Significant differences exist in the taxonomic composition of the gut microbiota between individuals with AMD and healthy subjects [53]. Clinical studies utilizing techniques such as 16S rRNA gene sequencing have revealed significant alterations in the gut microbiota of patients with AMD compared to healthy controls. A prominent finding is an increased Firmicutes/Bacteroidetes (F/B) ratio, which is considered a hallmark of gut dysbiosis [54]. The rise in Firmicutes abundance may contribute to elevated systemic inflammation in AMD patients, whereas the decrease in Bacteroidetes could compromise intestinal barrier integrity and disrupt nutrient metabolism [55]. Through metagenomic sequencing, Xue et al. identified additional features of gut microbial dysbiosis in AMD, including reduced alpha diversity, a decreased F/B ratio, and impaired activity in three degradation pathways: N-acetylneuraminate degradation, glycerol degradation to butanol, and glycogen degradation I. Notably, this study also provided the first evidence linking AMD to intestinal phage dysbiosis, identifying Bacteroidaceae as the primary host for AMD-associated phages. Collectively, these microbial alterations may promote increased intestinal permeability and bacterial translocation, thereby accelerating the formation and progression of vitreous deposits and RPE abnormalities [56]. Li et al. conducted gut microbiota and fecal metabolomic analyses in a laser-induced CNV mouse model alongside normal controls. Their findings revealed significant alterations in the gut microbiota of CNV mice, characterized by a marked upregulation of Candidatus Saccharimonas and relatively lower abundances of the Prevotellaceae_NK3B31_group, Candidatus Soleaferrea, and Truepera. Fecal metabolomics identified 73 altered metabolites. Further analysis demonstrated a significant correlation between the Prevotellaceae_NK3B31_group and Candidatus Saccharimonas [57]. The differences in gut microbiome composition between patients with AMD and healthy controls are summarized in Table 2.

Gut microbiota-derived metabolites are highly diverse and play a significant role in the pathogenesis of AMD [58]. SCFAs, including acetate, propionate, and butyrate, are major products of dietary fiber fermentation by gut microbes. SCFAs regulate host metabolism and immune function through multiple pathways [59, 60]. In AMD, abnormal SCFA levels may disrupt retinal cell metabolism and inflammatory responses. For example, butyrate exerts anti-inflammatory effects by inhibiting the NF-κB signaling pathway and reducing the production of inflammatory cytokines. A reduction in butyrate-producing bacteria in AMD patients leads to decreased butyrate levels, which may attenuate its anti-inflammatory protection in the retina and thereby promote AMD progression.

Further supporting the therapeutic relevance of this axis, Zhang et al [61] demonstrated that metformin may exert protective effects in neovascular AMD by modulating the gut microbiota and the Gut-Eye axis. Specifically, metformin treatment significantly altered gut microbial composition, increasing the abundance of Bifidobacterium and Akkermansia, and elevated fecal concentrations of butyrate, other SCFAs, and Bile acids. These metabolites are considered key mediators of its protective effects: butyrate inhibits pathological angiogenesis via the TXNIP/VEGFR2 signaling pathway, while SCFAs activate the G-protein coupled receptors GPR41 and GPR43 on intestinal epithelial cells, subsequently triggering the MAPK pathway and promoting the secretion of chemokines and cytokines, which may ultimately modulate retinal inflammation and angiogenesis [62].

In addition, gut microbiota metabolize tryptophan into indole derivatives, such as indole-3-lactic acid and indole-3-propionic acid (IPA). These metabolites can activate the aryl hydrocarbon receptor (AHR), thereby regulating immune cell function and retinal tissue homeostasis, and influencing the development of ocular diseases [63].

The intestinal mucosal epithelium forms a physical barrier through tight junction proteins, such as occludin and claudin family proteins, which prevents gut bacteria and their metabolites from entering the systemic circulation. However, damage to this barrier—caused by factors such as gut dysbiosis, dietary insults, or oxidative stress—can lead to a “leaky gut” condition, resulting in increased intestinal permeability. Under conditions of “leaky gut,” bacteria and their metabolites, such as lipopolysaccharide (LPS), can translocate across the compromised intestinal mucosal barrier into the systemic circulation. As a key inflammatory trigger, LPS specifically binds to Toll-like receptor 4 (TLR4) expressed on immune cells—including monocytes and macrophages. This binding activates intracellular inflammatory signaling pathways, such as NF-κB, leading to the robust secretion of pro-inflammatory cytokines by these immune cells [64]. Among these cytokines, IL-6 amplifies the inflammatory cascade by activating the JAK-STAT signaling pathway and promotes vascular endothelial cell activation [65]. Meanwhile, TNF-α directly induces apoptosis and enhances the expression of other inflammatory mediators, such as the chemokine CCL2, thereby further recruiting inflammatory cells to the site [66].

These LPS-induced pro-inflammatory cytokines serve as a critical link between “leaky gut” and AMD. A central pathological feature of AMD is dysfunction of the RPE, a cell layer essential for maintaining retinal homeostasis through its barrier and phagocytic functions. When cytokines such as IL-6 and TNF-α reach the retina via systemic circulation, they contribute to AMD pathogenesis through multiple mechanisms [67]. These cytokines contribute to AMD pathogenesis through several key mechanisms. Notably, they can disrupt tight junctions between RPE cells, which exacerbates damage to the blood-retinal barrier and impairs the phagocytic capacity of RPE cells. This dysfunction leads to the accumulation of metabolic waste, thereby promoting the formation of drusen—a hallmark of Dry AMD.

A well-defined molecular link exists between IL-6 and CNV in Wet AMD. IL-6 binding to its receptor complex (IL-6R/gp130) on retinal cells activates the JAK/STAT3 signaling pathway. Following phosphorylation and dimerization, STAT3 translocates to the nucleus and directly binds specific response elements in the VEGF gene promoter, driving its transcription [68]. IL-6 can additionally activate the Ras/MAPK pathway, further amplifying VEGF expression. The consequent elevation in VEGF levels induces abnormal proliferation of choroidal capillary endothelial cells, facilitating their penetration through the compromised Bruch’s membrane into the subretinal space to form CNV [69]. These fragile neovessels are prone to leakage and hemorrhage, leading to acute vision loss—a defining characteristic of Wet AMD.

Concurrently, TNF-α exacerbates oxidative stress and drives RPE degeneration through multifaceted mechanisms. Upon binding to TNFR1 on RPE cells, TNF-α activates the NF-κB pathway, upregulating NADPH oxidases such as NOX4 and increasing intracellular reactive oxygen species (ROS) [70]. It also impairs mitochondrial electron transport chain function, promoting mitochondrial ROS production. The resulting ROS overload damages cellular proteins, lipids, and DNA, disrupting homeostasis [71]. Furthermore, TNF-α activates the p38 MAPK pathway, upregulating senescence-associated proteins including p53 to induce RPE cell senescence, and initiates the apoptotic cascade via caspase-8, leading to caspase-3-dependent apoptosis [72, 73]. Collectively, these TNF-α-mediated processes contribute to RPE cell loss, compromise the outer blood-retinal barrier, and accelerate the progression to advanced AMD features such as drusen expansion and GA [74].

The complement system, a crucial component of innate immunity, can be initiated through three pathways: the lectin, classical, and alternative pathways. Accumulating evidence indicates a close relationship between the gut microbiota and the complement system. For example, Wu et al. reported that the production of complement component 3 (C3) in the host intestine is associated with gut microbial abundance, and its baseline level is influenced by microbial composition in both humans and mice, exhibiting inter-individual variation [75]. Complement activation is also an important factor influencing the progression of AMD. Specifically, complement factor H (CFH), a key regulator of complement activation, is strongly linked to the genetic risk of AMD. The CFH Y402H polymorphism has been associated with alterations in various microbial taxa and leads to elevated levels of the membrane attack complex in carriers, which may exacerbate inflammatory responses and thereby promote AMD development [76]. In a long-term follow-up cohort of patients with intermediate AMD, Anne M. et al. identified significant associations between progression to late AMD and several systemic complement factors and ratios—such as C4, C4b, C3a/C3, C5a/C5, sC5b-9/C5, and factor I—with some indicators showing hazard ratios exceeding tenfold [77]. In 2023, the FDA approved two intravitreal injectable complement inhibitors: pegcetacoplan (SYFOVRE), which targets C3, and avacincaptad pegol (IZERVAY), which targets C5. This milestone marks the entry of AMD treatment into the “complement inhibition era” and provides the first disease-modifying therapy for patients with GA [78, 79].

Furthermore, research by Denise C. Zysset-Burri et al. revealed consistent alterations in both human AMD patients and C3-deficient mice, including enrichment of Firmicutes, reduction in Bacteroidetes, and dysregulation of purine metabolism pathways. These findings suggest that the complement system may indirectly influence AMD progression by modulating the composition and function of the gut microbiome. Specifically, the class Negativicutes showed a positive correlation with CFH and may exacerbate AMD via alternative pathway activation, whereas the genus Bacteroides likely confers protection by suppressing excessive complement activation [80]. These results align with the same team’s earlier findings from 2017 and provide additional evidence linking the complement system to AMD pathogenesis, further supporting the notion that the gut microbiome and complement system are interconnected and may jointly contribute to AMD development [54].

Aimée Parker et al. employed an integrated approach combining metagenomic sequencing, NMR-based metabolomics, and immunohistochemistry to investigate the role of gut microbiota in regulating age-related damage to the intestinal barrier, Central Nervous System, and retina. Their findings demonstrated that fecal microbiota transplantation (FMT) from aged donors to young recipients significantly accelerated intestinal barrier leakage, activated microglia in the brain, and induced retinal inflammation, evidenced by elevated complement C3 and reduced RPE65 protein levels. Conversely, when aged mice received microbiota from young donors, complement C3 and RPE65 levels were restored, underscoring the critical role of gut microbiota in modulating inflammatory processes relevant to AMD [81].

Andriessen et al. reported that mice fed a high-fat diet developed gut dysbiosis characterized by an elevated F/B ratio and increased intestinal permeability. These animals exhibited a chronic low-grade inflammatory state, marked by elevated levels of TNF-α, IL-6, IL-1β, and VEGF-A. Such inflammatory mediators are known to exacerbate CNV, thereby promoting the development of neovascular AMD. Furthermore, studies have shown that increased abundances of Anaerotruncus and Ruminococcaceae in aged mice correlate with elevated serum levels of MCP-1. As a member of the chemokine family, MCP-1 recruits monocytes/macrophages into the retina, stimulating the secretion of TNF-α, IL-1β, and VEGF, and thereby contributing to retinal inflammation and angiogenesis. These findings suggest that gut microbiota may modulate inflammatory responses via mediators such as TNF-α and MCP-1, thereby influencing the pathogenesis of AMD [82]. The key mechanisms linking gut microbiota dysbiosis to the pathogenesis of AMD are summarized in Table 3.

Diet is a central driver in shaping the gut microbiota, influencing the host metabolome through microbial metabolism. These diet and microbiota-related metabolites subsequently affect the initiation and progression of AMD via the Gut-Eye axis. Rowan et al. demonstrated that an HG diet induced multiple AMD-like features in mice, including RPE atrophy, lipofuscin accumulation, and photoreceptor degeneration. In contrast, an LG diet prevented such pathological changes. Even when initiated in aged mice, switching from an HG to an LG diet halted or reversed AMD characteristics. Mechanistically, the LG diet reduced the accumulation of advanced glycation end products (AGEs) and lipid peroxidation products such as CEP and 4-HNE. It also modulated the gut microbiota—with Clostridiales associated with HG/AMD susceptibility and Bacteroidales linked to LG/AMD protection—and increased levels of protective microbial metabolites such as serotonin. These effects collectively underlie the protective role of the LG diet against diet- and age-induced AMD, mediated through the Gut-Eye axis [23]. Studies have shown that compared to the Western diet rich in sugar and fat, the Mediterranean diet—characterized by high consumption of fish, vegetables, olive oil, and moderate intake of meat—is associated with a reduced risk of progression to late-stage AMD, Fish and vegetables are identified as key protective components of this dietary pattern [83, 84]. Its protective effects are mediated through several gut-centric mechanisms: (1) It promotes a higher abundance of Bacteroidetes and a lower Firmicutes/Bacteroidetes ratio, a profile linked to lower systemic inflammation. (2) It enhances the production of SCFAs like butyrate, which strengthen the intestinal epithelial barrier and exert systemic anti-inflammatory effects. (3) By improving barrier function and reducing systemic inflammatory tone such as lowering TNF-α, IL-6, it indirectly dampens microglial activation in the retina and the propensity for CNV [51]. Thus, the Mediterranean diet acts as a multi-modal intervention targeting metabolite production, barrier integrity, and inflammatory pathways.

Certain drugs or natural metabolites can exert part of their therapeutic effects through gut microbiota remodeling, thereby linking pharmaceutical intervention to the Gut-Eye axis. Metformin, beyond its glucose-lowering effects, has shown promise in neovascular AMD models. Zhang et al. demonstrated that its protective effect is mediated via gut microbiota modulation [61]. Specifically, metformin treatment increases the abundance of beneficial genera including Bifidobacterium and Akkermansia, and elevates fecal levels of SCFAs and Bile acids. The subsequent increase in butyrate inhibits pathological angiogenesis through the TXNIP/VEGFR2 pathway, providing a direct example of how a drug can harness the SCFA-mediated mechanism to achieve ocular therapeutic effects. Prasad’s research confirmed that direct supplementation of IPA and other related interventions improve glucose homeostasis and retinal function. This is achieved by regulating the gut microbiota, enhancing intestinal barrier function, activating the AhR and pregnane X receptor (PXR), and inhibiting the TLR4/NLRP3 inflammatory pathway [85].

Additionally, the recent FDA approval of complement C3 and C5 inhibitors (pegcetacoplan, avacincaptad pegol) for GA represents a breakthrough in AMD treatment [78, 79]. The complement system and gut microbiome are known to be interrelated: studies have shown that complement factor polymorphisms such as CFH Y402H are associated with distinct gut microbial profiles [76], and complement deficiency such as C3 deficiency alters gut microbiota in mice [80]. Although current complement inhibitors are administered intravitreally, their systemic effects or the status of the gut-complement axis may influence treatment response. Therefore, future research into oral agents that modulate the complement system, such as those acting via factor I, should consider their impact on the gut microbiome or potential synergistic effects with the gut microbiome as part of their mechanism of action.

Probiotics are recognized for their ability to inhibit pathogen colonization, modulate gut microbiota and immune responses, and enhance intestinal epithelial barrier function [86]. By primarily acting through the Gut-Eye axis, orally administered probiotics represent a systemic therapeutic strategy with potential relevance to retinal diseases like AMD. In a randomized controlled trial involving 57 AMD patients, an 8-week oral probiotic intervention containing Bacillus, Lactobacillus, and Bifidobacterium strains did not lead to significant improvements in clinical symptoms or other metabolic parameters. However, it exerted positive effects on systemic oxidative stress markers by reducing the pro-oxidant malondialdehyde (MDA) and enhancing total antioxidant capacity (TAC) [87]. This mechanistic link is relevant because oxidative stress contributes to the pathology of both Dry and Wet AMD. By reducing systemic oxidative load, probiotics may help lower the risk of damage to the RPE and photoreceptors.

Studies in animal models of retinal degeneration have shown that specific probiotic strains can attenuate photoreceptor cell death, reduce retinal glial activation, and improve visual function, likely through the modulation of systemic and local immune responses [88, 89]. While direct translation to human AMD requires validation, these findings underscore the potential of probiotics not merely as gut modulators, but as agents capable of influencing the neuroinflammatory milieu of the retina itself. Future research should focus on identifying strain-specific effects, optimal dosing regimens, and their potential role as adjunctive therapy to standard AMD treatments.

Prebiotics are substrates selectively utilized by host gut microorganisms, conferring health benefits to the host [90, 91]. A defining characteristic of prebiotics is their resistance to degradation by host enzymes [91]. By selectively stimulating the growth and activity of beneficial bacteria such as Lactobacillus and Bifidobacterium, prebiotics modulate the composition of the gut microbiota and thereby enhance the functional efficacy of probiotics [92].

In the context of ocular diseases, a double-blind, randomized controlled trial investigated the potential of oral probiotics and prebiotics in managing dry eye disease. The results demonstrated that after 4 months of intervention, the mean Ocular Surface Disease Index score in the treatment group was significantly improved compared to the control group [93]. Nevertheless, research on prebiotics in ocular pathologies remains limited, and their specific contributions to the observed effects require further clarification.

FMT involves transferring functional microbial communities from the feces of healthy donors into the gastrointestinal tract of recipients to reconstitute a balanced gut microbiota. This procedure enhances microbial diversity, restores Bile acids metabolism, and improves intestinal function, demonstrating notable efficacy in eradicating Clostridium difficile infection in patients with colitis [94]. In adults, the gut microbiota typically maintains relative stability; however, its diversity gradually declines with aging. Compared to younger individuals, older persons subjects exhibit significant alterations in microbial composition, characterized by reduced abundances of Bacteroides, Bifidobacterium, and Enterobacteriaceae, alongside a relative increase in Clostridia [95].

However, research on the application of FMT for treating AMD remains limited. In the context of ocular disorders, Jiao et al. demonstrated that aging induces gut microbial dysbiosis in mice, which in turn triggers chronic inflammation, lipid accumulation, and circadian disruption in the lacrimal gland. Importantly, FMT from young donors reversed these pathological changes by remodeling the gut microbiota, thereby restoring lacrimal secretory function and circadian transcriptional rhythms [87]. Aimée Parker et al. demonstrated that FMT from aged donors to young recipients significantly accelerated intestinal barrier leakage, activated cerebral microglia, and induced retinal inflammation, characterized by elevated complement C3 and reduced RPE65 levels. Conversely, aged mice receiving young donor microbiota showed reversal of these biomarkers, with normalized complement C3 and RPE65 expression. These findings suggest that FMT may represent a potential therapeutic strategy for AMD [81]. Table 4 provides a comparative overview of these microbiome-targeted therapeutic strategies.