Angiotensin-(1-7) Expressed From Lactobacillus Bacteria Protect Diabetic Retina in Mice

Transl Vis Sci Technol. 2020 Dec 14;9(13):20. doi: 10.1167/tvst.9.13.20. eCollection 2020 Dec.

Abstract

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.

Keywords: Lactobacillus; Lactobacillus paracasei; angiotensin-(1–7); diabetes; diabetic complications; diabetic retinopathy; probiotics; renin angiotensin system.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin I
  • Animals
  • Diabetes Mellitus*
  • Lactobacillus*
  • Mice
  • Peptide Fragments
  • Retina

Substances

  • Peptide Fragments
  • Angiotensin I
  • angiotensin I (1-7)