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Angiotensin-(1-7) Expressed From Lactobacillus Bacteria Protect Diabetic Retina in Mice
Amrisha Verma1, Ping Zhu1, Kang Xu1
1Department of Ophthalmology, College of Medicine, University of Florida, Gainesville, Florida, USA.
Purpose:
A multitude of animal studies substantiates the beneficial effects of Ang-(1-7), a peptide hormone in the protective axis of the renin angiotensin system, in diabetes and its associated complications including diabetic retinopathy (DR). However, the clinical application of Ang-(1-7) is limited due to unfavorable pharmacological properties. As emerging evidence implicates gut dysbiosis in pathogenesis of diabetes and supports beneficial effects of probiotics, we sought to develop probiotics-based expression and delivery system to enhance Ang-(1-7) and evaluate the efficacy of engineered probiotics expressing Ang-(1-7) in attenuation of DR in animal models.
Methods:
Ang-(1-7) was expressed in the Lactobacillus species as a secreted fusion protein with a trans-epithelial carrier to allow uptake into circulation. To evaluate the effects of Ang-(1-7) expressed from Lactobacillus paracasei (LP), adult diabetic eNOS-/- and Akita mice were orally gavaged with either 1 × 109 CFU of LP secreting Ang-(1-7) (LP-A), LP alone or vehicle, 3 times/week, for 8 and 12 weeks, respectively.
Results:
Ang-(1-7) is efficiently expressed from different Lactobacillus species and secreted into circulation in mice fed with LP-A. Oral administration of LP-A significantly reduced diabetes-induced loss of retinal vascular capillaries. LP-A treatment also prevented loss of retinal ganglion cells, and significantly decreased retinal inflammatory cytokine expression in both diabetic eNOS-/- and Akita mice.
Conclusions:
These results provide proof-of-concept for feasibility and efficacy of using engineered probiotic species as live vector for delivery of Ang-(1-7) with enhanced bioavailability.
Translational Relevance:
Probiotics-based delivery of Ang-(1-7) may hold important therapeutic potential for the treatment of DR and other diabetic complications.
Insights
Engineered probiotics successfully delivered Angiotensin-(1-7) (Ang-(1-7)) in diabetic mice, significantly reducing diabetic retinopathy complications. This novel approach enhances Ang-(1-7) bioavailability for potential therapeutic use.
Area of Science:
- Cardiovascular Research
- Microbiology
- Ophthalmology
Background:
- The peptide hormone Angiotensin-(1-7) (Ang-(1-7)) shows promise in mitigating diabetes complications like diabetic retinopathy (DR).
- Clinical use of Ang-(1-7) is hindered by poor pharmacological properties.
- Gut dysbiosis is implicated in diabetes, and probiotics offer therapeutic benefits.
Purpose of the Study:
- To develop a probiotic-based system for enhanced expression and delivery of Ang-(1-7).
- To evaluate the efficacy of engineered probiotics expressing Ang-(1-7) in an animal model of diabetic retinopathy.
Main Methods:
- Ang-(1-7) was engineered for secretion from Lactobacillus paracasei (LP) using a trans-epithelial carrier.
- Diabetic mice (eNOS-/- and Akita) were orally administered LP secreting Ang-(1-7) (LP-A), LP alone, or vehicle.
Main Results:
- LP-A efficiently secreted Ang-(1-7) into circulation in mice.
- LP-A treatment significantly reduced diabetes-induced loss of retinal vascular capillaries and retinal ganglion cells.
- LP-A administration decreased retinal inflammatory cytokine expression in diabetic mice.
Conclusions:
- Engineered probiotics serve as effective live vectors for delivering Ang-(1-7) with improved bioavailability.
- Probiotic-based delivery of Ang-(1-7) demonstrates therapeutic potential for diabetic retinopathy and other diabetic complications.
