Exploring Endotoxemia in Age-Related Macular Degeneration, Glaucoma, and Diabetic Retinopathy

Lipopolysaccharide (LPS), a component of Gram-negative bacteria, is a potent activator of the innate immune system and has been implicated in the pathogenesis of eye diseases, including age-related macular degeneration (AMD), primary open-angle glaucoma (POAG), and diabetic retinopathy (DR). LPS enters systemic circulation through bacterial lysis or active secretion, leading to endotoxemia-either acute or chronic. Chronic endotoxemia, often resulting from gut dysbiosis, may link microbial imbalances to eye diseases. Indeed, chronic LPS exposure may contribute to both systemic and local inflammation. Within the retina, it activates resident immune and structural cells triggering pro-inflammatory cytokine production, oxidative stress, complement cascade activation, and inflammasome activation. These immune cascades compromise blood-retinal barrier integrity, increase vascular leakage, and impair neuronal viability. LPS exposure can stimulate the secretion of pro-angiogenic factors, promoting the development of neovascularization within the retina. Furthermore, the aging retina may be particularly vulnerable to LPS-mediated damage due to an increased exposure to LPS (linked to microbial dysbiosis and alterations of both intestinal and blood-retinal barriers) as well as a reduced capacity for repair. Although direct human evidence remains limited, emerging experimental data support a mechanistic role for LPS in AMD, glaucoma, and DR. This review emphasizes that addressing the impact of chronic endotoxemia represents a promising avenue for both understanding and treating eye diseases. Continued investigation into the multifaceted roles of LPS may yield innovative biomarkers and therapeutic targets to slow or prevent neurodegenerative, vascular, and inflammatory processes underlying conditions such as AMD, glaucoma, and DR.