Maria Grant, MD, leader of the research team and a professor in the University of Alabama at Birmingham Department of Ophthalmology and Visual Sciences.

A leading cause of blindness in American adults is diabetic retinopathy, and investigators believe the source of this damage may lie in the belly — mainly a leaky small intestine that weakens the barrier between gut bacteria and the blood system, according to a study published in the journal Circulation Research. 1

According to an University associated with Alabama in Birmingham (UAB) news release, the particular research blood from human subjects with Type 1 diabetes and a mouse model of Type one diabetes were used in order to explore mechanisms underlying diabetic retinopathy. The results show a way to possibly prevent, or even reverse, the eye damage.

“To our knowledge, this study represents the first time that gut barrier disruption has been implicated within the pathogenesis of diabetic retinopathy and also directly links gut leakage with retinopathy severity in human subjects with Type 1 diabetes, ” Maria Grant, MD, leader from the research team and a professor inside the University of Alabama at Birmingham Department of Ophthalmology plus Visual Sciences, said within the UAB online press release service. Grant holds the Eivor and Alston Callahan, M. D., Endowed Chair in Ophthalmology.

The news release offered some background that is useful to understand Grant’s study.

First, it is known that Kind 1 diabetes dysregulates the systemic renin-angiotensin system, or RAS. RAS is a system of hormones and enzymes that regulates blood pressure and other metabolic changes. Besides systemic RAS, there are also local RAS networks that will act in diverse tissues. One key RAS enzyme is ACE2, or angiotensin-converting enzyme 2. The loss of ACE2 in diabetes activates the particular vasodeleterious RAS axis plus lessens the vasoprotective RAS axis. Intriguingly, in a mouse type of Type 1 diabetes, feeding mice with a modified gut bacterial strain associated with Lactobacillus paracasei, which was engineered to produce human being ACE2, protects the rodents against diabetic retinopathy progression. Finally, lack of ACE2 in the particular gut was known to increase gut permeability and systemic inflammation.

The particular human studies, published within Prasad, Floyd et al. compared people with Type 1 diabetes versus controls. The subjects along with Type one diabetes had been further stratified into three groups: no diabetic retinopathy, non-proliferative diabetic retinopathy as well as the more serious disease called proliferative diabetic retinopathy. By measuring levels of certain immune cells and biomarkers in the blood, including gut microbial antigens, the particular researchers found that individual subjects with retinopathy had a dysregulated systemic RAS and profound gut permeability defects that activated components of both the adaptive and innate immune response.

The particular UAB news release furthermore noted that will increases in the severity of diabetic retinopathy were discovered to correlate with increased levels of stomach permeability biomarkers and a gut microbial antigen. This included increased amounts of angiotensin II, the particular RAS hormone that activates the vasodeleterious RAS axis.

According to the UAB news release, using the Akita mouse-Type 1 diabetes model, researchers first gave the ACE2-producing Lactobacillus paracasei, developed by Qiuhong Li, PhD, from the particular University associated with Florida, in order to the rats orally beginning at the onset of diabetes. This probiotic treatment prevented the particular loss associated with gut epithelial ACE2 typically seen in Akita mice, plus importantly, it prevented intestinal epithelial and endothelial hurdle damage. It also reduced the high blood sugar levels recognized as hyperglycemia.

UAB noted that when the oral ACE2-producing Lactobacillus paracasei treatment was withheld until six months after diabetes was established, that delayed therapy reversed the gut barrier dysfunction plus diabetic retinopathy that experienced already formed in the particular mice, which includes reducing the number of damaged capillaries within the retina.

Grant and colleagues, according to the particular seo press releases, also found evidence for several mechanisms that will contributed to the ACE2-reduced gut hurdle damage plus ACE2-lowering associated with blood sugar. To validate results from the Akita/ACE2-producing Lactobacillus paracasei design, they created a second model — a genetically modified Akita strain that overexpresses human ACE2 in small intestinal tract epithelial tissues.

“The significance of the particular work will be we demonstrated that dysregulated intestinal RAS results in translocation of stomach microbial antigens into the plasma, ” Give said within the news release.

Grant added that the bacterial peptides activate the particular endothelium via toll-like receptors, creating a good inflammatory endothelium that has been strongly implicated inside the pathogenesis of vascular diseases, including diabetic retinopathy.

“We exhibited loss of intestinal barrier function in human topics with Kind 1 diabetes using belly barrier biomarkers, and this boost in permeability was associated with gut-derived defense cell activation, ” she concluded in the news launch.

Support came from National Institutes associated with Health grants EY012601, EY028858, EY028037, EY025383, EY032753, HL134640-01 and HL105349; Canadian Institutes of Health Research grant 883612; and Heart plus Stroke Foundation grant 55542.

Reference

Ram Prasad; Jason L. Floyd; Mariana Dupont; Angela Harbour; Yvonne Adu-Agyeiwaah; Bright Asare-Bediako; Dibyendu Chakraborty; Kara Kichler; Aayush Rohella; Sergio Li Calzi; Michael E. Boulton; Regina Lammendella; Justin Wright; Gavin Y. Ouditl; Mohan K. Raizada; Bruce R. Stevens; Qiuhong Li. “Maintenance of enteral ACE2 helps prevent diabetic retinopathy in Type 1 diabetes. ” Circulation Research. Published January 6, 2023. DOI: 10. 1161/CIRCRESAHA. 122. 322003.

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