The Investigation into Correlation between Type 2 Diabetes Mellitus and the Gut Microbiota

Shuran Liu, Alex Zhu^*

School of Nursing, Huazhong University of Science and Technology, Wuhan, China.

DOI: 10.4236/ojemd.2025.1511022                

Abstract

This study investigates the complex interactions between gut microbiota and the pathogenesis of type 2 diabetes mellitus (T2DM). T2DM, a prevalent metabolic disorder, is closely linked to both insulin resistance and inflammation, conditions that have been increasingly associated with gut microbial composition. Recent evidence suggests that dysbiosis—the imbalance in gut microbial populations—contributes to T2DM progression by altering short-chain fatty acid (SCFA) production, influencing bile acid metabolism, and increasing systemic inflammation through pathways such as endotoxemia and modulation of immune responses. This review analyzes the critical role of SCFAs, bile acids, and gut-brain axis signaling in metabolic regulation, focusing on their mechanisms of action in glucose homeostasis and insulin sensitivity. Furthermore, the potential of microbiome-targeted therapies, including probiotics, prebiotics, fecal microbiota transplantation (FMT), and innovative engineered bacterial treatments, is evaluated. While therapeutic interventions targeting gut microbiota demonstrate promise in improving T2DM outcomes, gaps remain in understanding optimal microbial compositions and long-term efficacy. This paper underscores the need for further research into the microbial ecology of T2DM and the development of personalized microbial therapies to mitigate the disorder’s complications.

Keywords

T2DM, Diabetes, Intestinal Flora, Microbe

1. Introduction

Type 2 diabetes mellitus (T2DM) is a complex chronic metabolic disease. Its global prevalence continues to rise and has become a major public health challenge [1]. The core feature of this disease lies in the progressive decline of the body’s ability to maintain blood glucose homeostasis. Its occurrence is due to the combined effect of genetic susceptibility and environmental factors, and it has significant multifactorial characteristics. The incidence of T2DM has been steadily increasing worldwide, both in developed and developing countries, affecting a wide range of people [2]. Although the exact etiology and pathogenesis of this disease have not been fully clarified, the current research consensus holds that insufficient insulin secretion and insulin resistance (IR) are its core pathophysiological basis. It is particularly worth noting that insulin resistance is closely related to obesity status, and obesity itself is the result of the complex interweaving of genetic background, lifestyle, and socio-economic factors [3].

Recent studies have emphasized the key role of the gut microbiota in the occurrence and development of type 2 diabetes mellitus (T2DM), revealing an important interaction between the gut microbiota ecosystem and the metabolic health of the host [4]-[10]. There are approximately 500 to 1,000 types of microorganisms colonizing the human intestinal tract, with a total cell count far exceeding that of the human body’s own cells (more than ten times). It is estimated to contain 10 to 14 bacteria and can be regarded as a complex “microbial organ”. The collective genetic material carried by these microbial communities, namely the “microbiome”, has a total number of genes that is more than 100 times that of the human nuclear genome [11].

Although the number of studies exploring the association between gut microbiota and type 2 diabetes mellitus (T2DM) is increasing, there is still a significant knowledge gap in our understanding of the specific mechanisms by which these microorganisms affect metabolic processes. For instance, although the associations between dietary patterns, gut microbiota composition, and type 2 diabetes mellitus (T2DM) have been well documented, there is still a lack of consensus in the academic community as to which specific microbial species or their metabolites have the greatest influence on the development of insulin resistance. Furthermore, existing studies often fail to fully consider the complex interactions between individual genetic factors and microbial diversity, as well as the influence of social determinants on dietary habits and the health status of the microbiome. Filling these research gaps is crucial for developing targeted intervention measures and individualized treatment strategies aimed at reducing the risk of T2DM and improving metabolic health [12].

2. The Crucial Role of Intestinal Flora in the Progression of T2DM

Intestinal flora, also known as gut microbiota, plays a crucial role in the progression of Type 2 Diabetes Mellitus (T2DM). The gut microbiota is a complex community of microorganisms living in the human digestive tract, and its composition and function are increasingly recognized as important factors in metabolic health and disease, including T2DM. When interpreting microbiota-diabetes associations, key confounders such as host genetics, dietary composition, and common medications (especially metformin and antibiotics) must be accounted for, as they independently influence both microbial composition and glucose homeostasis, potentially obscuring causal relationships. In this paper, these factors have been considered seriously.

2.1. Common Intestinal Flora and Its Classification

The human gastrointestinal tract harbors a vast microbial ecosystem dominated by bacteria, with biomass reaching 1 - 1.5 kg and cell counts approximating 10¹⁴—exceeding human somatic cells by an order of magnitude [6]. Although over 500 species may reside in the gut, only about 100 have been characterized, and more than 99% of total abundance is attributable to just 30 - 40 predominant species [13] (Figure 1). The community is dominated by four major phyla—Firmicutes (64%), Bacteroidetes (23%), Proteobacteria (8%), and Actinobacteria (3%)—which together constitute approximately 98% of the microbiota [12]. Functionally, these bacteria fall into three categories: commensal/protective, pathogenic, and opportunistic pathogens, with Firmicutes and Bacteroidetes hosting most functional groups [14].

Figure 1. The classification of intestinal flora and their basic function.

2.2. Potential Pathways of Intestinal Flora Effects on T2DM

The gut microbiota affects T2DM through multiple pathways, including inflammation, SCFA production, bile acid metabolism, and the gut-brain axis. Dysbiosis, or an imbalance in gut microbiota, can exacerbate insulin resistance, alter glucose metabolism, and promote systemic inflammation, all of which are critical factors in the progression of T2DM. Understanding these pathways highlights the potential for therapeutic interventions targeting gut microbiota to manage or prevent T2DM.

Short-Chain Fatty Acid (SCFA) Production

Short-chain fatty acids (SCFAs), alternatively termed volatile fatty acids, are low-molecular-weight carboxylates containing 1 - 6 carbon atoms. These compounds are principally synthesized within the human colon through anaerobic microbial fermentation of indigestible carbohydrates. The predominant SCFAs include acetate, propionate, and butyrate, which collectively represent the most abundant fractions. Key bacterial producers encompass Bacteroides, Clostridium, Bifidobacterium, Eubacterium, Streptococcus, and Peptostreptococcus species.

Growing research implicates SCFAs as significant modulators in type 2 diabetes mellitus (T2DM) pathogenesis (Figure 2). Experimental studies report diminished SCFA levels (acetate, propionate, butyrate) in high-fat-diet/streptozotocin-induced diabetic rodents compared to healthy controls [15] [16]. Clinically, fecal propionate and butyrate concentrations are markedly reduced in T2DM patients relative to healthy individuals, with acetate also demonstrating a non-significant decreasing trend [17]. Proposed mechanisms for SCFA-mediated effects on T2DM involve: Enhanced insulin secretion, Improved insulin sensitivity, Activation of intestinal gluconeogenesis, Increased energy expenditure, Attenuation of adiposity, and inflammatory responses.

Short-chain fatty acids (SCFAs) demonstrate modulatory effects on pancreatic insulin secretion, confer protection against dietary insulin resistance, and potentiate insulin sensitivity [18] [19]. Clinical evidence indicates inverse correlations between circulating concentrations of total SCFAs, acetate, and propionate with fasting insulin levels and HOMA-IR indices [20]. Experimental models reveal that SCFAs—notably propionate—enhance glucose-dependent insulin secretion while preserving β-cell integrity through suppression of apoptosis, stimulation of proliferation, and inhibition of trans-differentiation toward α-cell phenotypes [19] [21].

Butyrate administration demonstrates efficacy in improving insulin sensitivity and mitigating insulin resistance across murine models and human cohort studies [22] [23], with proposed mechanisms involving enhanced energy expenditure and mitochondrial biogenesis [22]. Intestinal gluconeogenesis (IGN) is the de novo synthesis of glucose from non-carbohydrate precursors within the enterocytes of the small intestinal mucosa. It is an endogenous metabolic process that contributes to systemic glucose homeostasis, independent of the liver and kidneys, the two principal organs traditionally associated with gluconeogenesis. It also contributes significantly to systemic glucose regulation. Butyrate and propionate activate IGN through distinct pathways—cAMP-mediated signaling and gut-brain neural circuits, respectively—leading to suppressed hepatic glucose output and improved glycemic control [24].

Figure 2. Possible pathways of intestinal flora effects on T2DM.

Six human G protein-coupled receptors (GPCRs, a large superfamily of integral membrane proteins characterized by a common architecture of seven transmembrane α-helices, which transduce extracellular signals into intracellular responses by activating heterotrimeric guanine nucleotide-binding proteins upon agonist binding) interact with SCFAs, including prominently expressed GPR41, GPR43, and GPR109a across immune cells, adipocytes, and neural tissues [25]. Ligand-specific activation occurs at: Propionate/butyrate-bound GPR41/GPR109a reduces cAMP, activating PKA and MAP kinases (ERK/p38); Acetate/butyrate/propionate-activated GPR43 similarly inhibits cAMP while stimulating PLCβ, Ca²⁺ mobilization, and PKC [26].

SCFAs (particularly acetate, propionate, butyrate) stimulate enteroendocrine L-cells to secrete PYY and GLP-1, and promote adipose leptin release via GPR41/43 activation [27]-[30]. Additionally, SCFAs elevate whole-body energy expenditure and lipid oxidation—demonstrated by colonic SCFA infusion increasing fat oxidation, resting energy expenditure, and PYY in overweight humans [31]. Dietary butyrate supplementation similarly enhances energy expenditure and confers resistance to diet-induced obesity in murine models [22].

Insulin Resistance and Inflammation

Perturbations in gut microbiota composition (dysbiosis) correlate with elevated intestinal permeability. This compromised barrier facilitates systemic translocation of bacterial endotoxins like lipopolysaccharides (LPS), triggering chronic low-grade inflammation. Such inflammation impairs insulin signaling cascades, thereby fostering insulin resistance—a central pathophysiological feature of T2DM.

Dysbiosis specifically reduces expression of intestinal tight junction proteins ZO-1 and occludin, which critically maintain barrier integrity by preventing paracellular passage of luminal macromolecules (including microbes and toxins). Additionally, it disrupts the dual-layered intestinal microbial barrier: Mucosa-adherent flora (primarily Bifidobacterium and Lactobacillus), Luminal flora (dominated by Escherichia coli and Enterococcus).

Concurrently, pathogenic bacteria colonize the intestinal mucosa unchecked. This barrier dysfunction may provoke bacterial translocation and endogenous infections, culminating in metabolic endotoxemia.

Endotoxins—notably LPS from Gram-negative bacterial outer membranes—enter circulation via dysbiosis-induced mechanisms: High-fat diets and other stressors alter microbial ecology (diminishing beneficial Bifidobacterium/Lactobacillus while expanding Gram-negative populations), increase intestinal permeability, and compromise barrier function. These shifts collectively enhance LPS production, absorption, and systemic dissemination. Within the circulation, LPS complexes with CD14 (a glycosylphosphatidylinositol-anchored receptor) and engages Toll-like receptor 4 (TLR4) on monocyte-macrophages. This interaction activates TLR4 and MAPK signaling pathways in skeletal muscle and adipose tissue, propagating inflammation and insulin resistance development.

Short-chain fatty acids (SCFAs) contribute to colonic acidification, restrict proliferation of pathogenic bacteria, stabilize water-electrolyte balance, and prevent intestinal dysregulation. Contemporary research confirms SCFAs’ capacity to attenuate proinflammatory cytokine production, facilitating mucosal repair and reducing colonic inflammation [32]-[35]. Intestinal dysbiosis diminishes SCFA biosynthesis, impairing anti-inflammatory responses and promoting inflammatory pathogenesis.

Type 2 diabetes mellitus (T2DM) progression is intrinsically linked to chronic low-grade inflammation, making inflammation modulation a therapeutic priority. Butyrate mitigates adipose-macrophage crosstalk-induced inflammation through suppressed lipolysis and inflammatory pathway inhibition [36]. Specifically, it significantly reduces: Tumor necrosis factor-alpha (TNF-α), Monocyte chemoattractant protein-1 (MCP-1), Interleukin-6 (IL-6), while inhibiting nuclear factor kappa-B (NF-κB) activation. Similarly, propionate demonstrates anti-inflammatory efficacy in adipose tissue, significantly downregulating inflammatory mediators including TNF-α and CC chemokine ligand 5 (CCL5) [37].

Modulation of Glucose Absorption and Metabolism

The gut microbiota regulates bile acid (BA, a kind of steroid-derived, amphipathic molecule synthesized in the liver from cholesterol that facilitates the emulsification, digestion, and absorption of dietary lipids and fat-soluble vitamins in the small intestine) profiles, subsequently influencing glucose metabolism through activation of nuclear receptors, including FXR and TGR5. Dysbiosis-induced alterations in BA composition can disrupt glucose homeostasis, contributing to hyperglycemia in T2DM.

Bile acids serve not only as primary biliary components but also as terminal metabolites of hepatic cholesterol catabolism. They facilitate fat and fat-soluble vitamin absorption/transport while functioning as signaling molecules that modulate energy metabolism and restrain bacterial overgrowth. Within the intestine, gut microbes transform conjugated BAs into secondary BAs via enzymatic reactions, yielding deoxycholic acid (DCA), lithocholic acid (LCA), ursodeoxycholic acid (UDCA), and rodent-specific ω-muricholic acid (ωMCA) [38]. Key bacterial genera involved include: Bacteroides, Clostridium, Lactobacillus, Bifidobacterium, and Listeria: Mediate BA deconjugation via bile salt hydrolases (BSH). Clostridium and Eubacterium: Generate secondary BAs through 7-α-dehydroxylation [39] [40]. Bacteroides, Eubacterium, Clostridium, Escherichia, and Eggerthella: Facilitate BA epimerization [39].

Most BAs (e.g., cholic acid/CA, chenodeoxycholic acid/CDCA, DCA, UDCA, αMCA, ωMCA) undergo enterohepatic recirculation via ileal reabsorption and portal venous return to the liver [39]. Crucially, gut flora convert primary BAs to secondary BAs, activating BA receptors [41]. This stimulates nuclear receptors (farnesoid X receptor/FXR, Takeda G-protein receptor 5/TGR5) that regulate: Hepatic BA synthesis, Intestinal BA reabsorption, lipid/glucose/energy metabolism [42] [43].

Additionally, BAs preserve intestinal barrier integrity, inhibiting bacterial translocation [44]. Consequently, dysbiosis reduces secondary BA production, impairing receptor activation and promoting glucose dysregulation in T2DM pathogenesis (Figure 2).

TGR5 represents one of the most critical bile acid receptors, widely expressed in multiple tissues, including intestinal and pancreatic epithelia. Its activation potency by bile acids follows the hierarchy: lithocholic acid (LCA) > deoxycholic acid (DCA) > chenodeoxycholic acid (CDCA) > cholic acid (CA) [45]. TGR5 agonism demonstrates therapeutic potential for type 2 diabetes mellitus (T2DM) management, exemplified by the significant glucose-lowering effects of high-dose TGR5 agonist SB-756050 in clinical trials [46]. The primary established mechanism involves TGR5-mediated potentiation of glucagon-like peptide-1 (GLP-1) secretion from intestinal L-cells [47]. Thomas et al. revealed this process involves elevated ATP/ADP ratios triggering subsequent intracellular calcium mobilization [48]. Beyond enteroendocrine cells, TGR5 activation in pancreatic α-cells stimulates proglucagon processing into GLP-1 and promotes its release [49]. The resultant GLP-1 acts on pancreatic β-cells to potentiate insulin secretion—a well-characterized pathway for glucose homeostasis restoration and T2DM amelioration [50].

FXR is another key receptor for bile acids (BAs) and is highly expressed in the liver, intestine, and kidneys. BAs is a natural ligand of FXR. Chenodeoxycholic acid (CDCA), deoxycholic acid (DCA), lithocholic acid (LCA), and cholic acid (CA) all belong to the high-affinity agonist ligands of FXR, among which CDCA has the strongest efficacy in activating FXR [51]. Multiple studies have pointed out that activating FXR is helpful for improving type 2 diabetes mellitus (T2DM). The research by Zhang et al. confirmed that FXR activation can enhance glycogen synthesis in the liver of diabetic mice and significantly improve their hyperglycemia and hyperlipidemia conditions [52]. Furthermore, studies have found that an intestinal-limiting FXR agonist (Fexaramine) can promote Browning of adipose tissue in mice, alleviate obesity, inflammation, and insulin resistance [53]. In terms of the mechanism of action, the activation of intestinal FXR can induce the release of fibroblast growth factor 15 (FGF15, which is FGF19 in the human body). This factor reaches hepatocytes through the portal vein and binds to the FGFR4/β Klotho receptor in the liver, thereby inhibiting the expression of CYP7A1. Ultimately, it reduces the synthesis of BAs in the liver [45] [51]. Meanwhile, FGF19 can also stimulate liver glycogen synthesis, but it does not promote adipogenesis [54]. Potthoff et al. found that FGF15/19 released from the small intestine inhibits hepatic gluconeogenesis by suppressing the CREB-PGC-1α pathway [55]. The apparent contradiction regarding FXR’s metabolic effects may stem from its tissue-specific functions, where intestinal FXR inhibition often improves glucose metabolism while hepatic FXR activation generally exerts beneficial systemic metabolic effects [56]. However, several studies have also shown that inhibiting FXR is beneficial for glucose metabolism, obesity, and diabetes. Intestinal selective inhibition of FXR exacerbates obesity-related metabolic dysfunction, including insulin resistance [57]. Another study revealed that the increase of taurine binding β-carnocholic acid (TβMCA) in the intestine would inhibit the intestinal FXR signal transduction, thereby reducing the synthesis of ceramides and further weakening liver gluconeogenesis [58]. Trabelsi et al. found that the deletion of FXR would increase the gene expression and secretion of glucagon-like peptide-1 (GLP-1), thereby improving glucose metabolism [59]. In addition, the treatment of ob/ob mice with colevilam (a bile acid chelating agent) can inhibit the FXR activity in intestinal L cells, promote the production and secretion of GLP-1, and improve blood glucose levels [56]. Recent studies have identified that the gut microbiota-GUDCA-gut FXR axis mediates the clinical benefits of metformin [59]. Specifically, the use of metformin in the treatment of newly diagnosed patients with type 2 diabetes mellitus (T2DM) leads to a decrease in the abundance of Bacteroides fragile and an increase in GUDCA levels. The latter further inhibits intestinal FXR, thereby improving metabolic dysfunction, including hyperglycemia.

A significant limitation in this area is the apparent dual role of FXR signaling in glucose metabolism, necessitating further research to clarify its context-dependent functions and therapeutic targeting potential.

3. The Damage and Associated Disease Induced by Gut Bacteria in T2DM

Diabetes is defined by chronically elevated blood glucose concentrations resulting from either deficient insulin secretion by pancreatic β-cells or reduced peripheral tissue responsiveness to insulin signaling [60]. Inadequately managed diabetes and concomitant metabolic dysfunctions—including dyslipidemia, heightened oxidative stress, and hypertension [61]—contribute to the development of both microvascular and macrovascular pathologies. Microvascular complications, involving damage to small-caliber vessels, manifest as diabetic nephropathy, neuropathy, and retinopathy. Conversely, macrovascular complications affecting large arteries comprise cerebrovascular disease, coronary artery disease, and peripheral vascular disease [62]. Furthermore, poorly regulated diabetes-driven macrovascular damage may precipitate congestive heart failure, dyslipidemia, stroke, systemic inflammation, increased adiposity, peripheral vascular impairment, and disturbances in electrolyte homeostasis [63].

Extensive research confirms a significant correlation between alterations in gut microbial profiles and diabetes pathogenesis. Specifically, dysbiosis—marked by disrupted Bacteroidetes-to-Firmicutes ratios—is associated with heightened intestinal permeability. This compromised barrier facilitates the translocation of bacterial metabolites, eliciting inflammatory cascades characteristic of diabetes. Conversely, several bacterial species demonstrate protective roles against diabetes development through the mitigation of proinflammatory mediators and the preservation of gut barrier function. Notably, Lactobacillus fermentum, Lactobacillus plantarum, Lactobacillus casei, Roseburia intestinalis, Akkermansia muciniphila, and Bacteroides fragilis collectively enhance glucose homeostasis and insulin sensitivity while suppressing proinflammatory cytokines. Pharmacological agents like metformin, a cornerstone of diabetes therapy, are recognized to alter gut microbiota composition. This suggests metformin’s therapeutic actions involve microbiota crosstalk through modulation of inflammatory pathways, glucose regulation, intestinal permeability, and enrichment of short-chain fatty acid (SCFA)-producing bacteria [64]. In diabetic patients with gut dysbiosis, metformin stimulates butyrate and propionate production, thereby promoting amino acid catabolism [65]. These microbial shifts, coupled with increased gastrointestinal Akkermansia abundance, potentially mediate metformin’s glucoregulatory benefits [66]. Chronic low-grade inflammation and oxidative stress—metabolic features linking gut dysbiosis to type 2 diabetes—also participate in diabetic complication initiation and progression [67] [68]. This interconnection underscores microbiota modulation as a promising therapeutic avenue for diabetes and its sequelae, which will be elaborated in subsequent sections.

3.1. Intestinal Flora and Diabetic Nephropathy

Diabetic nephropathy (DN, a progressive microvascular complication of diabetes mellitus, characterized histopathologically by glomerular basement membrane thickening, mesangial expansion, nodular glomerulosclerosis, and albuminuria, ultimately leading to a decline in glomerular filtration rate and end-stage renal disease) develops in nearly 40% of individuals with suboptimally managed diabetes [69], of whom approximately 20% necessitate hemodialysis intervention [70]. This pathology frequently progresses to end-stage renal disease (ESRD) and concomitant cardiovascular sequelae [71]. The rising incidence of DN and ESRD correlates strongly with modern lifestyle patterns and behavioral factors implicated in diabetes and hypertension pathogenesis [72] [73]. Emerging evidence indicates gut microbial dysbiosis may play a role in chronic kidney disease (CKD) development [74]. Notably, metabolites derived from gut bacteria influence both CKD initiation and advancement [75], while deteriorating renal function conversely worsens microbial imbalance—establishing a pathological feedback loop [76].

3.2. Intestinal Flora and Diabetic Retinopathy

In suboptimally controlled diabetes, elevated intraocular pressure and vascular glucose accumulation compromise visual function [77]. These pathological processes drive ocular microvascular complications, including cataract formation, glaucoma development, and retinopathy progression [78]. Diabetic retinopathy (DR, a progressive microvascular complication of diabetes mellitus characterized by retinal microvascular damage, including microaneurysms, intraretinal hemorrhages, capillary non-perfusion, and pathological neovascularization, which can lead to macular edema, vitreous hemorrhage, and retinal detachment, ultimately causing vision impairment and blindness)—a vision-threatening consequence of inadequate diabetes management—may ultimately progress to blindness [79]. Pathological features of DR include retinal microglial hyperactivation and immune cell infiltration into retinal tissues [80]. Moreover, amplified oxidative stress and inflammatory responses impair renin-angiotensin system (RAS) functionality, thereby potentiating metabolic dysregulation underlying conditions like DR [81]-[87]. Notably, gut microbial dysbiosis has been implicated in the pathogenesis of diabetic retinopathy.

Microbial communities exhibit site-specific compositional differences throughout the body, including ocular tissues. Whereas gut microbiota is predominantly colonized by Firmicutes and Bacteroidetes [88], the ocular surface microbiome is chiefly characterized by Proteobacteria and Actinobacteria [89] [90]. Collectively, these three phyla constitute over 87% of ocular microorganisms [91]. Dysbiosis in either intestinal or ocular surface microbiota correlates with various ophthalmic pathologies. Patients with diabetic retinopathy (DR) demonstrate significantly reduced proportions of Bacteroidetes and Actinobacteria relative to healthy controls. Concurrently, Acidaminococcus, Escherichia, and Enterobacter genera are substantially enriched in DR patients [92]. Recent investigations reveal decreased Mucoromycota filamentation in DR subjects compared to non-afflicted individuals. Similarly, among type 2 diabetics with DR, 12 of 18 microbial genera exhibit depletion [93]. Microbiota-derived metabolites—notably trimethylamine N-oxide (TMAO) from dietary choline—associate with DR pathogenesis. DR patients display elevated plasma TMAO and proinflammatory cytokines versus diabetics without retinopathy, with concentrations correlating with disease severity [94]. Microbiome analyses further identify marked Pasteurellaceae reduction in DR [95]. These collective findings implicate distinct compositional shifts in both gut bacterial and fungal microbiota in diabetic retinopathy development.

3.3. Intestinal Flora and Diabetic Neuropathy

Persistently unmanaged diabetes causes diabetic neuropathy—a neurodegenerative condition involving peripheral nerve damage that manifests as pain and sensory loss [96] [97]. Hallmark pathological features include substantially reduced peripheral innervation, heightened neuroinflammation, demyelination, axonal degeneration, and diminished neural regenerative potential [98]. Affecting ~50% of diabetic patients [97], this disorder impacts multiple physiological systems, contributing to cardiovascular dysfunction, gastrointestinal motility impairment (including gastroparesis), dyshidrosis, and endocrine disturbances. The pathogenesis of diabetic peripheral neuropathy involves interconnected mechanisms: oxidative stress, polyol pathway hyperactivation, and inflammatory cascades [99] [100]. Insulin resistance further contributes to peripheral neuropathic development. Despite being a principal complication of diabetes mellitus, the complete pathomechanisms underlying peripheral diabetic neuropathy remain incompletely elucidated.

Diabetic neuropathy correlates with disrupted gut microbial diversity and elevated pathogenic abundance [101]. Comparative assessment of gut microbiota among diabetic neuropathy patients, non-neuropathic diabetics, and healthy controls demonstrated increased Firmicutes and Actinobacteria, coupled with reduced Bacteroidetes in neuropathy subjects relative to both comparator cohorts. At genus resolution, Bacteroides and Faecalibacterium exhibited depletion, while Escherichia-Shigella, Lachnoclostridium, Blautia, Megasphaera, and Ruminococcus torques demonstrated enrichment. These microbial perturbations may arise from the pathophysiology of insulin resistance. Notably, Megasphaera abundance directly associates with Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) scores in diabetic neuropathy patients, indicating an insulin resistance-peripheral neuropathy nexus [101].

3.4. Intestinal Flora and Cerebrovascular Disease

Globally, stroke represents a predominant contributor to disability, with diabetes mellitus constituting a significant risk factor [102]. Suboptimal glycemic control exacerbates cerebrovascular disease progression and elevates mortality [103]. Emerging evidence links gut microbial dysbiosis to stroke occurrence [104], potentially mediated through microbiota’s endocrine, neural, and immunomodulatory interactions with the central nervous system that directly modulate neurochemistry [105].

Trimethylamine-N-oxide (TMAO), previously referenced, remains extensively investigated in gut microbiota-stroke pathophysiology. This metabolite originates from phosphatidylcholine and L-carnitine conversion to trimethylamine, followed by hepatic oxidation via flavin monooxygenases [106]. Although associations between TMAO, atherosclerosis, and stroke risk are established, the mechanistic underpinnings remain incompletely characterized. TMAO concentrations significantly correlate with proinflammatory intermediate monocytes, potentially promoting monocyte-mediated inflammatory responses [107]. Additional proposed pathways connecting TMAO to cerebrovascular events include: Potentiation of platelet hyperreactivity [108], disruption of cholesterol homeostasis [109], and acceleration of foam cell formation [110]. TMAO further associates with established ischemic stroke risk factors, including atrial fibrillation [111] and diabetes mellitus [112].

3.5. Intestinal Flora and Coronary Heart Disease

Nowadays, coronary artery disease (CAD) represents the primary contributor to disease burden and mortality, while also serving as a crucial prognostic indicator for long-term outcomes in diabetic patients. Individuals with diabetes and concomitant heart disease exhibit a 2- to 4-fold elevated mortality risk [113]. Substantial evidence confirms gut microbiota’s pivotal involvement in fundamental metabolic pathways—particularly cholesterol and uric acid homeostasis—while concurrently modulating oxidative stress and inflammatory cascades through bioactive metabolites implicated in atherogenesis and coronary heart disease pathogenesis [114].

Overall, while associations between gut dysbiosis and various T2DM complications are increasingly established, the current evidence is largely correlative, and definitive causal mechanisms, as well as the therapeutic potential of targeting these microbial pathways, require further rigorous investigation (Figure 3).

Figure 3. The physiological changes induced by gut bacteria in T2DM are classified by systems.

4. Management and Treatment of Diabetes in Relation to Gut Microbiota

Gut microbiota modulation offers promising therapeutic avenues for diabetes management. Fecal microbiota transplantation (FMT) demonstrates potential for enhancing insulin sensitivity, though outcomes exhibit interstudy variability and long-term efficacy remains undetermined. Metformin’s glucose-regulating effects are partially mediated by microbial compositional shifts, while probiotics, prebiotics, and their synergistic combinations (symbiotics) collectively improve glycemic regulation and attenuate inflammatory responses. Dietary interventions like intermittent fasting (IF) and fasting-mimicking diets (FMDs) may ameliorate diabetic parameters through gut microbial restructuring. Novel biotherapeutic approaches—including genetically engineered bacteria and bacteriophage-based therapies—represent precision-targeted modalities for future diabetes interventions.

4.1. Fecal Microbiota Transplantation (FMT)

Fecal microbiota transplantation (FMT) has emerged as a significant investigative modality in gut microbiome research, garnering substantial attention for elucidating microbial roles across disease states. While most clinical trials have prioritized Clostridium difficile infections with favorable outcomes [115] [116], this foundation has prompted exploration of FMT as a therapeutic intervention for type 2 diabetes (T2D) [117]. Rodent studies demonstrate notable metabolic improvements following microbiota transfer: MyD88-deficient NOD mice exhibited enhanced insulin sensitivity [118]; db/db diabetic mice receiving microbiota from healthy Chinese donors showed reduced fasting glycemia [119]; Germ-free murine models transplanted with microbiota from metformin-treated patients developed improved glucose tolerance [120]. Preliminary human studies suggest lean-donor FMT may boost insulin sensitivity, potentially mediated by enrichment of butyrate-producing taxa [117]. In metabolic syndrome patients, lean-donor FMT outperformed autologous transplantation in male recipients, with insulin sensitivity enhancements observed at 6-week follow-up [121]. Contrastingly, FMT from vegan donors—despite distinctive microbial signatures [122]—failed to reduce recipient TMAO levels [123], underscoring outcome variability. The intervention’s long-term efficacy, safety profile, and sustained clinical effects remain inadequately characterized, warranting expanded investigation. A study found that repeated FMT treatments, especially when combined with lifestyle intervention, led to a significantly higher proportion of patients acquiring beneficial donor microbiota compared to the control group. This successful engraftment resulted in specific beneficial changes, such as an increase in butyrate-producing bacteria, and was associated with clinical improvements, including reduced cholesterol and liver stiffness.

4.2. Anti-Diabetic Drugs

Metformin represents a cornerstone therapeutic for type 2 diabetes (T2D), with emerging evidence implicating gut microbiota in its antihyperglycemic mechanism. The gut’s essential role is highlighted by observations that intravenous metformin administration—unlike oral delivery—fails to reduce hyperglycemia, underscoring enteric microbial involvement in its efficacy [124]. Metformin consistently restructures gut microbial communities in both preclinical models and humans, driving compositional shifts toward healthier profiles [121] [125] [126]. Notably, these alterations occur irrespective of glycemic outcomes, suggesting microbiota remodeling represents a glucose-independent effect. Specific taxonomic changes include: Enriched taxa: Akkermansia muciniphila, Bifidobacterium bifidum, Escherichia spp., Lactobacillus spp., Shigella spp. Depleted taxa: Clostridium spp., Intestinibacter spp. [121] [127] [128]. These compositional shifts associate with functional modifications in short-chain fatty acid (SCFA) biosynthetic pathways—particularly butyrate and propionate production [129] [130]. Metformin further enhances metabolic function through: Bile acid metabolism regulation, Gut barrier fortification, Endotoxemia reduction, Stimulated GLP-1 and PYY secretion [131]. Additionally, it lowers circulating TMAO by suppressing trimethylamine-producing bacteria [132]. Transfer of metformin-modified microbiota confers metabolic benefits to recipient animals, demonstrating therapeutic transmissibility [121]. Contradictory evidence exists regarding microbiota dependency: microbiota ablation failed to abolish metformin’s T2D benefits in some models [133]. While microbial contributions remain subject to ongoing debate, metformin’s intrinsic anti-inflammatory properties may independently mediate therapeutic effects.

4.3. Probiotics

Probiotics, live microorganisms that confer health benefits, have attracted attention in T2D management, although clinical studies remain limited. Preliminary findings suggest that altering gut microbiota composition via probiotic supplementation may improve T2D outcomes by reducing inflammation, intestinal permeability, and oxidative stress. Common probiotics include Bifidobacterium longum subsp. infantis, Lactobacillus, Streptococcus, Pediococcus, and Lactococcus species [134]. Several species, such as L. gasseri, Lactobacillus helveticus, Lactobacillus casei, and Bifidobacterium bifidum, have been shown to lower fasting blood glucose and HbA1c levels [135]-[137]. Probiotics exhibit antioxidant and immunomodulatory properties by mitigating oxidative stress and inflammatory cytokines, which may help reduce blood glucose levels and T2D risk [138]. A recent meta-analysis revealed that probiotic supplementation significantly improves fasting blood glucose, HbA1c levels, and insulin resistance. Therefore, probiotics may serve as a complementary strategy to pharmacological treatments and lifestyle interventions for managing T2D [139] [140].

4.4. Prebiotics

Prebiotics constitute indigestible dietary substrates that confer host benefits through selective stimulation of beneficial gut microorganisms [141]. Inulin—an extensively researched prebiotic—improves glycemic regulation by stimulating colonic GLP-1 secretion and suppressing plasma ghrelin in preclinical models [142]. Nevertheless, direct effects of inulin supplementation on human type 2 diabetes (T2D) demonstrate inconsistent clinical evidence. Divergent findings exist: certain studies report reductions in fasting glucose, HbA1c, and inflammatory markers among T2D patients, while others show negligible metabolic impact. Beyond glycemic modulation, inulin and similar prebiotics modify gut microbial ecology by enriching beneficial taxa, including Bifidobacterium and Bacteroides. Synergistic combinations of prebiotics with probiotics (termed symbiotics) potentiate beneficial effects beyond monotherapeutic approaches. Research indicates specific probiotic-inulin pairings elevate butyrate generation beyond isolated interventions. Clinically, symbiotic formulations improve fasting glycemia and HbA1c levels, suggesting potential for T2D risk mitigation.

4.5. Intermittent Fasting (IF)

Intermittent fasting (IF), defined by cyclic caloric restriction, extends longevity and attenuates age-related disease risk—including type 2 diabetes (T2D)—in experimental models [143]. Preclinical studies demonstrate enhancements in body composition, glycemic control, and inflammatory markers, with gut microbiota mediating these benefits [144] [145]. Human evidence, however, exhibits limited consensus. Recent murine research demonstrated that IF restructured gut microbial communities in diabetic models, enriching beneficial taxa while depleting pathogenic organisms [146]. This microbial reorganization correlated with enhanced glycemic regulation and insulin sensitivity. Fasting-mimicking diets (FMDs)—designed to pharmacologically emulate IF effects—similarly demonstrated capacity to reconstruct gut microbiota and improve insulin responsiveness. Collectively, these findings propose that IF may ameliorate T2D pathophysiology through microbiota modulation, though longitudinal human trials are required to establish sustained efficacy.

4.6. Engineering Bacteria and Phages

Synthetic biology has enabled the engineering of bacteria for therapeutic purposes. For example, engineered *Lactobacillus reuteri* can produce interleukin-22 (IL-22), enhancing gut defense mechanisms and providing resistance against bacterial infections [147]. Engineered *Lactobacillus gasseri* secreting GLP-1 has shown promise in lowering blood glucose in diabetic rats. Similarly, *Escherichia coli* modified to secrete GLP-1 or PDX-1 can induce insulin secretion in response to glucose [148]. Bacteriophages, which specifically target bacteria, are also being explored as tools to manipulate gut microbiota [149]. Fecal virome transplantation has been shown to alter gut microbiota composition and improve metabolic outcomes, suggesting a potential role for phages in T2D management [150]. These approaches hold promise for the development of targeted microbial therapies for T2D in future clinical applications.

Overall, while these microbiota-targeting interventions show considerable promise, their clinical translation is often constrained by limited large-scale human trials, incomplete understanding of underlying mechanisms, and interindividual variability in treatment responses [151].

Another clinical study shows that Fecal Microbiota Transplantation (FMT) demonstrates a direct and beneficial impact on type 2 diabetes (T2D) by significantly improving insulin resistance (HOMA-IR) and reducing body mass index (BMI) in patients. The engraftment of donor microbiota successfully altered the gut microbial community, increasing its diversity and showing a significant correlation with clinical improvements. Notably, specific bacteria that colonized after FMT were negatively associated with insulin resistance, underscoring a mechanistic link between microbiota changes and T2D metabolic enhancement [152].

5. Conclusion

This study highlights the significant influence of gut microbiota on insulin resistance, glucose metabolism, and inflammation in T2DM, exploring therapies like fecal microbiota transplantation (FMT), probiotics, prebiotics, and metformin. While these approaches show potential for improving insulin sensitivity and managing glycemic levels, inconsistencies in results and long-term effects suggest the need for more comprehensive research. Future research should focus on large-scale, longitudinal human studies to better understand the sustained impacts of gut microbiota interventions, the optimal compositions of beneficial bacteria, and the integration of personalized microbiome-based therapies for diabetes management. Additionally, investigations into the role of engineered bacteria and phages could provide targeted approaches to restoring healthy microbiota and mitigating complications associated with T2DM.

Authors’ Contributions

Shuran Liu contributed mostly to this work; Shuran Liu conceptualized and designed the study, created the artwork, supervised, and made critical revisions, conducted the literature review, did the analysis, interpretation of data, and drafted the original manuscript; Alex Zhu finished the total abstract of the paper. All authors prepared and approved the submitted version.

NOTES

*Corresponding author.

Conflicts of Interest

The authors declare no conflicts of interest regarding the publication of this paper.

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