Abstract
BackgroundGlaucoma is a progressive optic nerve degenerative disease that often leads to blindness. Local inflammatory responses are implicated in the pathology of glaucoma. Although inflammatory episodes outside the CNS, such as those due to acute systemic infections, have been linked to central neurodegeneration, they do not appear to be relevant to glaucoma. Based on clinical observations, we hypothesized that chronic subclinical peripheral inflammation contributes to neurodegeneration in glaucoma.MethodsMouthwash specimens from patients with glaucoma and control subjects were analyzed for the amount of bacteria. To determine a possible pathogenic mechanism, low-dose subcutaneous lipopolysaccharide (LPS) was administered in two separate animal models of glaucoma. Glaucomatous neurodegeneration was assessed in the retina and optic nerve two months later. Changes in gene expression of toll-like receptor 4 (TLR4) signaling pathway and complement as well as changes in microglial numbers and morphology were analyzed in the retina and optic nerve. The effect of pharmacologic blockade of TLR4 with naloxone was determined.FindingsPatients with glaucoma had higher bacterial oral counts compared to control subjects (p<0.017). Low-dose LPS administration in glaucoma animal models resulted in enhancement of axonal degeneration and neuronal loss. Microglial activation in the optic nerve and retina as well as upregulation of TLR4 signaling and complement system were observed. Pharmacologic blockade of TLR4 partially ameliorated the enhanced damage.ConclusionsThe above findings suggest that the oral microbiome contributes to glaucoma pathophysiology. A plausible mechanism by which increased bacterial loads can lead to neurodegeneration is provided by experiments in animal models of the disease and involves activation of microglia in the retina and optic nerve, mediated through TLR4 signaling and complement upregulation. The finding that commensal bacteria may play a role in the development and/or progression of glaucomatous pathology may also be relevant to other chronic neurodegenerative disorders.
Highlights
Glaucoma is a chronic neurodegenerative disease that affects the retinal ganglion cells (RGCs) in the neural retina and their axons in the optic nerve
A plausible mechanism by which increased bacterial loads can lead to neurodegeneration is provided by experiments in animal models of the disease and involves activation of microglia in the retina and optic nerve, mediated through toll-like receptor 4 (TLR4) signaling and complement upregulation
The finding that commensal bacteria may play a role in the development and/or progression of glaucomatous pathology may be relevant to other chronic neurodegenerative disorders
Summary
Glaucoma is a chronic neurodegenerative disease that affects the retinal ganglion cells (RGCs) in the neural retina and their axons in the optic nerve It is the second most common cause of blindness worldwide [1]. A similar finding has been reported in an animal model of PD where peripheral overexpression of IL-1b accelerated the disease process [11] These studies suggest that overt peripheral inflammation can exacerbate neurodegeneration. Clinical observations in glaucoma patients (JD), led us to hypothesize that chronic subclinical inflammatory processes such as that caused by microbiota colonizing humans may exacerbate neurodegeneration in glaucoma. We tested this hypothesis by analyzing human samples and utilizing animal models of glaucoma. We hypothesized that chronic subclinical peripheral inflammation contributes to neurodegeneration in glaucoma
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