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Heterologous Expression and Delivery of Biologically Active Exendin-4 by Lactobacillus paracasei L14
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Heterologous Expression and Delivery of Biologically Active Exendin-4 by Lactobacillus paracasei L14
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Journal Article
Heterologous Expression and Delivery of Biologically Active Exendin-4 by Lactobacillus paracasei L14
2016
Overview
Exendin-4, a glucagon-like protein-1 (GLP-1) receptor agonist, is an excellent therapeutic peptide drug for type 2 diabetes due to longer lasting biological activity compared to GLP-1. This study explored the feasibility of using probiotic Lactobacillus paracasei as an oral vector for recombinant exendin-4 peptide delivery, an alternative to costly chemical synthesis and inconvenient administration by injection. L. paracasei transformed with a plasmid encoding the exendin-4 gene (L. paracasei L14/pMG76e-exendin-4) with a constitutive promotor was successfully constructed and showed efficient secretion of exendin-4. The secreted exendin-4 significantly enhanced insulin secretion of INS-1 β-cells, along with an increment in their proliferation and inhibition of their apoptosis, corresponding to the effect of GLP-1 on these cells. The transcription level of the pancreatic duodenal homeobox-1 gene (PDX-1), a key transcription factor for cellular insulin synthesis and secretion, was upregulated by the treatment with secreted exendin-4, paralleling the upregulation of insulin gene expression. Caco-2 cell monolayer permeability assay showed a 34-fold increase in the transport of exendin-4 delivered by L. paracasei vs. that of free exendin-4 (control), suggesting effective facilitation of exendin-4 transport across the intestinal barrier by this delivery system. This study demonstrates that the probiotic Lactobacillus can be engineered to secrete bioactive exendin-4 and facilitate its transport through the intestinal barrier, providing a novel strategy for oral exendin-4 delivery using this lactic acid bacterium.
Publisher
Public Library of Science,Public Library of Science (PLoS)
Subject
/ Animals
/ Bacteria
/ Cell Proliferation - drug effects
/ Diabetes
/ Diabetes mellitus (non-insulin dependent)
/ Enzymes
/ Gene Expression Regulation, Bacterial - drug effects
/ Glucagon
/ Homeobox
/ Homeodomain Proteins - genetics
/ Homeodomain Proteins - metabolism
/ Humans
/ Insulin
/ Kinases
/ Lactobacillus paracasei - genetics
/ Lactobacillus paracasei - metabolism
/ Medicine and Health Sciences
/ Pancreas
/ Peptides
/ Peptides - administration & dosage
/ Proteins
/ Rats
/ Recombinant Proteins - administration & dosage
/ Recombinant Proteins - biosynthesis
/ Recombinant Proteins - genetics
/ Recombinant Proteins - pharmacology
/ Research and Analysis Methods
/ Rodents
/ Trans-Activators - metabolism
/ Up-Regulation - drug effects
