 2 diabetes mellitus (T2DM). Unlike previous reviews that primarily focus on microbial compositional alterations, this review highlights that functional dysregulation of the gut microbiota is the central driver of T2DM pathogenesis. We propose an integrated metabolic-immune-barrier-endocrine framework linking microbial metabolites, inflammation, intestinal barrier dysfunction, and endocrine signaling to glucose dysregulation. We further summarize emerging microbiota-targeted interventions and their translational potential for personalized T2DM management.

INTRODUCTION

Type 2 diabetes mellitus (T2DM) is one of the most prevalent chronic metabolic disorders worldwide and accounts for approximately 90% of all diabetes cases globally[1-3]. It is characterized by persistent hyperglycemia resulting from insulin resistance and progressive loss of pancreatic β-cell function[4], accompanied by increased risks of cardiovascular disease, chronic kidney disease, and premature mortality[5]. Despite advances in drug therapy and lifestyle-based preventive strategies[6], the global incidence and prevalence of T2DM continue to rise, highlighting significant gaps in our current understanding of its pathogenic mechanisms and management. Most reviews have focused on characterizing changes in microbial community composition; that is, documenting which taxonomic groups increase or decrease in T2DM. However, there remains a lack of comprehensive analysis of the functional impacts of metabolites and signaling pathways derived from the microbial community, leaving a critical gap in translating compositional data into mechanistic insights.

Traditional pathogenesis models of T2DM focus on ectopic fat deposition, chronic low-grade inflammation[7], mitochondrial dysfunction[8], and impaired insulin signaling in the liver, skeletal muscle, and adipose tissue[9]. These mechanisms provide a theoretical foundation for developing hypoglycemic drugs, but they do not fully explain individual differences in disease susceptibility, progression rates, and treatment responses[10]. Consequently, researchers have begun to focus on other regulatory systems that interact with host metabolic dynamics[11].

The gut microbiota has emerged as a key determinant of host metabolic homeostasis[12]. The human gastrointestinal tract harbors a dense and diverse microbial ecosystem that participates in nutrient metabolism, bile acid conversion, immune maturation, and enteroendocrine signaling[13]. Breakthroughs in metagenomics and metabolomics have revealed significant associations between gut microbial composition and function in individuals with insulin resistance and T2DM[14]. Experimental and clinical studies increasingly confirm that the gut microbiota has a causal effect in shaping metabolic phenotypes, rather than a correlative association[15]. In individuals with T2DM, gut dysbiosis manifests as functional alterations including increased endotoxin production, reduced short-chain fatty acid (SCFA) biosynthesis, altered branched-chain amino acid (BCAA) metabolism, and disrupted bile acid signaling[16]. These microbial alterations compromise intestinal barrier integrity, promote metabolic inflammation, and modulate incretin signaling, thereby exacerbating insulin resistance and β-cell stress[17]. A key discovery in recent research is that functional dysregulation of the microbiota, rather than compositional changes, is central to the pathogenesis of T2DM. Therefore, the focus of this review is to systematically explore the functional changes driven by the microbiota rather than re-examine the microbial taxa associated with T2DM. We discuss how these changes influence the onset and progression of T2DM through metabolites, immunoregulation, intestinal barrier integrity, and endocrine signaling. We synthesize current evidence on the mechanisms by which the gut microbiota drives the progression or suppression of T2DM and evaluate emerging microbiota-targeted interventions, including dietary modifications, prebiotics, probiotics, fecal microbiota transplantation (FMT), drug therapy, and traditional Chinese medicine (TCM). By integrating mechanistic insights with a translational medicine perspective, we aim to establish a theoretical framework for microbiota-based strategies to prevent and treat T2DM (Figure 1).

Figure 1 Gut microbiota involvement in the regulation of type 2 diabetes mellitus. T2DM: Type 2 diabetes; LPS: Lipopolysaccharide; SCFA: Short-chain fatty acid; TCM: Traditional Chinese medicine; HbA1c: Glycated hemoglobin; FBG: Fasting blood glucose; NF-κB: Nuclear factor-kappa B; IL: Interleukin; TNF: Tumor necrosis factor; AMPK: Adenosine 5’-monophosphate-activated protein kinase; GLUT4: Glucose transporter 4.

A BRIEF OVERVIEW OF T2DM

T2DM is one of the most common chronic metabolic disorders globally. T2DM arises from a complex interplay of genetic susceptibility, environmental and lifestyle factors, progressive β-cell dysfunction, insulin resistance, lipotoxicity and glucotoxicity, impaired incretin effect, and chronic low-grade inflammation. In many individuals, a major contributor is excessive ectopic fat accumulation in the liver and pancreas, as proposed by the twin-cycle hypothesis; however, this represents only one component within the broader multifactorial pathogenesis of the disease[18]. T2DM is characterized by elevated blood glucose resulting from progressively impaired insulin secretion or increased tissue resistance to insulin[19,20]. T2DM has spread globally, accounting for nearly 90% of the approximately 537 million cases[3]. It can also trigger digestive system symptoms[21], neurological disorders[22], cardiovascular diseases[23], endocrine disturbances[24], and other chronic and critical illnesses[25]. Despite increasing knowledge regarding risk factors for T2DM and evidence for successful prevention, the incidence and prevalence of the disease continue to increase[10]. Therefore, T2DM remains a major public health challenge.

Prediabetes is the earliest identifiable stage of glycemic dysregulation, and its progression can be delayed by effective control of risk factors[26]. T2DM arises from the complex interplay of risk factors including genetics, environment, diet, and sedentary lifestyles[26]. In some recent studies, the gut metagenome was shown to be a factor in the development of T2DM. A strong family history of DM, age, obesity, and physical inactivity identify those individuals at highest risk[27]. The ability to prevent or delay T2DM by modifying certain risk factors has been suggested for decades[28]. Currently, interventions primarily target environmental risk factors, such as reducing obesity and promoting physical activity[27]. Additionally, high intake of the Mediterranean diet (MD) and the dietary approaches to stop hypertension (DASH) diet, along with interventions to improve dietary quality, can also significantly reduce the risk of T2DM, particularly in high-risk populations[29].

Several mechanisms have been proposed for T2DM, including increased non-esterified fatty acids, inflammatory cytokines, adipokines, and mitochondrial dysfunction for insulin resistance, and glucotoxicity, lipotoxicity, and amyloid formation for b-cell dysfunction[4,30]. Insulin resistance is considered to be the cornerstone of T2DM[31]. It primarily manifests as reduced responsiveness to insulin in muscle, liver, and fat tissue[32,33]; however, the influence of the gut microbiota on T2DM should not be overlooked. A growing body of new evidence indicates that the gut microbiota can affect the host by influencing body weight, bile acid metabolism, proinflammatory activity, and insulin resistance, as well as by regulating gut hormones[34].

In contrast to previous reviews that focus on alterations in gut microbial composition (i.e., increased or decreased abundance of specific taxa), this review emphasizes that gut-microbiota-related functional dysregulation is the central driver of T2DM pathogenesis. Microbial contributions to T2DM are not determined solely by taxonomic shifts, but rather by changes in functional outputs, including metabolic products (e.g., SCFAs, chain amino acids, and bile acids); immunoregulation [e.g., Toll-like receptor/nuclear factor-kappa B (TLR/NF-κB)-mediated inflammatory signaling]; intestinal barrier integrity and endotoxemia; and endocrine signaling pathways such as glucagon-like peptide (GLP)-1 and farnesoid X receptor/Takeda G protein-coupled receptor 5 (FXR/TGR5) axes.

Accordingly, we propose a unified functional framework in which the gut microbiota influences host glucose homeostasis through coordinated metabolic-immune-barrier-endocrine interactions, providing a more integrated perspective compared with traditional microbial-composition-based interpretations.

GUT MICROBIOTA DYSBIOSIS IN T2DM

What is the gut microbiota?

To improve clarity, we organize gut microbiota-host interactions in T2DM into a hierarchical functional framework rather than a collection of independent pathways. In this model, intestinal barrier dysfunction represents an upstream initiation that promotes metabolic endotoxemia, thereby triggering systemic inflammatory cascades. Downstream of this process, microbiota-derived metabolic alterations, including reduced SCFAs, disrupted bile acid signaling, and enhanced BCAA metabolism, act as key mediators linking dysbiosis to host metabolic reprogramming. These convergent metabolic and inflammatory signals ultimately impair endocrine regulation, particularly GLP-1 secretion and insulin signaling, thereby contributing to insulin resistance and T2DM progression.

The gut microbiota functions like an endocrine organ, producing bioactive metabolites that influence host physiology[35]. Recent advances in genome sequencing technology, bioinformatics, and cultivationalomics have enabled researchers to explore microbial communities and their physiological functions more deeply[36]. The primary functions of the gut microbiota include aiding in the digestion of complex carbohydrates and fibers that human enzymes cannot break down[37]. It also synthesizes vitamins, such as vitamin K and several B-vitamins, which are essential for maintaining proper metabolic functions[38]. It contributes to the production of SCFAs, including acetate, propionate, and butyrate, which serve as energy sources for colonocytes and help maintain gut integrity[39].

The gut microbiota also plays a crucial part in the development of the immune system[40]. It interacts with the host’s innate and adaptive immune cells, influencing immune responses and immunotolerance[41]. By preventing excessive activation of proinflammatory pathways while supporting immunotolerance to harmless antigens[42], the gut microbiota helps maintain balance of the immune system. When the balance of the gut microbiota is disrupted, it can lead to dysbiosis[43]. T2DM, atherosclerosis, hypertension[44], Alzheimer’s disease[45], obesity, inflammatory bowel disease[46], dermatological conditions, and cancer are associated with dysbiosis of the gut microbiota[47].

Gut-microbiota-driven mechanisms promoting T2DM

Gut-microbiota-driven pathogenic mechanisms of T2DM are hierarchically interconnected rather than functioning independently. Metabolic endotoxemia and inflammatory activation act as central converging pathways that integrate upstream barrier dysfunction and downstream metabolic signaling disturbances. Accumulating evidence indicates that specific gut microbial taxa actively contribute to the initiation and progression of T2DM rather than merely reflecting metabolic dysregulation[48]. Dysbiotic signatures associated with T2DM consistently include enrichment of proinflammatory[49], endotoxin-producing[50], or metabolically deleterious microorganisms, alongside depletion of beneficial taxa. At the species or genus level, microorganisms repeatedly implicated in promoting T2DM include Megamonas, Bacteroides, Roseburia[51], Prevotella copri[52], and Escherichia coli[53] (Table 1). These bacteria contribute to disease progression through diverse yet convergent mechanisms, such as increased lipopolysaccharide (LPS) production, disruption of gut barrier integrity, aberrant bile acid metabolism, excessive BCAA biosynthesis, and amplification of mucosal and systemic inflammation[54].

Table 1 The relationship between gut microbiota dysbiosis and type 2 diabetes mellitus[59,60,64-66,69,79,80,81,85].

Microbe	Impact on T2DM	Mechanism	Ref.
Colidextribacter; Desulfovibrionaceae; Morganella	Promote	Promote LPS production, upregulate pro-inflammatory cytokines, exacerbate pancreatic β-cell dedifferentiation, reduce acetate, butyrate, and overall SCFA levels, ultimately leading to impaired islet function	Cao et al[59]
Acetatifactor; Clostridiales unclassified; Lacchnospiraceae unclassified; Oscillibacter; Murinomas; Tuzzerella		Inhibit GPR43/GPR109A signaling within the AMPK pathway, activate the Toll-like receptor 9-myeloid differentiation primary response protein 88-interferon-γ signaling pathway, increase the expression of TNF-α, IL-1β, and IL-6, and reduce the levels of ZO-1 and occludin	Zhang et al[60]
Anaerovorax; Bilophila; Blautia; Colidextribacter; Dubosiella; Lachnoclostridium; Roseburia		Upregulate the expression of pro-inflammatory cytokines, promote bacterial biosynthesis of BCAAs, and suppress the tissue-specific expression of BCAA catabolic enzymes	Zheng et al[64]
Bacteroides vulgatus		Reduce TLCA levels, inhibit TGR5 signaling, downregulate UCP-1 expression, and diminish thermogenic activity in white adipose tissue	Chen et al[65]
Bacteroides uniformis		Promote leukocyte production, reduce CA and CDCA levels, inhibit the TGR5/AMPK signaling pathway, and disrupt glucose and lipid metabolism	Zhu et al[66]
Akkermansia muciniphila	Alleviate	Strengthening the intestinal epithelial barrier to reduce the entry of microbial products such as LPS into the bloodstream, thereby preventing the activation of the innate immune system	Sabatino et al[69]
Eubacterium hallii		Increase energy expenditure, elevate butyrate levels, and regulate bile acid metabolism	Udayappan et al[79]
Parabacteroides distasonis		Alter the bile acid profile, with increased levels of LCA, UDCA, and succinate, thereby activating intestinal IGN and FXR signaling pathways	Wang et al[80]
Bacteroides uniformis CECT 7771		Increased Tregs, reduced B cells and total macrophages, decreased the M1/M2 ratio, upregulated the expression of IL-10, TSLP, and TLR5	Gauffin Cano et al[81]
Lactobacillus plantarum HAC01		Increase the area of insulin-positive pancreatic β cells, reduce the expression of gluconeogenesis-related enzymes phosphoenolpyruvate carboxykinase and glucose-6-phosphatase, promote phosphorylation of AMPK and Akt, and upregulate serum levels of SCFAs	Lee et al[85]

T2DM: Type 2 diabetes; LPS: Lipopolysaccharide; SCFA: Short-chain fatty acid; GPR: G protein-coupled receptor; IL: Interleukin; TNF: Tumor necrosis factor; AMPK: Adenosine 5’-monophosphate-activated protein kinase; ZO-1: Zonula occludens-1; BCAA: Branched-chain amino acid; TLCA: Taurolithocholic acid; TGR5: Takeda G protein-coupled receptor 5; UCP-1: Uncoupling protein 1; CA: Cholic acid; CDCA: Chenodeoxycholic acid; LCA: Lithocholic acid; UDCA: Ursodeoxycholic acid; IGN: Intestinal gluconeogenesis; FXR: Farnesoid X receptor; Treg: Regulatory T; TSLP: Thymic stromal lymphopoietin; TLR: Toll-like receptor; Akt: Protein kinase B.

Endotoxin-mediated metabolic inflammation is a central mechanism by which gut microorganisms promote T2DM[55]. Gram-negative bacteria are the primary source of LPS[56]. When the intestinal barrier is compromised, LPS enters the circulatory system, activating TLR4 signaling pathways in adipose tissue, liver, and skeletal muscle. This subsequently initiates NF-κB and C-Jun N-terminal kinase cascades[57], thereby inhibiting insulin receptor signaling[58]. Animal studies indicate that increased abundance of LPS-producing bacteria (e.g., Colidextribacter, Desulfovibrionaceae, and Morganella) disrupts the intestinal barrier, promotes inflammatory responses and β-cell de-differentiation, reduces acetate and butyrate levels, induces metabolic abnormalities, and ultimately leads to T2DM[59]. Harmful bacteria Acetatifactor, Clostridiales unclassified, Colidextribacter, Desulfovibrionaceae, GCA-900066575, Lachnospiraceae, Oscillibacter, Murinomas, and Tuzzerella increase circulating LPS and proinflammatory factors [such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-10] levels. This leads to activation of the TLR9-myeloid differentiation primary response protein 88-interferon-γ signaling pathway in the colon and reduced insulin sensitivity[60].

Another major diabetogenic pathway involves gut microbial production of BCAAs, which are strongly associated with insulin resistance[61]. Prevotella copri has enriched gene clusters for BCAA biosynthesis, leading to elevated circulating levels in insulin-resistant hosts[62,63]. Anaerovorax, Bilophila, Blautia, Colidextribacter, Dubosiella, Intestinimonas, Lachnoclostridium, Lachnospiraceae NK4A136, Oscillibacter, and Roseburia promote BCAA synthesis, inflammatory cytokine expression, and blood glucose and insulin levels[64]. These findings establish microbial BCAA overproduction as a mechanistic bridge between dysbiosis and impaired insulin action.

Gut microorganisms that disrupt bile acid signaling and epithelial integrity accelerate T2DM progression. In mice, reduced abundance of Bacteroides vulgatus inhibits TGR5 in adipose tissue, and downregulates expression of uncoupling protein uncoupling protein 1, which affects bile acid metabolism and modulates T2DM[65]. Zhu et al[66] found that reduced Bacteroides uniformis (B. uniformis) inhibits bile acid production, downregulates cholic acid and chenodeoxycholic acid levels, and disrupts hepatic gluconeogenesis and lipolysis via the TGR5/adenosine 5’-monophosphate-activated protein kinase (AMPK) signaling pathway, thereby triggering disorders in glucose and lipid metabolism[66]. T2DM leads to a reduction in the abundance of Bacteroides, Lactobacillus, and Bifidobacterium species possessing bile-salt hydrolase activity, inhibits accumulation of free bile acids such as chenodeoxycholic acid and deoxycholic acid, and downregulates intestinal FXR/fibroblast growth factor (FGF) 15 and TGR5/GLP-1 signaling pathways[67].

Gut-microbiota-driven mechanisms alleviate T2DM

There is increasing evidence that beneficial gut microorganisms are not only indicators of metabolic status, and they actively influence glucose homeostasis and insulin sensitivity by regulating key pathways such as inflammation, intestinal barrier homeostasis, and the incretin axis[12]. Large metagenome-wide studies in Chinese and European cohorts have consistently reported that individuals with T2DM show depletion of several butyrate-producing or health-associated taxa, which suggests that loss of beneficial functions (e.g., SCFA production and bile-acid remodeling) is a core feature of dysbiosis in T2DM[12,14]. In human and animal studies, the gut microbiota was associated with improved glycemic phenotypes, including Akkermansia muciniphila (A. muciniphila), Faecalibacterium prausnitzii (F. prausnitzii), Roseburia spp., Eubacterium rectale, Eubacterium hallii (Anaerobutyricum hallii), Bifidobacterium adolescentis, Lactobacillus spp., Parabacteroides distasonis (P. distasonis), and B. uniformis. These bacteria collectively reduce endotoxemia, enhance GLP-1 signaling[68], and promote SCFA and bile-acid-driven immunometabolic reprogramming[69,70].

SCFAs are not uniform signaling metabolites, and their biological effects are context dependent. Acetate is primarily involved in peripheral lipogenesis and central appetite regulation, whereas propionate is closely associated with hepatic and intestinal gluconeogenesis. Butyrate is the main energy source for colonocytes and exerts potent anti-inflammatory and epigenetic regulatory effects through inhibition of histone deacetylase. SCFA-mediated signaling is strongly influenced by local concentration gradients, site-specific distribution along the gut-portal-systemic axis, and host metabolic status. Receptor expression patterns, particularly free fatty acid receptor (FFAR) 2 and FFAR3, are dynamically altered in metabolic diseases such as T2DM, thereby modulating downstream signaling outcomes.

A. muciniphila is among the best-characterized anti-metabolic-disease candidates[71], because it interfaces directly with the mucous layer and host immune tone, which limits the metabolic endotoxemia that drives insulin resistance[72]. In obesity and T2DM mouse models, heat-inactivated A. muciniphila and its outer membrane protein components improve insulin resistance and dyslipidemia[73]. Thus, specific microbial molecules can confer metabolic benefits without relying entirely on live bacterial colonization. A proof-of-concept human study involving overweight/obese volunteers demonstrated improved insulin sensitivity following supplementation with A. muciniphila, consistent with the known mechanisms of action of the bacterium through barrier and inflammation-related pathways[74]. Strengthening the intestinal epithelial barrier reduces the entry of microbial products such as LPS into the bloodstream, and prevents activation of the innate immune system and induction of chronic low-grade inflammation characteristic of T2DM[72]. Therefore, A. muciniphila suppresses insulin resistance and hyperglycemia through the mucous-layer-barrier homeostasis-immunoregulation pathway.

The second category of typical protective mechanisms originates from SCFA-producing bacteria, particularly butyrate-producing bacteria such as F. prausnitzii, Roseburia spp., and Eubacterium rectale[75]. This type of bacteria has been consistently shown to decrease in T2DM metagenomic studies[12]. Butyrate can prevent high-fat-diet-induced insulin resistance and increase energy expenditure, providing a strong theoretical basis for the metabolic benefits of SCFAs[76]. SCFAs can act as signaling molecules that stimulate intestinal L cells to secrete GLP-1 via FFAR2/FFAR3, directly linking microbial fermentation to the incretin axis and influencing postprandial glucose regulation[77]. Beyond their endocrine effects, SCFAs also modulate adaptive immunity by promoting expansion of colonic regulatory T (Treg) cells and maintaining mucosal homeostasis, while inflammation serves as a key amplifier of insulin resistance[78]. Therefore, restoring butyrate-producing microbiota may inhibit T2DM progression through a synergistic triple action: Repairing the barrier, enhancing GLP-1, and inducing anti-inflammatory immune activity. Similarly, beneficial gut microorganisms exert coordinated effects through restoration of barrier integrity, modulation of microbial metabolites, and enhancement of endocrine signaling pathways, thereby reversing the hierarchical dysfunction observed in T2DM.

Current intervention studies targeting specific bacterial strains are coming into focus (Table 1). Oral administration of Eubacterium hallii improves insulin sensitivity in mice, accompanied by alterations in fecal butyrate and bile acid profiles, suggesting it may exert effects through dual pathways involving SCFA and bile acids[79]. P. distasonis has been reported to exert hypoglycemic effects by alleviating metabolic abnormalities through influencing bile acid metabolism and associated host signaling[80]. Oral administration of B. uniformis CECT 7771 reduces serum cholesterol, triglycerides, glucose, insulin, and leptin levels, enhances TNF-α phagocytosis, and alleviates metabolic and immune dysfunctions associated with gut microbiota dysbiosis[81]. Fabersani et al[82] found that B. uniformis CECT 7771 increased Treg cells, reduced B cells and total macrophages, decreased the M1/M2 ratio in the gut and epididymal adipose tissue of obese mice, and upregulated expression of IL-10, thymic stromal lymphopoietin, and TLR5[82]. Several studies have suggested that specific strains of Bifidobacterium and Lactobacillus enhance insulin sensitivity and reduce inflammation levels, potentially through downregulating LPS-related pathways and promoting SCFA niches[83-85]. However, these effects are typically strain and context dependent.

TREATMENT AND INTERVENTIONS

In 2024, the number of adults aged 20-79 with diabetes worldwide reached 589 million[86], and by 2050, the total is projected to rise to 853 million[87]. Due to long-term insulin resistance and relative insulin secretion deficiency caused by T2DM[19], patients often experience impaired lung function[88], cardiovascular disease[89], neuropathy[90], and metabolic abnormalities[91]. Individuals with dysbiosis are more prone to hyperglycemia, and gut microbiota intervention offers a novel approach for treating T2DM. Existing interventions include dietary adjustments; prebiotics, probiotics, and synbiotics; FMT; and drug therapy[92].

Dietary adjustment

Diet is not only essential for sustaining human growth, reproduction, and health, but it also regulates and supports the symbiotic microbial community colonizing the digestive tract the gut microbiota[93]. The gut microbiota is responsible for recovering energy from food, providing vitamins to the host, and serving as a barrier against exogenous pathogens[94]. The mutual regulation between dietary nutrients and gut microorganisms may influence host health and mediate immune-related diseases[95]. A diet rich in plant antioxidants such as polyphenols and flavonoids reduces oxidative stress and chronic inflammation, thereby alleviating insulin resistance[96].

Western diet (WD)-high-fat, ketogenic diet (KD), and MD (plant-based) all influence the composition of the gut microbiota in mice and humans[96] (Table 2). The WD is unhealthy and characterized by high fat intake, excessive eating, frequent snacking, and prolonged postprandial states[97]. Individuals with a WD consume large amounts of refined sugars, animal fats, processed meats, refined grains, and high-fat dairy products, while their intake of unprocessed foods such as fruits, vegetables, whole grains, nuts, and seeds is low[98]. Consequently, WD leads to insufficient dietary fiber, vitamins, minerals, and other plant-derived molecules (such as antioxidants)[99,100]. In mice fed a WD, TNF-α messenger RNA expression is upregulated in the ileum, activating NF-κB in small intestinal epithelial cells, immune cells, and endothelial cells[101]. Liu et al[102] found that supplementing mice with Dioscorea opposita (D. opposita) polysaccharides increased the abundance of Firmicutes and Bacteroidetes in the gut; decreased the abundance of Actinobacteria and Proteobacteria; altered the gut microbiota; enhanced superoxide dismutase, catalase, and glutathione peroxidase activity; and reduced malondialdehyde levels[102]. This exerted an antidiabetic effect, improving WD-induced T2DM in mice.

Table 2 Dietary modulation of the gut microbiota and its impact on type 2 diabetes mellitus[106,108,113,114,118-122].

Method	Alterations in the gut microbiota	Strengths and weaknesses	Mechanism	Ref.
WD	Increased: Escherichia coli; Actinobacteria; Proteobacteria. Decreased: Firmicutes; Bacteroidetes	WD are associated with a higher risk of developing T2DM. WD induces gut microbiota dysbiosis, increases endotoxin levels, and disrupts the intestinal mucosal barrier, thereby exacerbating inflammation and obesity-related metabolic abnormalities	Reduce protective gut microbiota, downregulate the expression of the short-chain fatty acid receptor GPR43, suppress the activities of superoxide dismutase, catalase, and glutathione peroxidase, activate the NF-κB signaling pathway, upregulate TNF-α expression, and thereby exacerbate inflammatory responses	Agus et al[118]
KD	Increased: Verrucomicrobiae; Akkermansia; Verrucomicrobiales; Akkermansiaceae; Christensenellaceae; Parabacteroides distasonis; Anaerotruncus; Enterococcus; Rothia; Enterorhabdus; Bacteroidetes. Decreased: Firmicutes; Actinobacteria; Clostridia; Alistipes; Dialister; Lactobacillus; Lactococcus; Faecalitalea; Bifidobacterium	KD can improve T2DM but may potentially increase LDL-C levels, necessitating individualized monitoring of lipid profiles and cardiovascular risk. Issues related to adherence, long-term safety, and suitability for specific populations (such as patients with kidney disease or other special groups) still require clarification through more high-quality randomized controlled trials	Improve the structure and function of the gut microbiota, increase the levels of ketone bodies β-hydroxybutyrate and β-hydroxybutyrate salts, inhibit NF-κB signaling, reduce the expression of pro-inflammatory intestinal Th17 cells, caspase-1, IL-1β, and IL-18, and decrease HbA1c and triglyceride levels	Palmas et al[106]; Ang et al[108]; Song et al[119]; Lindefeldt et al[120]; Dowis and Banga[121]
MD	Increased: Clostridium leptum; Eubacterium rectale; Bifidobacteria; Bacteroides; Faecalibacterium prausnitzii. Decreased: Firmicutes; Blautia	MD is associated with a lower risk of T2DM, delays the initiation of glucose-lowering medications, and improves disease remission rates. MD is more oriented toward long-term, sustainable risk reduction; therefore, short-term glycemic control goals often require combination with pharmacotherapy or structured management programs	Promote the proliferation of short-chain fatty acid producing bacterial strains (particularly butyrate producers), reduce the levels of the pro-inflammatory cytokine IL-6 and the oxidative stress marker 8-hydroxy-2’-deoxyguanosine, and improve FBG and HbA1c	Barber et al[113]; Dimba et al[114]; Al-Aubaidy et al[122]

WD: Western diet; KD: Ketogenic diet; MD: Mediterranean diet; T2DM: Type 2 diabetes; LDL-C: Low-density lipoprotein cholesterol; NF-κB: Nuclear factor-kappa B; GPR: G protein-coupled receptor; IL: Interleukin; TNF: Tumor necrosis factor; Th17: T helper 17 cells; HbA1c: Glycated hemoglobin; FBG: Fasting blood glucose.

The KD has become increasing popular in recent years[103]. Its defining feature is a reduction in carbohydrate intake (typically < 50 g/day), while increasing the proportion of protein and fat[104,105]. The latest research indicates that KD influences the gut microbiota composition of untreated T2DM patients, increasing markers of human health-associated bacteria such as the Verrucomicrobiota phylum and its members (Verrucomicrobiae, Akkermansiaceae, Verrucomicrobiales, and Akkermansia), and improving glycated hemoglobin (HbA1c) and triglyceride levels[106]. KD also reduces proinflammatory T helper cell-17 (Th17) cells in the gut and visceral fat by increasing ketone bodies (particularly β-hydroxybutyrate), leading to decreased levels of the probiotic Bifidobacterium[107,108], and may reverse insulin resistance[109]. Although evidence suggests that the KD can reduce body weight and improve glycemic control in patients with T2DM, data on its long-term sustainability, safety, and efficacy remain scarce[110]. Overall, KD alters gut microbial diversity, influences its metabolites, promotes beneficial biomarker changes, reduces inflammation levels, and improves T2DM.

The MD is one of the most extensively researched and widely recognized diets globally, and has been proven to offer numerous health benefits[111]. It is an anti-inflammatory diet characterized by high intake of polyunsaturated fatty acids (PUFAs) and monounsaturated fatty acids (MUFAs), high fiber intake, and lower intake of saturated fatty acids[112]. This dietary pattern promotes the proliferation of bacterial strains producing SCFAs (butyrate), such as Clostridium leptum and Eubacterium rectale, through its core components primarily dietary fiber, extra virgin olive oil, and PUFAs[113]. It also promotes the growth of Bifidobacteria, Bacteroides, and F. prausnitzii, while inhibiting the proliferation of Firmicutes and Blautia[113]. The health benefits of the MD and DASH diet are largely mediated through specific bioactive dietary components that interact with the gut microbiota[114]. Dietary fiber serves as a key substrate for microbial fermentation, leading to increased production of SCFAs[115], which improve intestinal barrier integrity and metabolic homeostasis. Polyphenols selectively enrich beneficial microbial taxa, including A. muciniphila and Bifidobacterium spp., while suppressing proinflammatory bacteria[116]. Unsaturated fatty acids, particularly MUFAs and PUFAs, modulate gut microbial composition and bile acid metabolism, thereby influencing FXR/TGR5 signaling pathways involved in glucose and lipid homeostasis[117]. In addition, minimally processed foods and fermented foods contribute to increased microbial diversity, functional redundancy, and ecological stability of the gut microbiota, collectively improving metabolic outcomes in T2DM. Subsequently, blood glucose levels in T2DM patients are controlled, including fasting blood glucose (FBG) and HbA1c[114]. However, the mechanism by which the MD improves T2DM through regulating gut microbiota remains to be explored (Table 2)[118-122].

Prebiotics, probiotics, and synbiotics

Prebiotics, probiotics, and synbiotics represent microbiota-targeted nutritional strategies designed to restore host-microorganism homeostasis and improve metabolic health[123]. Prebiotics are selectively fermented substrates that promote the growth or activity of beneficial gut microorganisms[124], whereas probiotics are live microorganisms that confer health benefits when administered in adequate amounts[125]. Synbiotics combine both components to enhance microbial survival, colonization, and functional output[126]. These interventions have been widely investigated in metabolic disorders[127], including obesity[128], metabolic syndrome, nonalcoholic fatty liver disease[129], and T2DM[130], due to their capacity to modulate gut microbial composition, microbial metabolites[131], intestinal barrier integrity[132], and systemic inflammation[133]. Importantly, their metabolic effects are closely linked to baseline gut microbiota structure, dietary context, and host metabolic status, highlighting the gut microbiota as the central mediator of their therapeutic potential in T2DM.

Prebiotics influence T2DM primarily by reshaping gut microbial ecology toward saccharolytic and SCFA-producing communities while suppressing proinflammatory taxa[69]. Supplementation with inulin-type fructans or galacto-oligosaccharides has been consistently shown to increase the abundance of Bifidobacterium and other beneficial anaerobes in humans[134]. However, clinical studies have demonstrated that, although prebiotics reliably modify microbiota composition, improvements in glycemic outcomes are not universal[135], suggesting that metabolic benefits depend on functional microbial outputs rather than compositional changes alone.

Probiotics modulate T2DM through strain-specific effects on gut microbiota composition, barrier function, and immune-metabolic interactions[136]. Clinical trials and meta-analyses have indicated that probiotic supplementation can reduce fasting plasma glucose, HbA1c, and insulin resistance in patients with T2DM[137], although the heterogeneity among the studies is substantial. Mechanistically, probiotics can suppress the expansion of opportunistic pathogens, reduce LPS production[138], and reinforce mucosal integrity[139], thereby attenuating systemic inflammation[140]. Some probiotic strains also influence bile acid deconjugation and transformation, modulating FXR- and TGR5-mediated pathways involved in glucose and lipid metabolism[141]. Probiotic-induced metabolic benefits do not necessarily require long-term colonization[142], implying that transient functional activity or ecological modulation may be sufficient to trigger host metabolic responses. These findings highlight the necessity of defining probiotic interventions based on strain-level functionality rather than taxonomic generalization.

Synbiotics are designed to achieve synergistic effects by pairing probiotics with compatible prebiotic substrates, thereby enhancing microbial survival, engraftment potential, and metabolic efficacy[143]. In T2DM populations, synbiotic interventions have been associated with improvements in glycemic control[144], insulin sensitivity, and inflammatory profiles[145]. The prebiotic component supplies fermentable substrates that support both endogenous beneficial microorganisms and administered probiotic strains, amplifying SCFA production and microbial cross-feeding networks[146]. Concurrently, probiotic components contribute to maintaining epithelial integrity and immune homeostasis[147]. Clinical evidence suggests that synbiotics may outperform single-component interventions in individuals with pronounced dysbiosis[130]. However, outcomes remain dependent on formulation design, dosing, and host-specific factors.

Beyond single-category supplementation, integrated strategies combining prebiotics, probiotics, and synbiotics often alongside conventional antidiabetic therapies represent a promising direction for microbiota-centered T2DM management[148]. Nevertheless, substantial interindividual variability, challenges in formulation standardization, and limited long-term safety data underscore the need for microbiota-stratified clinical trials to identify responders and optimize precision interventions.

FMT

FMT represents a high-intensity intervention strategy that aims to restore gut microbial ecosystem structure and function through the transfer of an entire microbial community from a healthy donor to a recipient[149]. Unlike prebiotics or probiotics, which selectively modulate specific microbial taxa or functions, FMT induces rapid and global reconfiguration of the gut microbiota[150], offering a unique opportunity to investigate causal relationships between microbial ecology and host metabolism. In metabolic disorders, including T2DM, FMT has attracted increasing attention.

There is currently an increase in the number of animal studies and clinical investigations examining the role of FMT in T2DM. FMT increases butyrate-producing bacteria, Bifidobacterium and Lactobacillus, and reduces total cholesterol, low-density lipoprotein cholesterol, and liver stiffness[151]. There is also evidence that, in patients with T2DM receiving FMT, the abundance of the family Rikenellaceae and genus Anaerotruncus (family Ruminococcaceae) is significantly increased in pretreatment fecal samples, accompanied by increases in HbA1c, blood glucose, and serum uric acid[152]. Wang et al[153] found that T2DM mice receiving FMT treatment showed decreased HbA1c levels, reduced IL-6 and TNF-α inflammatory factors in pancreatic tissue, inhibited β-cell apoptosis, and improved insulin resistance and pancreatic β-cell function. Zhang et al[154] proposed that FMT reshapes the gut microbiota and metabolite profiles, alters intestinal structure, and alleviates insulin and leptin resistance through modulation of the Janus kinase 2/insulin receptor substrate/protein kinase B (Akt) signaling pathway[154]. FMT, combined with metformin or not, significantly improves insulin resistance, body mass index, and gut microbiota composition in patients with T2DM through colonization of donor-derived microbes. The feasibility and limitations of FMT for treatment of T2DM require further research[155].

Despite its mechanistic appeal, several challenges currently limit the clinical translation of FMT for T2DM. These include concerns regarding long-term safety, donor selection and screening, standardization of preparation and delivery routes, and regulatory oversight[156]. The broad and nonspecific nature of FMT raises the possibility of unintended microbial or immunological consequences, particularly in metabolically vulnerable populations. As a result, FMT remains primarily a research tool in the context of T2DM, offering valuable insights into microbiota-host causality rather than serving as a routine therapeutic option. Future efforts may focus on identifying defined microbial consortia or functionally engineered communities that capture the metabolic benefits of FMT while minimizing associated risks.

Drug therapy

Drug therapy for T2DM has traditionally been developed to directly target host metabolic pathways. However, increasing evidence indicates that many antidiabetic drugs exert some therapeutic effects through modulation of the gut microbiota[157]. Currently, there are 10 categories of Food and Drug Administration-approved drugs for treating T2DM, including traditional drugs such as insulin, metformin, and sulfonylureas[158,159]. Novel drugs target new pathways to lower blood glucose, such as GLP-1 receptor agonists (GLP-1RAs) and dipeptidyl peptidase-4 inhibitors (such as sitagliptin)[158,160]. Sodium-glucose cotransporter 2 inhibitor canagliflozin is used in patients with T2DM and cardiovascular disease or risk of chronic kidney disease to reduce the incidence of myocardial infarction[161].

Currently, metformin is the first-line treatment for T2DM in most guidelines and is used daily by > 200 million patients[162]. Importantly, the therapeutic effects of metformin are not solely mediated by direct actions on host tissues but are also significantly influenced by gut-microbiota-dependent mechanisms. Metformin increases the abundance of A. muciniphila and other SCFA-producing bacteria, which are closely associated with improved glucose homeostasis. In addition, metformin modulates bile acid metabolism by altering the intestinal FXR-FGF15 and TGR5 signaling axes, thereby contributing to its systemic metabolic benefits. Sun et al[163] proposed that the glucose-lowering effect of metformin is not entirely dependent on its direct pharmacological actions on host tissues, but is mediated, at least in part, through gut-microbiota-dependent mechanisms. It helps to improve gut microbiota dysbiosis during treatment of T2DM. Metformin alters gut microbiota composition by increasing mucin-degrading A. muciniphila and multiple SCFA-producing microbial populations, enhancing the capacity to produce butyrate and propionate, which are closely associated with glucose homeostasis[164]. The findings of Sun et al[163] demonstrated that metformin reduces the abundance of Bacteroides fragilis in the gut of patients with T2DM, reshapes the bile acid metabolic profile, and leads to the intestinal accumulation of the FXR-antagonistic bile acid glycoursodeoxycholic acid. This, in turn, suppresses intestinal FXR signaling and improves glucose metabolism, insulin sensitivity, and overall metabolic homeostasis[163]. Li et al[165] found that metformin increased the abundance of Lactobacillus and Bifidobacterium, while reducing the levels of Enterobacteriaceae and Enterococcus. In parallel, serum levels of LPS, IL-6, and C-reactive protein were significantly decreased, accompanied by marked reductions in fasting plasma glucose, 2-hour postprandial plasma glucose, and HbA1c[165]. Metformin increased the abundance of Bifidobacterium, Muribaculaceae, P. distasonis, and Alloprevotella in the gut of experimental animals, thereby alleviating sepsis-induced hepatic inflammation and improving intestinal barrier function[166]. More broadly, pharmacological agents can reshape gut microbial composition and metabolic activity, while the gut microbiota can reciprocally influence drug absorption, bioavailability, therapeutic efficacy, and adverse effect profiles, forming a bidirectional drug-microbiota-host interaction network in T2DM.

Alpha-glucosidase (AGS) inhibitors delay the digestion of complex carbohydrates and reduce monosaccharide absorption in the intestines, attenuating postprandial glucose variations and making them an important therapeutic option for T2DM[167,168]. Since the 1990s, three AGS inhibitors: Acarbose, voglibose, and miglitol have been widely used in clinical practice[169]. Acarbose is metabolized exclusively within the gastrointestinal tract, and its beneficial effects in T2DM may be associated with selective modulation of the gut microbiota[170]. At the genus level, acarbose treatment led to the marked expansion of Lactobacillus and Dialister, while the abundance of Butyricicoccus, Phascolarctobacterium, and Ruminococcus was significantly reduced[170]. Acarbose markedly increases bacterial diversity and richness in experimental animals and modulates the Th17/Treg cell balance in gut mucosal immunity, alleviating inflammatory responses[171].

GLP-1RAs are widely used in the treatment of T2DM because of their multiple benefits, including weight reduction, protection of pancreatic β cells, promotion of β-cell proliferation, regulation of lipid metabolism, reduction of fat deposition, and a low incidence of adverse effects[172]. In vivo studies have indicated that GLP-1RAs participate in the regulation of food intake by stimulating vagal sensory neurons, interacting with the hypothalamus and hindbrain, and modulating inflammatory responses and the gut microbiota[173]. Zhao et al[174] found that GLP-1RAs significantly reduced the overall abundance and diversity of the gut microbiota, attenuated obesity-associated microbial phenotypes, and promoted lean-associated microbial profiles. Specifically, GLP-1RA treatment decreased the abundance of Firmicutes and an increase in Bacteroidetes, accompanied by inhibition of hepatic glucose production, reduction of hepatic lipid accumulation and lipogenesis, and enhancement of fatty acid β-oxidation[174]. Tirzepatide, a dual agonist of glucose-dependent insulinotropic polypeptide and GLP-1 receptor, increases the abundance of the beneficial genus Akkermansia, improves insulin resistance, reduces serum and hepatic lipid levels, and modulates gut microbiota dysbiosis and bile acid metabolism in mice with T2DM[175].

TCM

TCM therapies, such as acupuncture, electroacupuncture (EA), and moxibustion, are emerging as adjunctive treatments for T2DM, targeting the microbiota[176]. Their core mechanism lies in reshaping microbial community structure, microbial metabolic networks, and host immune-metabolic pathways. In addition to these physical stimulation-based interventions, TCM compounds and formulations have been increasingly recognized to exert microbiota-modulating effects through well-defined molecular and metabolic mechanisms.

The representative alkaloid berberine has been shown to increase the abundance of A. muciniphila, suppress pathogenic bacteria, and regulate bile acid metabolism via FXR signaling inhibition, thereby improving glucose homeostasis. Polysaccharides derived from Astragalus membranaceus and D. opposita act as prebiotic-like substrates that selectively enrich SCFA-producing bacteria, increase SCFA production, and strengthen intestinal barrier integrity. Curcumin modulates gut microbial composition while simultaneously reducing inflammatory signaling and improving insulin resistance.

At a systems level, multicomponent formulations such as Gegen Qinlian Decoction further extend these microbiota-mediated effects by coordinately modulating gut microbiota composition, SCFA levels, bile acid metabolism, and inflammatory pathways, providing a more integrated mechanistic basis for their antidiabetic efficacy. TCM and its bioactive components are gaining increasing attention. These compounds typically exhibit low systemic bioavailability but achieve high exposure concentrations within the gut.

Acupuncture is effective for treating T2DM[177,178]. Several studies have indicated that stimulating specific acupuncture points such as “Zusanli” (ST36), “Pishu” (BL20), “Weishu” (BL21), and “Sanyinjiao” (SP6) promotes the production of key microbial metabolites (butyrate and propionate), improves insulin sensitivity, and enhances glucose metabolism[179]. Acupuncture at “Tianshu” (ST25) and “Zusanli” (ST36) enhances secondary bile acid synthesis, elevating hepatic insulin sensitivity by activating the FXR and TGR5 signaling pathways along the gut-liver axis[179]. Acupuncture can also regulate the phosphatidylinositol 3-kinase (PI3K)/Akt, NF-κB[180], and AMPK[181] signaling pathways to reduce the release of inflammatory mediators, inhibit pancreatic β-cell apoptosis, decrease reactive oxygen species and lipid peroxidation, improve energy metabolism disorders, and treat T2DM[182]. However, the current evidence regarding the metabolic benefits of acupuncture for T2DM primarily comes from animal studies and small clinical trials. Several recent systematic reviews have pointed out that most existing randomized controlled trials (RCTs) on acupuncture for T2DM are small single-center studies. Methodological quality assessments have indicated that these studies have deficiencies in blinding procedures and incomplete reporting of details[183]. Although meta-analyses have suggested that acupuncture reduces HbA1c and the insulin resistance index in patients with T2DM[184], there was significant heterogeneity among the studies, and the overall quality of the evidence remains moderate to low.

EA is a modern neuromodulation technique that integrates traditional Chinese acupuncture with contemporary electrical stimulation[185]. Compared to traditional acupuncture, EA offers rapid onset of action, simplicity, and safety. By targeting specific acupoints and regulating metabolic homeostasis, it can alleviate various diseases, including T2DM[186]. EA can promote an increase of probiotics such as Blautia and Lactobacillus, while reducing opportunistic pathogens including Alistipes, Helicobacter, and Prevotella[187]. This enhanced the total amount of SCFAs in the feces of T2DM mice and alleviated systemic inflammation[187]. Cao et al[188] found that EA significantly reduced FBG and fasting insulin levels by enhancing gut community richness and diversity through decreasing abundance of Clostridium and increasing that of Lactobacillus. Wang et al[189] demonstrated that EA reduced expression of diabetes-related markers with effects similar to those of metformin. They proposed that EA primarily treats T2DM by increasing abundance of Firmicutes and the Firmicutes-to-Bacteroidetes ratio, while decreasing the abundance of Bacteroidetes and Eubacterium, thereby lowering serum levels of LPS and TNF-α[189]. EA contributes to maintaining intestinal mucosal barrier integrity through anti-inflammatory and antiapoptotic effects mediated by the PI3K/Akt pathway[190]. It influences the regulation of gut-brain peptides, reduces insulin resistance, and improves feeding behavior in T2DM rats[190].

Moxibustion, a thermal stimulation therapy, has also been shown to ameliorate insulin resistance and metabolic inflammation through partial restoration of gut microbiota homeostasis[191]. By modulating intestinal barrier integrity and mucosal immune responses, moxibustion reduces endotoxin translocation and reshapes microbial-host interactions[192]. Acupuncture/EA and moxibustion exert indirect metabolic benefits by synchronizing neural, immune, and microbial signals rather than acting on a single molecular target. These findings support the concept that physical TCM interventions function as systemic regulators of the gut microbiota-host metabolic network, providing a complementary strategy for T2DM management. However, the clinical evidence for moxibustion in the management of T2DM remains preliminary. Most existing studies are small, and standardized protocols for moxibustion parameters, including treatment duration, frequency, and acupoint selection, have not yet been established. Most mechanism-of-action studies have been conducted in animal models; therefore, there is an urgent need to design rigorous, large RCTs to validate these findings.

TCM and its active components demonstrate unique advantages in the treatment of T2DM. Many TCM compounds exert their antidiabetic effects not solely through direct action on host signaling pathways, but rather by reshaping the gut microbiota structure, regulating microbial metabolites, and restoring host-microbiota metabolic homeostasis. Berberine, the most extensively studied representative compound, exhibits hypoglycemic effects comparable to metformin while significantly modulating gut microbiota composition[193]. Mechanistic studies indicate that berberine effectively inhibits Ruminococcus bromii, Desulfovibrionaceae, Proteobacteria, F. prausnitzii, Bifidobacterium spp., and Bacteroides fragilis[194], while increasing the abundance of beneficial Akkermansiaceae[195]. It also reduces the concentration of aromatic amino acids including tyrosine, tryptophan, and phenylalanine[196], improves impaired glucose tolerance, and regulates bile acid signaling pathways[197], thereby alleviating diabetic symptoms.

Beyond alkaloids, polysaccharides from Astragalus membranaceus and D. opposita function as prebiotic-like substrates, selectively enriching SCFA-producing bacteria such as Lactobacillus, Bifidobacterium, and Faecalibacterium, enhancing gut barrier integrity, and attenuating systemic inflammation[198,199]. Curcumin exhibits bidirectional interactions with the gut microbiota, regulating the expression of long noncoding RNAs[200], alleviating insulin resistance, suppressing oxidative stress responses, and reducing inflammation and hepatic lipid accumulation[201].

The role of saponin-based Chinese herbal extracts in T2DM should not be overlooked. Ginsenosides reverse colonic dysbiosis, restore intestinal barrier function, alleviate inflammation associated with metabolic endotoxemia, and improve hyperglycemic symptoms[202]. Polygonatum sibiricum saponins are converted by gut microbiota into active metabolites, and their hypoglycemic effects are closely related to their metabolic activity[203]. Saponins from Panax japonicus and total Astragalus saponins influence T2DM by regulating the gut microbiota[204,205]. Multiherb formulations provide a systems-level approach to microbiota modulation. Gegen Qinlian Decoction has been shown in randomized trials to improve glycemic control while inducing reproducible shifts in gut microbial composition and carbohydrate metabolism pathways, highlighting the ecological robustness of multicomponent interventions[206]. Collectively, these findings support a unifying paradigm in which TCM acts as microbiota-centered metabolic regulator, offering complementary and mechanistically distinct strategies for T2DM management.

CHALLENGES AND FUTURE PERSPECTIVES

Limitations of probiotic-based interventions

Despite accumulating evidence supporting the beneficial roles of probiotics in metabolic regulation[117], their clinical efficacy in T2DM remains inconsistent. A major limitation lies in the strain-specific and context-dependent effects of probiotic supplementation, which result in substantial heterogeneity across clinical studies. Baseline interindividual differences in gut microbiota composition further contribute to variable therapeutic responses. These findings indicate that probiotic interventions should shift from a generalized approach toward precision, microbiome-stratified therapeutic strategies rather than uniform administration.

Limitations of FMT

FMT has emerged as a promising microbiota-targeted intervention[207]; however, its clinical translation in T2DM is constrained by several critical challenges. First, donor-dependent variability significantly influences microbial engraftment and therapeutic outcomes. Second, the absence of standardized donor screening criteria and transplantation protocols limits reproducibility across studies. Third, the long-term safety profile of FMT in metabolic diseases remains insufficiently characterized, particularly regarding metabolic and immunological consequences. Collectively, these limitations highlight the need for standardized and rigorously controlled FMT frameworks before widespread clinical implementation.

Limitations of TCM

Although TCM exhibits promising microbiota-modulating potential, several translational barriers remain. A primary limitation is the poor systemic bioavailability of many bioactive compounds, which complicates pharmacokinetic interpretation and dose standardization. In addition, variability in herbal composition due to cultivation conditions, processing methods, and formulation differences introduces inter batch inconsistency, limiting reproducibility. Incomplete characterization of pharmacodynamic mechanisms and host-microbiota interactions hinders the establishment of standardized therapeutic protocols in clinical settings.

Need for microbiota-stratified and function-oriented clinical trials

Future research should move beyond descriptive microbiota profiling toward functionally and clinically stratified study designs. Integrating multiomics approaches, including metagenomics, metabolomics, and transcriptomics, will be essential to link microbial taxa with functional metabolic outputs and host signaling pathways. Moreover, the development of microbiota-stratified RCT is critical to account for interindividual variability in microbial composition and treatment responsiveness. Future studies should prioritize functional endpoints (e.g., SCFAs, bile acids, and inflammatory markers) rather than relying solely on taxonomic changes.

Translational challenges and systems-level integration

A major translational challenge in microbiota-based therapy lies in the lack of standardized frameworks for integrating dietary, pharmacological, and traditional interventions. While each modality individually demonstrates metabolic benefits, their interactions within the gut-microbiota-host axis remain insufficiently defined. Establishing systems-level models that incorporate metabolic, immunological, and microbial networks will be essential for advancing precision microbiome medicine in T2DM.

CONCLUSION

With rapid advances in metagenomics and metabolomics, a growing body of evidence has established the gut microbiota as a biologically relevant regulator of host glucose metabolism rather than a passive correlate of T2DM. Large population-based studies have consistently demonstrated that T2DM is associated with reproducible alterations in gut microbial composition and functional capacity, particularly involving SCFA production[208], bile acid metabolism[209], and inflammatory signaling pathways[12]. In this review, we summarized current knowledge on how specific microbial functions contribute to progression or attenuation of T2DM and outlined emerging interventions that target the gut microbiota across nutritional, pharmacological, and TCM frameworks. In addition to blood glucose regulation, the impact of host-microbiota interactions on cardiovascular and cerebrovascular health is receiving increasing attention. A growing body of evidence suggests that gut microbiota dysbiosis leads to systemic low-grade inflammation, dyslipidemia, and endothelial dysfunction pathological mechanisms common to T2DM and cardiovascular/cerebrovascular diseases[210]. Diet-induced modulation of the microbiota can influence cardiovascular health. Therefore, interventions targeting the microbiota including dietary adjustments, drug treatments, and TCM may provide additional cardiometabolic and neurovascular protective effects beyond simple blood glucose control through overlapping pathways involving inflammation and lipid metabolism. Despite this progress, several important challenges remain. First, many microbiota signatures reported in T2DM are influenced by confounding factors, especially antidiabetic medications such as metformin, which can profoundly reshape gut microbial communities and obscure disease-specific associations[211]. Second, most studies remain descriptive, and only a limited number of microbial taxa or metabolites have been functionally validated in human interventional settings. Even for approaches with mechanistic promise, such as FMT, long-term efficacy, safety, and reproducibility remain insufficiently characterized[212]. To address these issues, future research should prioritize functional and mechanism-oriented strategies over taxonomic cataloging. This includes integrating multiomics approaches to link microbial genes, metabolites, and host signaling pathways, as well as designing longitudinal and microbiota-stratified clinical trials with standardized dietary and pharmacological controls. In parallel, defining minimal microbial consortia or key metabolic pathways may provide a more tractable and safer alternative to broad-spectrum microbiota modulation. In clinical practice, T2DM management increasingly relies on combined therapeutic modalities. Accordingly, microbiota-targeted interventions are unlikely to function as stand-alone treatments but may serve as effective adjuncts to existing pharmacological and lifestyle-based strategies. The integration of dietary modulation, microbiota-informed drug use, and TCM approaches may offer synergistic benefits by acting on complementary host-microorganism pathways. We anticipate that future T2DM therapies will move toward precision, function-driven, and combination-based strategies that harness the gut microbiota to improve metabolic health while minimizing unintended systemic effects.