Microbial control of ocular homeostasis and disease: mechanisms, metabolites, and therapeutic opportunities

The relationship between microbiota and ocular disease is reshaping current views of eye health. Ocular homeostasis depends not only on local tissues but also on interactions among several systems. These systems include the ocular surface microbiota, gut microbiota, systemic immune and metabolic networks, the blood–eye barrier, and the neurovascular unit. Commensal microbial signals can preserve epithelial integrity, barrier immunity, wound repair, immune tolerance, vascular stability, and neuroprotection. Dysbiosis can convert this regulatory network into a source of ocular injury. This occurs through several mechanisms, such as lipopolysaccharide exposure, loss of short chain fatty acids, disturbed tryptophan, bile acid, and lipid metabolism, Th17 and Treg imbalance, complement activation, microglial reprogramming, and molecular mimicry. These regulatory interactions operate along an integrated, multi-compartment spatial network. Locally, the exposed ocular surface and contiguous periocular niches calibrate epithelial renewal and barrier immunity. Systemically, intestinal microbial communities regulate intraocular vascular integrity and neuroimmune tone through circulating metabolites, pathogen-associated molecular patterns, and immune cell trafficking. Low-biomass intraocular signals and the ocular virome provide additional layers of local immune governance. Disruption of this compartmentalized network characterizes ocular surface diseases, uveitis, diabetic retinopathy, age-related macular degeneration, glaucoma, and retinal degeneration. Therapeutic strategies are consequently shifting from empirical antimicrobial eradication toward targeted microbiota-directed interventions, including postbiotics, metabolite supplementation, and barrier-reinforcing platforms. Characterizing these host-microbial circuits may guide the development of therapies that restore ocular health by stabilizing local and systemic microenvironments.