Gut-hormone receptor systems in the eye: Pharmacological, local and putative endocrine signalling

The neural retina has traditionally been viewed as a downstream target of systemic metabolic disease, yet experimental and clinical evidence suggests that ocular tissues may also respond directly to peptide-hormone signalling. This review critically examines gut-hormone-related receptor systems in the eye across three biologically distinct evidence streams: endogenous circulating gut peptides, pharmacological receptor agonism, and locally synthesised ocular peptides. Physiological retinal access of native gut peptides remains poorly characterised, while receptor localisation is highly dependent on species and detection methodology. Mechanistic evidence is strongest for pharmacological GLP-1 receptor activation and local NPY and ghrelin systems, particularly in relation to neuroprotection, immunomodulation, metabolic and oxidative homeostasis, and neurovascular regulation. Human evidence remains disease-specific: diabetic retinopathy findings vary with glycaemic trajectory and endpoint definition; age-related macular degeneration associations are heterogeneous; glaucoma studies suggest a possible reduction in incidence without establishing protection against progression; and dry-eye evidence remains preliminary. Semaglutide also carries a regulatory safety signal for non-arteritic anterior ischaemic optic neuropathy. Future research should establish physiological ligand access and receptor engagement, validate ocular receptor localisation, characterise retinal and optic-nerve-head microvascular responses, and incorporate prospective ophthalmic phenotyping into metabolic-drug trials. Overall, current evidence supports pharmacological and local ocular peptide-receptor signalling, whereas direct physiological endocrine communication between the gut and eye remains unproven.