LP-ACE2 attenuates diabetic visual impairment by improving gut barrier integrity and intestinal lymphatics in type 1 diabetes

Abstract

Purpose : Previously, we showed a key role of angiotensin converting enzyme 2 (ACE2) in the gut-retinal axis and diabetic retinopathy (DR). Prevention of diabetes-induced reduction of intestinal ACE2 maintains normal gut barrier integrity, prevents retinal endothelial cell permeability, and suppresses the DR phenotype in Akita mice, a model of type 1 diabetes (T1D). Intestinal lacteals absorb and transport dietary lipids and immune cells to mesenteric lymph nodes; however, their contribution to the gut-retinal axis has not been studied. Here, we examined the impact of diabetes on intestinal lymphatics and the impact of ACE-2 expressing probiotics on the gut-retinal axis and DR.

Methods : Akita mice with six months of diabetes were orally gavaged LP-ACE2 (3x/week for three months), an engineered probiotic (Lactobacillus paracasei; LP) expressing hACE2. After three months, immunohistochemistry (IHC) was used to evaluate intestinal lymphatics and gut epithelial/endothelial barrier integrity. DR was assessed using visual acuity/function and enumeration of acellular capillaries.

Results : LP-ACE2 significantly restored intestinal lacteal integrity (LYVE-1 expression) in Akita mice (p<0.005). LP-ACE2-treated Akita mice exhibited significantly improved gut epithelial (ZO1, p120-catenin) and endothelial (PV1) barrier integrity. Elevated plasma level of LDL cholesterol was significantly reduced (p<0.01) in LP-ACE2-treated Akita mice. Expression of ATP-binding cassette transporter A1 (ABCA1), a mediator of cholesterol efflux, was significantly upregulated (p<0.02) in the RPE of the LP-ACE2-treated Akita cohort. LP-ACE2 corrected BRB dysfunction as observed by increased ZO1 (p<0.05) and decreased VCAM-1 expression. LP-ACE2 treated mice showed an improved retinal electrical response and visual acuity as measured by ERG (scotopic a wave, p<0.008; scotopic b wave, p<0.009) and OKN (p<0.0002), respectively. LP-ACE2-treated Akita mice exhibit significantly decreased numbers of acellular capillaries in the retina (p<0.002).

Conclusions : Our study reveals that LP-ACE2 treatment repairs the disrupted intestinal lacteals, which play a key role in gut barrier integrity and retinal lipid metabolism. Maintaining the integrity of these components of the gut barrier improved visual function and decreased DR severity in T1D mice.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.