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Sustained ACE2 Expression by Probiotic Improves Integrity of Intestinal Lymphatics and Retinopathy in Type 1 Diabetic Model

Intestinal lymphatic, known as lacteal, plays a critical role in maintaining intestinal homeostasis by regulating several key functions, including the absorption of dietary lipids, immune cell trafficking, and interstitial fluid balance in the gut. The absorption of dietary lipids relies on lacteal...

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Autores principales: Prasad, Ram, Adu-Agyeiwaah, Yvonne, Floyd, Jason L., Asare-Bediako, Bright, Li Calzi, Sergio, Chakraborty, Dibyendu, Harbour, Angela, Rohella, Aayush, Busik, Julia V., Li, Qiuhong, Grant, Maria B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10003436/
https://www.ncbi.nlm.nih.gov/pubmed/36902558
http://dx.doi.org/10.3390/jcm12051771
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author Prasad, Ram
Adu-Agyeiwaah, Yvonne
Floyd, Jason L.
Asare-Bediako, Bright
Li Calzi, Sergio
Chakraborty, Dibyendu
Harbour, Angela
Rohella, Aayush
Busik, Julia V.
Li, Qiuhong
Grant, Maria B.
author_facet Prasad, Ram
Adu-Agyeiwaah, Yvonne
Floyd, Jason L.
Asare-Bediako, Bright
Li Calzi, Sergio
Chakraborty, Dibyendu
Harbour, Angela
Rohella, Aayush
Busik, Julia V.
Li, Qiuhong
Grant, Maria B.
author_sort Prasad, Ram
collection PubMed
description Intestinal lymphatic, known as lacteal, plays a critical role in maintaining intestinal homeostasis by regulating several key functions, including the absorption of dietary lipids, immune cell trafficking, and interstitial fluid balance in the gut. The absorption of dietary lipids relies on lacteal integrity, mediated by button-like and zipper-like junctions. Although the intestinal lymphatic system is well studied in many diseases, including obesity, the contribution of lacteals to the gut–retinal axis in type 1 diabetes (T1D) has not been examined. Previously, we showed that diabetes induces a reduction in intestinal angiotensin-converting enzyme 2 (ACE2), leading to gut barrier disruption. However, when ACE2 levels are maintained, a preservation of gut barrier integrity occurs, resulting in less systemic inflammation and a reduction in endothelial cell permeability, ultimately retarding the development of diabetic complications, such as diabetic retinopathy. Here, we examined the impact of T1D on intestinal lymphatics and circulating lipids and tested the impact of intervention with ACE-2-expressing probiotics on key aspects of gut and retinal function. Akita mice with 6 months of diabetes were orally gavaged LP-ACE2 (3x/week for 3 months), an engineered probiotic (Lactobacillus paracasei; LP) expressing human ACE2. After three months, immunohistochemistry (IHC) was used to evaluate intestinal lymphatics, gut epithelial, and endothelial barrier integrity. Retinal function was assessed using visual acuity, electroretinograms, and enumeration of acellular capillaries. LP-ACE2 significantly restored intestinal lacteal integrity as assessed by the increased expression of lymphatic vessel hyaluronan receptor 1 (LYVE-1) expression in LP-ACE2-treated Akita mice. This was accompanied by improved gut epithelial (Zonula occludens-1 (ZO-1), p120-catenin) and endothelial (plasmalemma vesicular protein -1 (PLVAP1)) barrier integrity. In Akita mice, the LP-ACE2 treatment reduced plasma levels of LDL cholesterol and increased the expression of ATP-binding cassette subfamily G member 1 (ABCG1) in retinal pigment epithelial cells (RPE), the population of cells responsible for lipid transport from the systemic circulation into the retina. LP-ACE2 also corrected blood–retinal barrier (BRB) dysfunction in the neural retina, as observed by increased ZO-1 and decreased VCAM-1 expression compared to untreated mice. LP-ACE2-treated Akita mice exhibit significantly decreased numbers of acellular capillaries in the retina. Our study supports the beneficial role of LP-ACE2 in the restoration of intestinal lacteal integrity, which plays a key role in gut barrier integrity and systemic lipid metabolism and decreased diabetic retinopathy severity.
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spelling pubmed-100034362023-03-11 Sustained ACE2 Expression by Probiotic Improves Integrity of Intestinal Lymphatics and Retinopathy in Type 1 Diabetic Model Prasad, Ram Adu-Agyeiwaah, Yvonne Floyd, Jason L. Asare-Bediako, Bright Li Calzi, Sergio Chakraborty, Dibyendu Harbour, Angela Rohella, Aayush Busik, Julia V. Li, Qiuhong Grant, Maria B. J Clin Med Article Intestinal lymphatic, known as lacteal, plays a critical role in maintaining intestinal homeostasis by regulating several key functions, including the absorption of dietary lipids, immune cell trafficking, and interstitial fluid balance in the gut. The absorption of dietary lipids relies on lacteal integrity, mediated by button-like and zipper-like junctions. Although the intestinal lymphatic system is well studied in many diseases, including obesity, the contribution of lacteals to the gut–retinal axis in type 1 diabetes (T1D) has not been examined. Previously, we showed that diabetes induces a reduction in intestinal angiotensin-converting enzyme 2 (ACE2), leading to gut barrier disruption. However, when ACE2 levels are maintained, a preservation of gut barrier integrity occurs, resulting in less systemic inflammation and a reduction in endothelial cell permeability, ultimately retarding the development of diabetic complications, such as diabetic retinopathy. Here, we examined the impact of T1D on intestinal lymphatics and circulating lipids and tested the impact of intervention with ACE-2-expressing probiotics on key aspects of gut and retinal function. Akita mice with 6 months of diabetes were orally gavaged LP-ACE2 (3x/week for 3 months), an engineered probiotic (Lactobacillus paracasei; LP) expressing human ACE2. After three months, immunohistochemistry (IHC) was used to evaluate intestinal lymphatics, gut epithelial, and endothelial barrier integrity. Retinal function was assessed using visual acuity, electroretinograms, and enumeration of acellular capillaries. LP-ACE2 significantly restored intestinal lacteal integrity as assessed by the increased expression of lymphatic vessel hyaluronan receptor 1 (LYVE-1) expression in LP-ACE2-treated Akita mice. This was accompanied by improved gut epithelial (Zonula occludens-1 (ZO-1), p120-catenin) and endothelial (plasmalemma vesicular protein -1 (PLVAP1)) barrier integrity. In Akita mice, the LP-ACE2 treatment reduced plasma levels of LDL cholesterol and increased the expression of ATP-binding cassette subfamily G member 1 (ABCG1) in retinal pigment epithelial cells (RPE), the population of cells responsible for lipid transport from the systemic circulation into the retina. LP-ACE2 also corrected blood–retinal barrier (BRB) dysfunction in the neural retina, as observed by increased ZO-1 and decreased VCAM-1 expression compared to untreated mice. LP-ACE2-treated Akita mice exhibit significantly decreased numbers of acellular capillaries in the retina. Our study supports the beneficial role of LP-ACE2 in the restoration of intestinal lacteal integrity, which plays a key role in gut barrier integrity and systemic lipid metabolism and decreased diabetic retinopathy severity. MDPI 2023-02-23 /pmc/articles/PMC10003436/ /pubmed/36902558 http://dx.doi.org/10.3390/jcm12051771 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Prasad, Ram
Adu-Agyeiwaah, Yvonne
Floyd, Jason L.
Asare-Bediako, Bright
Li Calzi, Sergio
Chakraborty, Dibyendu
Harbour, Angela
Rohella, Aayush
Busik, Julia V.
Li, Qiuhong
Grant, Maria B.
Sustained ACE2 Expression by Probiotic Improves Integrity of Intestinal Lymphatics and Retinopathy in Type 1 Diabetic Model
title Sustained ACE2 Expression by Probiotic Improves Integrity of Intestinal Lymphatics and Retinopathy in Type 1 Diabetic Model
title_full Sustained ACE2 Expression by Probiotic Improves Integrity of Intestinal Lymphatics and Retinopathy in Type 1 Diabetic Model
title_fullStr Sustained ACE2 Expression by Probiotic Improves Integrity of Intestinal Lymphatics and Retinopathy in Type 1 Diabetic Model
title_full_unstemmed Sustained ACE2 Expression by Probiotic Improves Integrity of Intestinal Lymphatics and Retinopathy in Type 1 Diabetic Model
title_short Sustained ACE2 Expression by Probiotic Improves Integrity of Intestinal Lymphatics and Retinopathy in Type 1 Diabetic Model
title_sort sustained ace2 expression by probiotic improves integrity of intestinal lymphatics and retinopathy in type 1 diabetic model
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10003436/
https://www.ncbi.nlm.nih.gov/pubmed/36902558
http://dx.doi.org/10.3390/jcm12051771
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