All ETDs from UAB

Advisory Committee Chair

Alexander J Szalai

Advisory Committee Members

Maria B Grant

Craig L Maynard

Robert S Welner

Bradley K Yoder

Document Type

Dissertation

Date of Award

2023

Degree Name by School

Doctor of Philosophy (PhD) School of Medicine

Abstract

Diabetic retinopathy (DR) is the most common microvascular complication of diabetes and, along with diabetic macular edema (DME), accounts for the greatest source of vision-threatening eye disease in the working-age community. DR is caused by weakening of the retinal vasculature, the blood-retinal barrier (BRB), by high levels of blood glucose (hyperglycemia), exacerbations of oxidative stress, and systemic inflammatory factors. Many of these inflammatory factors are metabolic by-products and cell membrane constituents of the gut microbiota, the resident community of microbial species which inhabit the lumen of the gastrointestinal tract. These factors are collectively termed gut microbial antigens (GMAs). In diabetes, both type 1 (T1D) and type 2 (T2D), increased permeability of the gut barrier allows for increased translocation of GMAs from the gut lumen into the systemic circulation (endotoxemia) where they travel to distant sites and activate pro-inflammatory signaling. The work herein characterizes mechanisms by which gut permeability is induced and sustained in T1D and T2D human subjects and rodents. In human subjects, we demonstrate that elevated gut permeability and endotoxemia are associated with worsened DR severity in human subjects with T1D and T2D, though by different mechanisms. In T1D, we demonstrate that dysfunction of the intestinal renin-angiotensin system (RAS), by the loss of angiotensin-converting enzyme 2 (ACE2), increases gut permeability and endotoxemia and is associated with severe eye disease in human subjects. In T1D Akita mice, we demonstrate that maintenance of intestinal ACE2, either by oral administration of an ACE2-expressing Lactobacillus paracasei probiotic (LP-ACE2) or genetic overexpression of human Ace2 within intestinal epithelial cells (Vil-Cre.hAce2KI-Akita), preserves integrity of the gut barrier, decreases systemic endotoxemia, and prevents the development of DR. In T2D db/db mice, we demonstrate that aberrant production of neutrophil extracellular traps (NETosis), a terminal effector function that is highly bactericidal and carries high risk for collateral tissue damage, within the small intestine is associated with elevated barrier disruption and endotoxemia; using a pharmacologic inhibitor of NETosis, we show that intestinal NETosis is decreased, gut barrier integrity is maintained, endotoxemia decreased, and DR severity lessened. Together, these studies provide valuable information which implicates a “leaky” gut in the pathogenesis of diabetic retinopathy; perhaps new therapeutics which protect the gut barrier would similarly protect the retina from development of vascular dysfunction.

Share

COinS