The Microbiome and Ocular-Related Research

Gut Microbiome Analysis and the Gut–Eye Axis

Analytic techniques for gut microbiota have evolved considerably over the past decade. While 16S rRNA-based gene sequencing remains a foundational approach for identifying bacterial taxa, shotgun metagenomic sequencing has emerged as the preferred method for comprehensive characterization, enabling various assessments such as taxonomic composition, metabolic functions, and microbial diversity at the species and strain level.^3,4 Shotgun metagenomics offers several advantages over 16S rRNA sequencing, including higher taxonomic resolution, the ability to detect nonbacterial microorganisms, and direct functional profiling of microbial genes and metabolic pathways. ³ These advances have facilitated the identification of disease-associated microbial signatures with greater precision.

At the phylum level, the healthy adult gut microbiome is dominated by Bacillota (formerly Firmicutes) and Bacteroidota (formerly Bacteroidetes), which together typically comprise over 90% of the gut bacterial community, with Actinomycetota (formerly Actinobacteria), Pseudomonadota (formerly Proteobacteria), and Verrucomicrobiota present in smaller proportions.^3,5 One approach to characterizing the “health” of a particular microbiome involves measuring the ratios with which each of these phyla are present within the gut; however, our current understanding of a “normal” gut microbiota remains incomplete due to the vast diversity and variations even amongst healthy individuals. ⁶ The composition of the gut microbiota varies substantially based on age, geography, diet, medication use, and host genetics, making universal definitions of a “healthy” microbiome challenging to establish. ⁶

More recently, researchers have drawn a link between intestinal dysbiosis and ocular disease states, including uveitis and age-related macular degeneration, establishing what has been termed the gut–eye axis. ² This concept proposes that the gut microbiome can influence ocular health through several hypothesized mechanisms. ² The recognition that distant gut microbiomes may influence eye health has opened new avenues for understanding ocular disease pathogenesis and potential therapeutic interventions.

Risk Factors for Age-Related Macular Degeneration

Age-related macular degeneration (AMD) is a progressive retinal disorder affecting the macula and represents a leading cause of severe vision impairment in older adults. AMD affects approximately 20 million people in the United States and 196 million people worldwide, with projections estimating 288 million affected individuals globally by 2040. ⁷ The annual incidence rises dramatically with age, from 0.3 per 1,000 in those aged 55–59 years to 36.7 per 1,000 in those aged 90 years or older, and the estimated global cost of visual impairment from AMD exceeds $300 billion. Neovascular (wet) AMD accounts for the most severe vision loss caused by AMD, and according to the National Eye Institute (NEI), the prevalence of AMD is projected to more than double from 2.07 million to 5.44 million affected individuals by 2050. ⁸

AMD results from a complex interplay of genetic predisposition and environmental factors. ⁷ Genome-wide association studies have identified variants at two major loci—CFH (complement factor H) on chromosome 1 and ARMS2-HTRA1 on chromosome 10—that are strongly linked to AMD and represent a significant portion of total heritability. ⁹ However, despite this substantial genetic contribution, modifiable environmental and lifestyle factors play critical roles in disease expression.

Cigarette smoking is the most consistently reported environmental risk factor for AMD, with large prospective cohort studies demonstrating that individuals smoking 20 or more cigarettes per day have approximately double the AMD incidence, compared with never-smokers. ⁷ Additional risk factors include uncontrolled hypertension, cardiovascular disease, obesity, and diets low in antioxidants and omega-3 fatty acids. ¹⁰ Importantly, lifestyle factors have a strong influence on the outcome of genetic risk—the European Eye Epidemiology Consortium demonstrated that an unfavorable lifestyle increased the risk of late AMD at least two-fold across all genetic risk categories, indicating that even individuals with high genetic susceptibility may benefit from lifestyle modifications. ⁷

The Age-Related Eye Disease Study (AREDS) and subsequently AREDS2, both sponsored by the NEI, provided landmark scientific evidence supporting nutritional intervention in eye care by demonstrating that specific dietary supplements can slow the progression of AMD. ¹⁰ The original AREDS trial showed that a daily formulation containing vitamin C, vitamin E, beta-carotene, zinc, and copper reduced the 5-year probability of progression to advanced AMD by approximately 25% and decreased the likelihood of significant visual acuity loss. ¹⁰ AREDS2 subsequently proved that replacing beta-carotene with lutein and zeaxanthin maintained efficacy while eliminating the increased lung cancer risk observed with beta-carotene in current and former smokers. ¹⁰ Long-term follow-up data confirmed that lutein/zeaxanthin supplementation was associated with a statistically significant reduction in progression to late AMD, and when directly, compared with beta-carotene, lutein/zeaxanthin demonstrated superior protection. These findings led to the current AREDS2 formulation and established that targeted nutritional supplementation represents an evidence-based strategy for preserving vision in certain at-risk individuals. ¹⁰ The success of AREDS/AREDS2 in demonstrating that modifiable factors can alter AMD progression provides a rationale for investigating novel environmental factors, including the gut microbiome.

Obesity, Gut Microbiota, and Age-Related Macular Degeneration

Epidemiological evidence has linked abdominal obesity to AMD risk. The Melbourne Collaborative Cohort Study demonstrated an association between early and late AMD in men with central adiposity, finding that for each increase of 0.1 in waist-to-hip ratio, there was a 13% increase in the odds of early AMD and a 75% increase in the odds of late AMD. ¹¹ These findings have been supported by various analyses; a meta-analysis of seven prospective cohort studies found a 32% increase in the risk of developing late AMD among obese individuals, with AMD risk increasing by 2% for each 1 kg/m² increase in BMI within the overweight and obese ranges. ¹² Additional studies have confirmed that abdominal fat distribution is significantly associated with AMD, with AMD patients demonstrating elevated inflammatory markers, including CRP, IL-6, and amyloid β1-42. ¹³ These observations raised the question of whether obesity-associated metabolic changes, including alterations in gut microbiota composition, might contribute to AMD pathogenesis.

Andriessen et al. investigated the influence of gut microbiota in obesity-driven choroidal neovascularization using a murine model. ¹⁴ Control mice were fed a regular-chow diet (RD) while the experimental group received a high-fat diet (HFD) beginning at 6 weeks of age. At 11 weeks, choroidal neovascularization was induced via laser photocoagulation. Mice receiving the HFD developed significantly larger neovascular lesions, compared with controls. However, when HFD mice were treated with oral antibiotics to modify gut microbial composition, the severity of choroidal neovascularization was markedly reduced despite no change in body weight. This finding suggested that diet-induced alterations in the gut microbiome, rather than obesity itself, contributed to the enhanced neovascular response.^14,15 In addition, HFD mice exhibited gut dysbiosis that increased intestinal permeability and promoted chronic low-grade systemic inflammation, with elevated levels of IL-6, IL-1β, TNF-α, and VEGF-A. These inflammatory changes are consistent with mechanisms known to drive angiogenesis and contribute to the development of neovascular AMD. ¹⁴ Further evidence supporting a microbiome-mediated mechanism was provided through fecal microbiota transplantation experiments. Transfer of microbiota from RD mice to HFD mice reduced both systemic and choroidal inflammation and significantly lowered intestinal permeability. Notably, while the microbial community of transplant recipients more closely resembled that of RD mice, the protective effects of antibiotic treatment likely occurred through a reduction in absolute bacterial load rather than restoration of a healthy microbial composition proposed to compromise barrier function of the gut epithelial layer, increasing translocation of pathogen-associated molecular patterns into the systemic circulation and promoting the low-grade chronic inflammation characteristic of AMD pathogenesis.^14,15 Together, these findings suggest that diet-induced gut dysbiosis may increase intestinal permeability and systemic inflammation, thereby contributing to pathological angiogenesis in the choroid and supporting a potential gut–retina axis in the development of neovascular AMD.

Zinkernagel et al. demonstrated a landmark investigation showing associations between compositional and functional alterations of the intestinal microbiome and neovascular age-related macular degeneration (AMD) in humans. The researchers employed whole-metagenome shotgun sequencing to analyze gut metagenomes of 57 neovascular AMD patients and 58 age-matched healthy controls. ¹⁶ This approach enabled simultaneous assessment of both taxonomic composition and functional genomic content, revealing that the genera Anaerotruncus and Oscillibacter, along with species Ruminococcus torques and Eubacterium ventriosum, were enriched in AMD patients, while Bacteroides eggerthii was enriched in controls. The highlight of this method lies in its capacity to move beyond bacterial identification to characterize metabolic pathway alterations, providing mechanistic hypotheses linking gut dysbiosis to retinal disease. The identification of functional metagenomic differences between groups revealed that AMD patients’ intestinal microbiomes showed enrichment in genes associated with L-alanine fermentation, glutamate degradation, and arginine biosynthesis pathways, while genes involved in fatty acid elongation were decreased. These functional findings are particularly important given that glutamate excitotoxicity contributes to retinal neurodegeneration, and fatty acid metabolism is critical for retinal structure and function. The authors concluded that AMD may be amenable to microbiome-altering interventions and help establish the gut–retina axis as a legitimate field of investigation for modifiable risk factors for AMD. ¹⁶

Cross-cohort metagenomic analysis comparing Chinese and Swiss populations confirmed consistent AMD-associated microbial signatures, with Ruminococcus callidus, Lactobacillus gasseri, and Prevotellaceae enriched in AMD patients, while Bacteroidaceae was depleted and negatively associated with hemorrhage size. ³ Functional profiling revealed that AMD patients’ gut microbiota showed increased abundance of genes involved in lipopolysaccharide (LPS) biosynthesis, suggesting a mechanism by which dysbiosis may promote systemic inflammation. ³

While these findings establish an association between gut dysbiosis and AMD, several important limitations must be taken into account. Most human studies remain cross-sectional, limiting causal inference. The wide variability in intestinal microbiome composition among different populations and disease states makes specific targeted therapy difficult to establish. ² Although preclinical studies demonstrate that microbiome modulation can influence AMD-like features in animal models, no randomized controlled trials have yet tested probiotics, prebiotics, or fecal microbiota transplantation specifically in AMD patients.^2,17 Current evidence suggests that consuming diets rich in fish, fruits, vegetables, and low glycemic index foods is most retina-healthful during aging, likely working in part through beneficial effects on gut microbiota composition. ¹⁷ These observations have led to the hypothesis that some nutritional interventions used in AMD, including those evaluated in the AREDS trials, may exert effects partially through modulation of the gut–retina axis. ² This provides a rationale for future interventional studies targeting the gut–retina axis, though the need for large longitudinal studies in patients and germ-free animal models remains imperative. ²

Risk Factors for Uveitis and the Gut–Eye Axis

Uveitis is an inflammatory condition of the uveal tract that can include adjacent ocular structures and remains a significant cause of preventable blindness worldwide. Uveitis is associated with 3%–10% of vision impairment in the United States and Europe and accounts for a substantial proportion of blindness in low- and middle-income countries. ¹⁸ The condition predominantly affects young and middle-aged adults, causing significant socioeconomic impact during peak productive years. Untreated uveitis may cause cataracts, glaucoma, macular edema, retinal detachment, optic nerve damage, and vision loss, with 5%–10% of patients with noninfectious intermediate, posterior, or panuveitis developing blindness or low vision over 5 years. ¹⁸

Uveitis results from a complex interplay of genetic susceptibility, immune dysregulation, and environmental factors, with the underlying cause remaining unknown. ¹⁸ A hallmark of noninfectious uveitis is its strong association with human leukocyte antigens (HLA), with acute anterior uveitis (AAU), Behçet’s disease, and birdshot chorioretinopathy strongly associated with HLA-B27, HLA-B51, and HLA-A29, respectively. ¹⁸ In the United States and Europe, one-third to nearly one-half of uveitis cases are associated with systemic disease.^18,19 Uveitis is commonly associated with inflammatory bowel disease (IBD), with the prevalence of uveitis in IBD patients estimated at 2.38%, while Crohn’s disease patients are significantly more likely to develop uveitis than those with ulcerative colitis (3.27% vs. 1.60%). ²⁰ A 2025 Mendelian randomization analysis provided genetic evidence supporting a potential causal relationship that IBD, ulcerative colitis, and Crohn’s disease have on uveitis development. ²¹

Emerging evidence implicates the gut microbiome as a critical environmental factor in uveitis pathogenesis, supporting the concept of a gut–eye axis where microbial dysbiosis alters intestinal barrier function, affects T-cell homeostasis, and drives systemic immune activation that can breach ocular immune privilege. ¹⁹ Four proposed mechanisms link gut dysbiosis to uveitis development: Molecular mimicry between microbial and ocular antigens, imbalance of regulatory and effector T -cells, increased intestinal permeability allowing bacterial translocation, and loss of protective intestinal metabolites such as short-chain fatty acids (SCFAs). ¹⁹ Specific taxa, including Prevotella, Desulfovibrio, and Ruminococcaceae, have been associated with uveitis in both preclinical experimental autoimmune uveitis models and clinical studies, while Faecalibacterium and its metabolites appear protective. ¹⁹ HLA alleles influence both microbiome composition and disease phenotype, suggesting a gene–microbiome–immunity triad in uveitis pathogenesis that may explain the link between IBD and ocular inflammation. These findings have opened new therapeutic potentials, with microbiome-informed strategies including probiotics, dietary modulation, and fecal microbiota transplantation holding promise for complementing existing immunosuppressive applications in noninfectious uveitis. ¹⁹

HLA-B27, the Gut Microbiome, and AAU

The connection between the presence of the HLA-B27 antigen and its carriers’ increased risk of developing AAU has been extensively studied, with recent reviews proposing four potential mechanisms linking gut dysbiosis to ocular inflammation.^1,22,23 The pathogenesis of HLA-B27-associated diseases such as AAU and ankylosing spondylitis remains incompletely understood, though Gram-negative bacteria and subclinical bowel inflammation are strongly implicated.^1,22

The first proposed mechanism involves increased intestinal permeability. In this scenario, gut dysbiosis compromises the intestinal epithelial barrier, allowing bacterial products such as LPS and microbial components to translocate from the intestine into the mesenteric lymph nodes, spleen, lymphatics, and systemic circulation.^1,22,23 Studies in experimental autoimmune uveitis models have demonstrated that increased intestinal permeability coincides temporally with peak intraocular inflammation, and the presence of endotoxins in the systemic circulation has been shown to alter vascular permeability of ocular vessels in laboratory mice. ²⁴ These bacterial products could potentially become trapped in the iris, activating an innate immune response cascade and triggering inflammation.^1,22

The second theory involves molecular mimicry, wherein bacterial peptides resemble ocular and joint autoantigens and provoke cross-reactive immune responses—similar to the mechanisms underlying rheumatic fever and Guillain–Barré syndrome.^1,22,23 Research published in Nature in 2022 provided support for this hypothesis by identifying orphan T cell receptors expressing a disease-associated public BV9-CDR3β motif from blood, synovial fluid, and ocular T cells of individuals with ankylosing spondylitis and AAU. ²⁵ These T cell receptors demonstrated cross-reactivity for both self-peptides and microbial peptides presented by HLA-B27. ²⁵

The third mechanism proposes that the gut microbiome alters systemic immune responses in ways that predispose to AAU development.^1,22,23 Certain gut bacteria can influence T cell production of interleukins (particularly IL-17 and IL-23) and transcription factors known to play a role in the inflammation associated with spondyloarthritis and related conditions.^1,22 A 2024 study of 277 patients identified a shared immune-mediated disease signal in spondyloarthritis, AAU, and Crohn’s disease represented by low abundances of Lachnospiraceae taxa, especially Fusicatenibacter—a finding that was associated with elevated serum C-reactive protein levels. Separately, HLA-B27-positive individuals displayed enriched Faecalibacterium, though this likely reflects a compensatory response or HLA-B27-driven microbiome effects rather than a pro-inflammatory mechanism, as Faecalibacterium prausnitzii is consistently characterized as anti-inflammatory in the literature.^26,27 This elevated inflammatory state may not directly cause but potentially predispose a patient to uveitis by creating an environment where ocular immune privilege is more easily compromised.^1,22

A fourth mechanism hypothesis involves the loss of protective intestinal metabolites, particularly SCFAs produced by commensal bacteria.^22,23 SCFAs, sucha as butyrate, play critical roles in maintaining intestinal barrier integrity and promoting regulatory T cell differentiation; its depletion in dysbiosis states may contribute to both increased intestinal permeability and systemic immune dysregulation.^22,23

Autoimmunity can affect the eye, especially when the protective barriers of immune privilege are compromised. Noninfectious uveitis that is autoimmune in nature can stem from immune responses initially primed in the gut, where microbial dysbiosis alters intestinal barrier function, affecting T cell homeostasis, and drives systemic immune activation that can breach ocular immune privilege.^22,23 Human leukocyte antigen alleles, notably HLA-B27 and HLA-A29, influence both microbiome composition and disease phenotype, suggesting a gene–microbiome–immunity triad in uveitis pathogenesis. These findings can open new therapeutic avenues, with microbiome-informed strategies including probiotics, dietary modulation, and fecal microbiota transplantation holding promise for complementing existing immunosuppressive regimens in noninfectious uveitis.^22,23

Conclusion

As personalized medicine continues to evolve and become more widely implemented, a deeper understanding of the relationships between ocular disease, nutritional status, and the intestinal microbiome is increasingly important. Emerging evidence suggests that dysbiosis may act as a modifier of inflammatory and metabolic processes implicated in autoimmune and degenerative ocular conditions. Continued research is essential to further define these associations and establish clinically meaningful applications within eye care. Accordingly, the eye care community bears a responsibility to remain informed of advancing literature and evolving evidence, as integrating these insights may play a critical role in optimizing patient outcomes and shaping the future of ocular health care.▪