Maintaining ACE2 enzymes in the intestine can prevent diabetic blindness

The leading cause of blindness in American adults is diabetic retinopathy, a condition
that progressively damages the blood vessels of the photoreceptor tissue at the back of the eye.
However, according to a study published in the journal, the root of this damage appears to lie in the abdomen — primarily a leaky small intestine that weakens the barrier
between gut bacteria and the blood system.

Research blood from type 1 diabetic patients and mouse models of type 1 diabetes was used to explore the mechanisms
of diabetic retinopathy.
The results show a possible way
to prevent or even reverse eye damage.

"To our knowledge, this study is the first to link intestinal barrier disruption to the pathogenesis of diabetic retinopathy and directly link intestinal leakage to the severity of retinopathy in people with type 1 diabetes," said
research team leader Dr.
Maria Grant, professor in the Department of Ophthalmology and Visual Sciences at the University of Alabama at Birmingham.

Some background knowledge is useful
for understanding Grant's research.

First, type 1 diabetes is known to cause dysregulation
of the renin-angiotensin system (RAS).
RAS is a system of hormones and enzymes that regulate blood pressure and other metabolic changes
.
In addition to systemic RAS, there are also local RAS networks
that act on different tissues.
A key RAS enzyme is ACE2, or angiotensin-converting enzyme 2
.
The loss of ACE2 in diabetic patients activates the RAS axis, which is harmful to blood vessels, and reduces the RAS axis
, which has a protective effect on blood vessels.
Interestingly, in a mouse model of type 1 diabetes, mice were fed with a modified Lactobacillus paracasei gut strain designed to produce human ACE2, which protects mice from the development of
diabetic retinopathy.
Finally, intestinal deficiencies in ACE2 are known to increase intestinal permeability and systemic inflammation
.

The human study, published in Prasad, Floyd et al.
, Circular Studies, compared people with type 1 diabetes with a control group
.
People with type 1 diabetes were further divided into three groups: non-diabetic retinopathy, non-proliferative diabetic retinopathy, and more severe proliferative diabetic retinopathy
.
By measuring levels of certain immune cells and biomarkers in the blood, including gut microbial antigens, the researchers found that human subjects with retinopathy had dysregulated systemic RAS and severe intestinal permeability defects that activate components of
the adaptive and innate immune response.
In addition, an increase in the severity of diabetic retinopathy was found to be associated with
increased levels of intestinal permeable biomarkers and gut microbial antigens.
This includes an increase in angiotensin II levels, where the RAS hormone activates the RAS axis
of harmful blood vessels.

Using the Akita Mouse-Type 1 Diabetes Model, the researchers first administered ACE2-producing Lactobacillus paracasei, developed by Dr.
Li Qiuhong of the University of Florida, orally to mice
from the time of diabetes attack.
This probiotic treatment prevented the loss of ACE2, typical of the intestinal epithelium, in Akita mice and, importantly, it prevented disruption of the intestinal epithelial and endothelial
barriers.
It also lowers hyperglycemic levels
.

When oral ACE2-producing Lactobacillus paracasei treatment was delayed until 6 months after diabetes was diagnosed, this delayed treatment reversed the intestinal barrier dysfunction and diabetic retinopathy that had developed in mice, including reducing the number of
damaged capillaries in the retina.

Grant and colleagues also found evidence of mechanisms that help ACE2 reduce intestinal barrier damage and ACE2 lower blood sugar
.
To validate the results from the Akita/ACE2-producing Lactobacillus paracasei model, they created a second model—a transgenic Akita strain
that overexpresses human ACE2 in small intestinal epithelial cells.

"The significance of this work is that we demonstrated that dysregulated gut RAS causes the transfer of gut microbial antigens into plasma
," Grant said.
"These bacterial peptides activate endothelial cells through toll-like receptors to produce inflammatory endothelial cells, which are closely linked to the pathogenesis of vascular diseases, including diabetic retinopathy
.

"We demonstrated loss of intestinal barrier function in patients with type 1 diabetes using intestinal barrier biomarkers, and this increased permeability is associated with
intestinal-derived immune cell activation.
"