In patients with diabetes mellitus, chronic hyperglycemia causes significant changes in the gut microenvironment, resulting in microbial dysbiosis and disruption of the homeostatic balance between anti-inflammatory and pro-inflammatory bacterial populations. This pathological cascade ultimately leads to systemic inflammatory responses through multiple pathways. Patients with T2DM show distinct gut microbiota composition compared to healthy controls(HC), with significantly reduced alpha diversity. T2DM patients have decreased abundance of anti-inflammatory bacteria including Roseburia, Lachnospira, Coprococcus, Phascolarctobacterium, and Anaerostipes, while demonstrating increased levels of the pro-inflammatory Methanobrevibacter (14). Elevated pro-inflammatory bacterial populations disrupt intestinal mucosal integrity, impairing gut barrier function. This impairment enables bacterial components and metabolites to enter circulation, inducing chronic systemic inflammation. The resulting inflammatory cascade directly contributes to the development of T2DM (15) (refer to Figure 1 ). Clinical studies have demonstrated that the pathogenesis of T2DM is closely linked to elevated serum levels of multiple proinflammatory cytokines and chemokines. In diabetic patients, peripheral blood levels of inflammatory markers such as ICAM-1, IL-6, IL-8, MCP-1, IL-1β, Vascular Cell Adhesion Molecule-1 (VCAM-1), and Vascular Endothelial Growth Factor (VEGF) are significantly higher than those in healthy individuals. These inflammatory factors circulate in the bloodstream and act on various tissues and organs, thereby triggering a systemic inflammatory response (16).

Within the gut microbiota’s complex regulation of inflammation, Roseburia species, especially Roseburia intestinalis, display multifaceted anti-inflammatory effects mediated primarily through their production of butyrate, a metabolite that effectively inhibits NF-κB signaling pathway activation. Furthermore, Roseburia intestinalis promotes the production of regulatory T cells (Tregs), upregulates transforming growth factor-β (TGF-β) expression, and enhances secretion of the anti-inflammatory cytokine IL-10. Moreover, it potently inhibits the secretion of pro-inflammatory cytokines, including interleukin-17 (IL-17) and interferon-gamma (IFN-γ), thereby exerting significant anti-inflammatory effects (17, 18). Additionally, Bacteroides fragilis, Akkermansia muciniphila, and Lactobacillus species (Lactobacillus plantarum and Lactobacillus casei) have been shown to markedly enhance the production of anti-inflammatory cytokines such as interleukin-10 (IL-10), collectively promoting intestinal immune homeostasis (18–22).

Lipopolysaccharide (LPS) is an endotoxin that is mainly found in the cell wall of Gram-negative bacteria. Studies have found that individuals with T2DM have higher levels of LPS in their bloodstream compared to HC. This phenomenon is associated with gut microbiota dysbiosis (23, 24). In the event of dysbiosis of the gut microbiota, certain intestinal bacteria (e.g. Desulfovibrionaceae) will affect the production of LPS (25). Toll-like Receptor 4 (TLR4) represents an essential receptor for recognizing LPS, which plays a critical role in the host’s immune response to bacterial infection (26). LPS activates the TLR4/Myeloid differentiation primary response protein 88(MyD88)/NF-κB signaling cascade in macrophages, triggering synthesis of pro-inflammatory mediators including TNF-α, IL-6, IL-1β, and inducible nitric oxide synthase (iNOS), which collectively drive the inflammatory response (refer to Figure 2 ). This inflammatory cascade activation results in the stimulation of serine kinases, specifically c-Jun N-terminal kinase (JNK) and IκB kinase (IKK). These kinases subsequently phosphorylate serine residues on Insulin Receptor Substrate (IRS), a critical component of the insulin receptor pathway. This post-translational modification impairs insulin signaling transduction, ultimately leading to the development of cellular insulin resistance (27). Furthermore, LPS has been demonstrated to activate the NOD-like receptor protein 3 (NLRP3) inflammasome complex, leading to the maturation and secretion of pro-inflammatory cytokines, particularly interleukin-1β (IL-1β) and interleukin-18 (IL-18). Releasing these cytokines will exacerbate insulin resistance, impair pancreatic β-cell function, and contribute to systemic inflammation (28, 29). Concurrently, LPS has been shown to induce structural and functional alterations in intestinal epithelial tight junctions by disrupting the organization and distribution of key tight junction proteins. The compromised barrier function facilitates the translocation of bacterial metabolites and endotoxins into the systemic circulation, thereby initiating a cascade of events that culminate in metabolic endotoxemia (30, 31) (refer to Figure 1 ).

Short-chain fatty acids (SCFAs) are metabolites generated by the gut microbiota during the fermentation of dietary fibers, including acetate, propionate, and butyrate. They regulate the host’s immune response, energy metabolism, and intestinal health (32). Zhao et al., through fecal SCFA analysis, demonstrated that SCFA levels were significantly lower in the T2DM group than in the healthy group (33). SCFAs exert anti-inflammatory properties through the suppression of pro-inflammatory mediators, including cytokines (TNF-α, IL-6, and IL-1β) as well as chemokines such as C-C motif ligand 2 (CCL2), C-C motif ligand 8 (CCL8), C-X-C motif ligand 5 (CXCL5), C-X-C motif ligand 8 (CXCL8), and C-X-C motif ligand 10 (CXCL10). These immunomodulatory effects are primarily mediated through the inhibition of the NF-κB p65 signaling pathway in immature histone H4 (H4) intestinal epithelial cells. The downregulation of this critical inflammatory pathway contributes to attenuating intestinal inflammation (34). In addition, Researchers have demonstrated that SCFAs regulate immune cell activity by activating G protein-coupled receptors (GPCRs), such as G Protein-Coupled Receptor 41 (GPR41) and G Protein-Coupled Receptor 43 (GPR43). These receptors suppress oxidative stress and abnormal activation of the NF-κB pathway, thereby inhibiting intestinal endotoxemia and inflammatory responses (35, 36). Diminished levels of SCFAs disrupt immune homeostasis, thereby enhancing the secretion of inflammatory cytokines and initiating a systemic inflammatory cascade (refer to Figure 2 ).

Bile Acids(BAs) play a crucial role in regulating the gut microbiota and host metabolism. Under healthy conditions, the synthesis, secretion, and reabsorption of BAs are closely associated with the composition and function of the gut microbiota, forming a dynamic balance between the two. However, in diabetes, gut microbiota dysbiosis disrupts the normal metabolic processes of BAs. Recent studies have revealed new roles of BAs in glucose metabolism (37), lipid metabolism (38),energy homeostasis (39), and systemic inflammatory responses. Studies have shown that in the fed state, the total BAs concentration is higher in patients with T2DM than in non-diabetic individuals (37). The study by Wang et al. demonstrated a significant upregulation of bacteria associated with BAs metabolism, such as Lactobacillus and Bifidobacterium, in patients with T2DM. These microbial populations are enriched with bile salt hydrolase (BSH), which plays a crucial role in BAs deconjugation. Multi-omics analysis further revealed that these bacteria are significantly associated with inflammatory genes, including MYD88 and NF-κB. Consistent with these findings, alterations in related inflammatory genes were also observed in the livers of T2DM mice, underscoring the correlation between BAs metabolism and inflammation (40). These results suggest that changes in the gut microbiota of diabetic patients may modulate inflammatory responses through their impact on bile acid metabolism.

In the diabetic state, dysbiosis of the gut microbiota and changes in its metabolites destroy the intestinal barrier function and increase intestinal permeability, leading to the release of bacterial metabolites (such as LPS) into the blood circulation, activating the immune system and triggering systemic inflammation. This inflammatory response is not only limited to the intestine, but also spreads to organs such as the liver, adipose tissue, and retina, affecting metabolic function and increasing the risk of DR and other related complications (41).

The gut microbiota composition demonstrated significant abundance variations between DR and T2DM patients. At the phylum level, DR patients exhibited reduced Firmicutes abundance with increased Bacteroidetes and Desulfobacterota levels compared to T2DM patients. At the family level, Pasteurellaceae abundance decreased in DR patients, while Eubacteriaceae showed an increasing trend (42). At the genus level, in DR patients, the abundance of anti-inflammatory bacteria such as Faecalibacterium, Bifidobacterium, Ruminococcus, Turicibacter, Streptococcus, Lactobacillus, and Butyricimonas was significantly reduced, while that of pro-inflammatory bacteria such as Shigella was significantly increased (14). Furthermore, Zhou et al. reported a significant increase in Prevotella abundance among DR patients (43). Studies have shown that Prevotella contributes to the pathogenesis of chronic inflammatory diseases through TLR2-mediated mechanisms. Prevotella activation of Toll-like receptor 2 (TLR2) stimulates antigen-presenting cells to produce IL-23 and IL-1, thereby promoting Th17 cell-mediated inflammatory responses (44). As the primary effector molecule of Th17 cells, interleukin-17A (IL-17A) contributes to retinal endothelial cell death through the IL-17A/IL-17 receptor (IL-17R) signaling axis. This pathway mediates its effects through sequential activation of the Act1 adaptor protein and Fas-associated death domain (FADD), ultimately triggering caspase-dependent apoptotic pathways in retinal vascular endothelial cells (45–47). These molecular mechanisms suggest that Prevotella enrichment in DR patients may exacerbate retinal tissue damage through Th17-mediated inflammatory processes.

Alterations in gut microbiota composition in diabetic patients have been implicated in the pathogenesis of systemic inflammation, which subsequently contributes to retinal damage in diabetic individuals. In a diabetic rat model, Di et al. demonstrated a significant correlation between increased abundance of Enterobacterial species and elevated serum levels of IL-6. Furthermore, Prevotellaceae species have been identified to show positive correlations with increased concentrations of IL-8, VEGF, and IL-1β. Similarly, Bacteroides species have been associated with upregulated levels of both IL-8 and IL-1β. Klebsiella species have been specifically linked to elevated VEGF levels in the systemic circulation. Faecalibaculum and Corynebacterium were respectively related to the decrease in the levels of inflammatory factors, IL-1β and MCP-1 (25). Moreover, experimental evidence indicates that diminished abundance of Bifidobacterium species is associated with upregulated expression of inflammatory mediators, including IL-6, TNF-α, and IFN-γ, while simultaneously leading to significant downregulation of the anti-inflammatory cytokine IL-10 (16, 48). Hyperglycemia induces a significant upregulation of inflammatory mediators, including pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) and chemokines (MCP-1, IL-8). These molecular alterations activate critical signaling pathways like NF-κB and Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways, which subsequently trigger oxidative stress and initiate inflammatory cascades. The resulting inflammatory responses compromise BRB integrity, leading to increased vascular permeability and facilitating the transmigration of inflammatory mediators into retinal tissues. Concurrently, the upregulated pro-inflammatory factors stimulate vascular endothelial cells to secrete pro-angiogenic factors, thereby promoting pathological neovascularization. This persistent inflammatory-angiogenic interplay leads to progressive disruption of retinal architecture and function, ultimately contributing to the progression of DR (23, 49, 50).

Dysbiosis of the gut microbiota leads to impairment of intestinal barrier integrity, facilitating the translocation of intestinal metabolites including LPS, SCFAs, BAs, and trimethylamine N-oxide (TMAO) across the intestinal epithelium into systemic circulation. Following their systemic distribution, these microbial-derived metabolites may ultimately reach the retinal compartment, where they have the potential to modulate the functional activity of resident immune cells (particularly microglia and Müller cells) and vascular endothelial cells. This cascade of events subsequently induces localized inflammatory responses and contributes to the pathogenesis of retinal neurovascular damage.

Metformin exerts regulatory effects on the gut microbiota and metabolic products (79, 80). Studies by Cuesta-Zuluaga et al. revealed that in patients with T2DM receiving metformin treatment, the abundance of beneficial bacteria, such as Akkermansia muciniphila, as well as specific microbial populations capable of producing SCFAs, including Butyrivibrio, Bifidobacterium bifidum, Megasphaera, and Prevotella, was increased. the abundance of potentially pathogenic microbial taxa, such as Clostridiaceae 02d06, Oscillospira, and Barnesiellaceae, was reduced (71). Similarly, Wu et al. demonstrated that metformin treatment in T2DM patients led to an increased abundance of Escherichia and Bifidobacterium within the gut microbiota, while the abundance of Intestinibacter was decreased. Furthermore, metformin treatment not only significantly elevated the fecal concentrations of SCFAs, such as propionate and butyrate, but also affected the metabolism of BAs, thereby leading to an increase in the concentration of BAs in the blood (72). In conclusion, these findings suggest that metformin may exert its anti-inflammatory effects by promoting the production of these metabolites, thereby mitigating the pathological progression of DR and providing protective benefits to the retina.

GLP-1 is a peptide hormone secreted by intestinal L cells (81). It not only plays a role in regulating blood glucose levels but also modulates the composition and structure of the gut microbiota through activation of intestinal GLP-1 receptors (82). Liraglutide, a GLP-1 receptor agonist, has been shown to regulate the composition and function of the gut microbiota, reducing the Firmicutes-to-Bacteroidetes ratio. During treatment, liraglutide increases the abundance of beneficial bacteria, such as Bacteroides, Lachnospiraceae, probiotic species, and Bifidobacterium, which are capable of producing SCFAs. Concurrently, liraglutide reduces the relative abundance of opportunistic pathogens, including Prevotella species and Mollicutes. In addition, Liraglutide reduces circulating levels of insulin and IL-6 (73). Studies have revealed that semaglutide modulates the gut microbiota. In a db/db diabetic mouse model, treatment with semaglutide significantly enhanced the alpha diversity of the gut microbiota, with increased abundance of Alloprevotella and Alistipes, and decreased abundance of Ligilactobacillus and Lactobacillus. The elevated abundance of Alloprevotella and Alistipes is associated with enhanced production of SCFAs (74). Therefore, GLP-1 receptor agonists may exert protective effects against DR by modulating the composition of the gut microbiota and reducing the production of inflammatory mediators.

Dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, primarily lowers blood glucose levels by inhibiting SGLT2 in the kidneys, thereby reducing glucose reabsorption and promoting urinary glucose excretion. Beyond their glucose-lowering effects, SGLT2 inhibitors modulate the gut microbiota and their metabolic products, exerting beneficial effects on the host. Studies have demonstrated that treatment with dapagliflozin in diabetic mice leads to significant alterations in the gut microbiota, characterized by a reduced Firmicutes-to-Bacteroidetes ratio, a decreased abundance of Oscillospira, and an increased population of Akkermansia muciniphila (83). Studies have revealed that SGLT2 inhibitors reduce levels of the intermediate metabolite succinate while increasing butyrate levels in SCFAs (75). Succinate, by binding to its specific receptor GPR91, activates VEGF in retinal ganglion cells under hypoxic conditions, thereby promoting neovascularization (84). Therefore, SGLT2 inhibitors may exert protective effects against DR by modulating the gut microbiota, reducing succinate levels, and elevating butyrate levels.

Alpha-glucosidase inhibitors (α-GIs) primarily target the brush border of the upper small intestine, slowing carbohydrate catabolism and absorption through the inhibition of α-glucosidase activity (85). Studies have demonstrated that α-GIs not only directly regulate blood glucose levels but also confer indirect protective effects against DR by modulating the composition of the gut microbiota. Acarbose, a representative α-GI, has been shown to increase the abundance of culturable Bifidobacterium longum and Enterococcus faecalis, reduce the abundance of Enterobacteriaceae, and lower LPS levels in patients with T2DM following treatment (76). Acarbose administration induced alterations in the composition of the gut microbial community and the concentrations of SCFAs in mice. These modifications in the gut microbiota, coupled with the elevated levels of fecal SCFAs, collectively contributed to the extension of the mice’s lifespan (63). Consequently, α-GIs may exert a protective effect against DR through their regulatory influence on both the gut microbiota and gut metabolites.

In the field of exploring the treatment of DR, traditional Chinese medicine (TCM) has garnered increasing attention owing to its therapeutic advantages of multi-pathway and multi-target mechanisms. TCM formulations such as Sangzhi Alkaloid Tablets (SZ-A), Astragalus Polysaccharide (APS), Luotong Formula (LTF), and Compound Qilian Tablets (CQLT) have demonstrated potential therapeutic value for DR through their actions in modulating gut microbiota, reducing inflammatory mediators, and inhibiting inflammatory signaling pathways.

SZ - A, extracted from the traditional Chinese herbal medicine Morus alba L, has been proven to improve hyperglycemia in T2DM and has been approved for clinical diabetes treatment (86). Studies have shown that administration of SZ-A in diabetic KKAy mouse models enhances insulin sensitivity and stimulates the secretion of GLP-1 (25, 86). Additionally, SZ-A modulates the gut microbiota by increasing the relative abundance of beneficial microbial taxa, including Bacteroidaceae, Erysipelotrichaceae, Verrucomicrobia, Bacteroides, Faecalibaculum, and Allobaculum. However, it effectively reduces the proliferation of potentially pathogenic microorganisms, such as Rikenellaceae, Desulfovibrionaceae, Aerococcaceae, Alistipes, Desulfovibrio, and Aerococcus. Furthermore, SZ-A increases the concentrations of acetate and propionate in fecal matter while reducing serum endotoxin levels. It also downregulates the expression of multiple inflammatory mediators and chemokines, including IL-1β, IL-6, CCL4, and CCL5. Moreover, SZ-A inhibits the activation of the NF-κB signaling pathway, thereby attenuating inflammatory responses (25). Consequently, through its regulatory effects on gut microbiota composition and intestinal metabolites, coupled with its anti-inflammatory properties, SZ-A may exert an indirect beneficial impact on DR.

APS, a bioactive compound extracted from Astragalus membranaceus, exhibits significant regulatory effects on gut microbiota composition (87). Studies by Zhang et al. have demonstrated that APS treatment enhances the abundance of beneficial bacterial taxa, including Lactobacillus and Bifidobacterium, while reducing the levels of potentially pathogenic bacteria such as Enterobacteriaceae, Escherichia-Shigella, and Parabacteroides (77). Furthermore, APS has been shown to downregulate the expression of pro-inflammatory mediators, including TNF-α and IL-6 in serum (88). These cytokines play crucial roles in the pathogenesis of chronic inflammation and the progression of diabetes mellitus (87). In addition, APS enhances the abundance of beneficial bacterial taxa, including Enterobacteriaceae, Enterobacter, and Lactobacillus, thereby elevating the concentrations of SCFAs and further improving the intestinal microenvironment (77, 87). Further investigations by Liu et al. revealed that APS downregulates the expression of Kir2.1 protein in retinal Müller cells and suppresses the production of VEGF in these cells, thereby contributing to the prevention and treatment of DR (89). Consequently, APS may exert its protective effects against DR through multiple mechanisms, including modulation of gut microbiota, preservation of intestinal barrier integrity, inhibition of inflammatory responses, and direct actions on retinal Müller cells.

LTF, a traditional Chinese herbal formulation, is composed of Radix Astragali (Huangqi), Radix Salviae Miltiorrhizae (Danshen), Radix Notoginseng (Sanqi), Hirudo (Shuizhi powder), and Rhubarb (Dahuang). It is traditionally recognized for its properties of promoting blood circulation, resolving blood stasis, and unblocking meridians (90). Research has revealed that its therapeutic mechanisms extend beyond these traditional effects to include modulation of gut microbiota. Studies by Di et al. demonstrated that LTF not only exhibits hypoglycemic effects but also alters the gut microbiota composition in diabetic rats. Following LTF treatment, the α-diversity of the gut microbiota was markedly enhanced. Additionally, LTF increased the relative abundance of Firmicutes while reducing that of Bacteroidetes, resulting in an elevated Firmicutes-to-Bacteroidetes ratio. LTF treatment enhances the relative abundance of beneficial bacterial taxa, including Faecalibaculum and Corynebacterium, while reducing serum levels of pro-inflammatory mediators such as ICAM - 1, IL - 6, IL - 8, MCP - 1, VCAM - 1, VEGF, and IL - 1β. Furthermore, LTF attenuates retinal inflammation through inhibition of the NF-κB signaling pathway. Moreover, LTF administration reduces BRB permeability, increases retinal thickness, and ameliorates retinal microvascular damage (16). These findings suggest that LTF may exert preventive and therapeutic effects on the progression of DR through its modulation of gut microbiota and associated anti-inflammatory mechanisms.

CQLT, a traditional Chinese herbal formulation, is composed of Radix Astragali, Rehmannia glutinosa, Coptis chinensis, and Panax notoginseng. It is clinically used to treat symptoms associated with DR, including blurred vision, visual field loss, and vitreous hemorrhage. Recent advances in the understanding of DR pathogenesis have highlighted the pivotal role of gut microbiota in disease progression, with the therapeutic efficacy of CQLT being closely linked to its modulatory effects on gut microbiota. Studies by Jia et al. have demonstrated that CQLT modulates the abundance and diversity of gut microbiota, enhancing the relative abundance of beneficial bacterial taxa such as Akkermansia and Clostridium_sensu_stricto_1, while reducing the relative abundance of potentially pathogenic bacteria, including Blautia, Butyricimonas, Family_XIII_AD3011_group, and Negativibacillus, thereby improving gut microbiota composition. Furthermore, CQLT enhances intestinal metabolic function by regulating the levels of key metabolites, including L-glutamine, fructose-6-phosphate, and asparagine. The alterations in these metabolites are closely associated with critical metabolic pathways, including glycolysis/gluconeogenesis, alanine, aspartate and glutamate metabolism, and starch and sucrose metabolism, all of which play essential roles in maintaining retinal homeostasis. Additionally, CQLT inhibits retinal neuroinflammation by downregulating the expression of retinal nerve damage markers, such as glial fibrillary acidic protein (GFAP) and ionized calcium-binding adapter molecule 1 (Iba-1) (78). These findings suggest that CQLT may confer protective effects on retinal neurons in DR rats through its ability to modulate and improve gut microbiota composition.