Rethinking Ophthalmology Through the Microbiome

What if the next revolution in ophthalmology isn’t engineered in a lab, but cultured in the gut? For centuries we’ve gazed through the cornea, peeled back retinal layers, and perfected intraocular technique – only to find ourselves staring into the microbial abyss. The eye, once thought sterile and immunoprivileged, is entangled in systemic crosstalk between microbial tenants and ocular health.

Welcome to the gut–eye axis – where the bacteria fermenting your lunch may be shaping meibomian glands, retinal vessels, and even glaucoma risk (1). It’s as disconcerting as it is exhilarating: treating dry eye, age-related macular degeneration (AMD) or uveitis might one day mean prescribing kefir with cyclosporine. But the question isn’t whether the microbiome matters – that ship has sailed. The real question is: how should ophthalmology respond?

Rewriting the origins: From van Leeuwenhoek to Dysbiosis (2)
It began, as many disruptions do, with curiosity and a crude lens.

In the 17th century, Antonie van Leeuwenhoek peered into water droplets and dental plaque with his handmade microscopes and discovered a universe. What he saw were the first glimpses of the microbial world: teeming, shape-shifting, complex. He could not have known that centuries later ophthalmologists would cite his name when discussing corneal inflammation, autoimmune uveitis, or intraocular flora (2). Yet here we are.

“Microbiome” is now scientific lingua franca – overused, underdefined, often blurred with “microbiota.” Think of it as a dynamic ecosystem of microbes, molecules, and metabolites that hums within and upon us, shaping physiology at every level. The human gut harbors tens of trillions of organisms – bacteria, viruses, fungi, archaea, and phages. The balance between Firmicutes and Bacteroidetes has been linked to metabolic and mental health disorders, and ophthalmology has now entered the dialogue.

Dysbiosis – microbial disequilibrium – is no longer just gastrointestinal. It is tied to dry eye, Sjögren’s syndrome, uveitis, glaucoma, even AMD. The gut doesn’t just digest – it whispers to the retina, nudges immunity, tweaks cytokines, and tilts the balance between health and disease.

The lacriome: rethinking tear duct disease one microbe at a time

The nasolacrimal system has long been viewed as plumbing: tubes, valves, drainage. Blockage meant backflow; inflammation meant infection. Case closed.

Enter the lacriome – the microbial and molecular microenvironment of the lacrimal drainage system (2). Not a gimmick, but a recognition that tear ducts are ecosystems, vulnerable to microbial imbalance.

Primary acquired nasolacrimal duct obstruction (PANDO) was long blamed on idiopathic fibrosis or aging. But metagenomic studies (3–7) tell a different story: lacrimal sacs harbor rich biodiversity – Acinetobacter johnsonii, Porphyromonas catoniae, Escherichia coli, Haemophilus influenzae, and more. Culture methods once gave us little beyond Staphylococcus aureus, whereas sequencing reveals an entire community.

Silicone stents after dacryocystorhinostomy? Colonized too – by Pseudomonas, Corynebacterium, Citrobacter. Their genes weren’t passive: metabolism, virulence, immune evasion – all active (5). Patients with failed dacryocystorhinostomy showed different microbial profiles to those whose DCR succeeded. Coincidence, or microbial sabotage disguised as fibrosis?

It’s time to abandon the sterile pipeline model. The lacriome is an immune-modulating frontier. Could microbial screening guide surgery? Could manipulation reduce post-op failure? The paradigm is shifting, and ophthalmology must follow.

MGD and the meibomian microbiome: where oil, skin, and soil collide

You probably blame “gland obstruction” for meibomian gland dysfunction (MGD), while ignoring the microbial elephant on the lid margin. MGD affects over a third of the world’s population (8), yet clinical narratives still reduce it to lipid deficiency, keratinisation, or hormones. True enough – but scratch beneath the surface and a microbial world emerges, shaping gland health, systemic inflammation, tear film stability, and surface immunity.

Cutibacterium, Corynebacterium, Staphylococcus – the regulars. But Zhao et al. (2020) (9) also identified Campylobacter jejuni and Enterococcus faecium in MGD, species linked to chemotaxis, immune evasion, and barrier disruption. Age shapes the microbiome too: youth favors Cutibacterium acnes, while older lids gravitate towards Corynebacterium and Neisseriaceae (10) – acne versus keratitis, coincidence or warning?

Soil adds another twist. A Finnish trial showed compost and moss exposure boosted skin microbial diversity within days (11). So could urban-driven biodiversity loss fuel atopic and ocular surface disease? Enter Nitrosomonas eutropha, a soil ammonia-oxidizer now tested for dermatitis – and perhaps MGD (12, 13). It consumes sweat ammonia, and releases nitric oxide: antimicrobial, anti-inflammatory, wound-healing.

Is this the future of MGD therapy – a bacterial balm instead of doxycycline? We’ve long prescribed antibiotics to silence microbes. Perhaps it’s time to listen.

Dry eye and the ocular surface microbiome: inflammation by a thousand cuts

If dry eye disease (DED) were a person, it would be that chronically misunderstood patient – symptomatic, elusive, often dismissed as psychosomatic. But perhaps DED is more than a tear film problem. Perhaps it is microbial – a slow inflammatory dialogue where dysbiosis whispers and immunity screams.

The ocular surface is no microbial desert. Even one bacterium per 17 conjunctival cells can tilt the balance toward disease (14). In Sjögren’s, non-Sjögren’s DED, and even healthy individuals, the tear film microbiome diverges in ways both taxonomically intriguing and functionally decisive.

Song and Qi showed Sjögren’s patients had more Actinobacteria, fewer Bacteroidetes, with Corynebacterium and Acinetobacter overrepresented (15, 16). These same taxa drive barrier dysfunction, chronic inflammation, and antigenic mimicry. The gut shows parallel disturbance: reduced Faecalibacterium, increased Prevotella, reversed Firmicutes/Bacteroidetes ratio – leading to elevated IL-6, Th17 skewing, and goblet-cell loss in germ-free mice (17).

Even the tear proteome reflects unrest. Cutibacterium acnes and Acinetobacter johnsonii express helicases and arsenical-resistance proteins, modifying host DNA repair and oxidative-stress responses (18).

DED is multifactorial, yes – but when gut and ocular microbiomes are simultaneously inflamed and depleted, the outcome is choreographed immunology. The uncomfortable question: by the time the Schirmer strip is dry and fluorescein pools, has the microbiome already dictated the course?

Aqueous humor and the intraocular microbiota: the myth of sterility

For decades we’ve been taught that the anterior chamber is sterile andimmunoprivileged.

But what if it never was?

In 2021, Deng et al. analyzed 1,000 aqueous humor samples collected under surgical sterility (19). With metagenomic sequencing and strict contamination controls, they found Cutibacterium acnes in >70% of samples – not as pathogen, but resident.

Others soon appeared: Enterococcus faecalis, Staphylococcus epidermidis, even anaerobes. Not post-op infections – present pre-incision. Controls were clean. The result was real. A supposedly sterile compartment wasn’t sterile. Implications? First, these microbes may quietly regulate ocular immune tone – complement, antigen presentation, T-cell trafficking. Second, they may explain unpredictable inflammation: why one patient develops fibrin after cataract surgery and another doesn’t, despite identical technique.

And third – most provocatively – this may be a missing link in glaucoma pathogenesis. Cutibacterium acnes in aqueous fluid could prime immune responses or oxidative-stress pathways in the trabecular meshwork.

We’ve long trusted anterior chamber taps to reveal pathology. But perhaps we’ve overlooked baseline physiology – its microbiome. “Sterility” was a comforting fiction. Biology, as ever, is messier – and more interesting – than we imagined.

Uveitis and the gut–retina axis: when T cells take the bait

Autoimmune uveitis has always been a riddle wrapped in inflammation. Genes, MHC haplotypes, retinal antigens like interphotoreceptor retinoid-binding protein have been blamed. But what if the true trigger isn’t in the eye – or even the bloodstream – but in the gut?

This is the gut–retina axis: once speculative, now backed by data. In the B10.RIII experimental autoimmune uveitis model, broad-spectrum oral antibiotics reduced not only gut bacteria but also retinal inflammation, T-cell infiltration, and cytokines (20).

Even single drugs like vancomycin or metronidazole cooled retinal disease. The gut was no bystander; it was an arsonist.

Germ-free mice sealed the case. R161H T-cell receptor transgenics rarely developed spontaneous uveitis without microbiota. Reintroduce commensals, and the retina flared (21).

This isn’t infection; it’s mimicry: gut bacteria expressing peptides resembling retinal antigens, priming naïve T cells for a misguided attack in the eye. T cells are being trained in the gut to strike the retina.

So why treat uveitis as a purely ocular disorder? If microbiota can induce or dampen retinal autoimmunity, gut-based immunomodulation isn’t speculative – it’s therapeutic. Yet probiotics, diet shifts, or microbiota-targeted therapies remain absent from clinical guidelines.

We’re comfortable injecting steroids into eyes. But adjusting gut flora? Still fringe. The gut–retina axis dares us to look upstream. The question is: will we?

Glaucoma and the microbial trigger hypothesis: when the pressure isn’t just ocular

We’ve spent decades staring at the optic nerve, measuring cup-to-disk ratios, lowering IOP – as if that alone could halt glaucoma. Yet visual fields keep declining, and socould the damage begin not at the lamina cribrosa, but in the gut itself? Evidence says yes. In animals and humans, altered gut microbiota links to retinal ganglion cell loss, oxidative stress, and immune activation – even with normal IOP (22, 23). Here too, the microbiome may play a hidden role.

Helicobacter pylori, found in the trabecular meshwork and iris of POAG patients (24), has been tied to glaucoma across studies and meta-analysis (25). Not by invading the eye, but by priming systemic inflammation. Its heat shock proteins (HSPs), together with TLR4 and TLR9 polymorphisms, can trigger retinal autoimmunity (26).

Chen et al. showed transient IOP elevation in mice activated T cells against HSPs – an immune memory persisting after pressure normalized (27). Germ-free mice? No microbiota, no neurodegeneration. Glaucoma may be as much immune priming as mechanical stress.

Gut profiles in POAG reinforce the case: more Prevotella, Enterobacteriaceae, Escherichia coli; fewer SCFA-producers (23). A dysbiotic gut may be stoking neuroinflammation.

Here’s the provocation: we already modulate glaucoma pharmacologically, but ignore a parallel axis. Should gut profiling, diet, or microbiota-directed therapies join treatment? Glaucoma has always been a thief of sight. Perhaps it has been an “inside” job all along?

AMD and the microbial signature of diet: a tale of drusen and dysbiosis

For a disease named after age, AMD is showing its youthful side – at least through the microbiome. AMD has long been blamed on time, smoking, genetics, and complement dysregulation. But evidence suggests our microbial residents – shaped by diet, antibiotics, and lifestyle – may be just as guilty in forming drusen as any complement factor H polymorphism. The gut–retina axis is not metaphorical. It’s metabolic.

Rowan et al. showed mice on high-glycemic diets developed AMD-like lesions, reversible with low-glycemic diets (28). The proposed mechanism: altered microbial metabolites – serotonin and SCFAs – modulating retinal inflammation and oxidative stress. Andriessen et al. found high-fat diets drove CNV with leaky vessels, microglial activation, and systemic inflammation; fecal transplants from healthy donors suppressed angiogenesis (29). Humans echo this. Zinkernagel et al. reported AMD patients enriched in Oscillibacter, Eubacterium ventriosum, and Ruminococcus torques – taxa tied to gut permeability and cytokine spillover (30).

Controls instead harbored SCFA-producing Bacteroides eggerthii. Even CFH genetics links back: carriers of risk alleles showed enrichment of Negativicutes, an obscure Firmicutes class (31).

AREDS hinted nutrition mattered. But zinc absorption, for example, is mediated by microbial competition (32), suggesting supplement efficacy may depend more on gut ecology than dosage.

So what now? Should retina clinics prescribe fiber with lutein? Should probiotic profiling join AMD management? We’ve focused on drusen, but perhaps the deeper story lies in microbial fingerprints shaping retinal health long before OCT shows damage.

Diabetic retinopathy and microbial metabolism: sugar, inflammation, and the bacterial middleman

We know the story of diabetic retinopathy (DR): hyperglycemia drives microvascular damage, ischemia, and neovascularization. But perhaps a co-author has been overlooked – one with its own metabolism: the gut microbiome.

Das et al. found patients with DR carried a distinct microbial signature – reduced Faecalibacterium and Roseburia (major butyrate producers) and increased Escherichia, Enterobacter, and Shigella, all pro-inflammatory and endotoxin-rich (33). These shifts lowered SCFA levels, increased gut permeability, and primed systemic inflammation to damage retinal vessels.

The pattern echoes Type 1 diabetes, where gut-derived bacterial amyloids may trigger autoimmunity through molecular mimicry – first against pancreatic β-cells, later affecting the retina (34). Contradictions exist. Huang et al. reported higher Bacteroidetes in DR (35) counter to its usual anti-inflammatory role. Even Lactobacillus and Bifidobacterium – probiotic “heroes” – were elevated.

Compensation? Or regional variation shaped by diet, drugs, and environment? These inconsistencies don’t negate the link; they emphasize complexity. The microbiome is no static fingerprint but a dynamic organ, metabolically entangled in diabetes: fermenting carbohydrates, modulating insulin sensitivity, and influencing cytokines that cross the blood–retina barrier.

So here’s the challenge: if metformin alters the microbiome, and metabolites like butyrate influence retinal inflammation, why aren’t we tracking microbial signatures alongside HbA1c in trials? We monitor glucose obsessively. Perhaps it’s time to measure microbial health with equal rigor.

The therapeutic frontier: fecal transplants, synbiotics, and the risks of playing God

It began with a fecal enema in 1958. Today, fecal microbiota transplantation (FMT) is FDA-approved for refractory Clostridioides difficile and is edging into new fields – even ophthalmology. Why? Because if gut dysbiosis can inflame the eye, rebalancing the gut might calm it. In small human studies, aqueous-deficient dry eye improved after FMT from healthy donors (36).

In mice, FMT restored goblet cells and ocular surface integrity (17, 37), while in AMD models, “old” microbiota transplanted into young mice accelerated retinal inflammation – reversed by the opposite transfer (38). This is medicine without molecules: not blocking cytokines, but reshaping ecosystems.

Yet the risks are sobering. FMT from patients with Behçet’s or Vogt–Koyanagi–Harada disease into germ-free mice worsened uveitis (38, 39).

The microbes carried pathogenic potential. Like early blood transfusions, we’re operating blind.

Probiotics and prebiotics – the consumer-friendly cousins – show mixed promise. Lactobacillus and Bifidobacterium improved mild DED, MGD, and vernal keratoconjunctivitis (40, 41). IRT5, a probiotic cocktail, reduced ocular inflammation in murine dry eye and autoimmune uveitis (42, 43). Yet results are inconsistent, and the risks, real: bloodstream infections, bowel ischemia, and even gene transfer of antibiotic resistance in immunocompromised hosts (44). The microbiome adapts, mutates, evolves.

So where does that leave us? We need rigorous, multiomics-driven human trials before racing to market synbiotics or FMT for ocular disease. Because manipulating the microbiome isn’t prescribing a pill. It’s akin to rewriting the rules of symbiosis.

Conclusion: the microbiome is watching

It’s tempting to dismiss the microbiome as just another “axis” fad – gut-brain, gut-lung, gut-eye. But that would be a mistake. The data are no longer suggestive; they are directive.

Across dry eye, MGD, AMD, uveitis, glaucoma, and even post-surgical fibrosis, microbial fingerprints keep appearing. Sometimes culprits, sometimes accomplices – always present, always evolving.

The question isn’t whether the microbiome matters, but how we adapt to our new understanding. This means reframing how we undertake trials, as well as how we view inflammation and risk. Should every immunomodulation study collect stool samples? Should “ocular health” include microbial diversity scores? Should cataract consent forms acknowledge intraocular microbes?

Beyond the clinic lies a cultural reckoning. Medicine long equated health with purity and disease with contamination. The microbiome shows otherwise: health is symbiosis, and disruption – not invasion – often drives pathology.

The microbiome responds to what we eat, how we prescribe, how we sterilize, how we interpret inflammation. It remembers what we forget. How we account for this – and adjust how we assess and treat patients – might redefine what it means to see clearly.