Effects of an engineered probiotic to express GLP-1 and GLP-2 peptides in preventing and combating obesity and type 2 diabetes mellitus

• Grant number: 24/17868-8
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: May 01, 2025
• End date: April 30, 2028
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Silvana Auxiliadora Bordin da Silva
• Grantee: Paulo Henrique Evangelista Silva
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 13/07607-8 - OCRC - Obesity and Comorbidities Research Center, AP.CEPID

Abstract

Injectable analogs of GLP-1 and GLP-2 are commonly used for the treatment of obesity type 2diabetes mellitus (T2DM). Currently, applications of these hormones in the form of the peptideitself are limited due to their short half-life. The oral administration of a therapeutic peptide (TP) represents a significant biomedical advancement, yet it faces challenges related to gastrointestinalinstability. Genetically modified bacteria present a novel tool for the delivery of TPs, with strainssuch as Lactococcus lactis (LL) standing out for their probiotic properties beneficial to humanhealth. Thus, we propose the development of a recombinant probiotic for GLP-1 and GLP-2peptides. We will utilize the LL strain engineered for express the GLP-1 and/or GLP-2 gene (LLGLP-1/GLP-2) in the prevention and/or treatment of obesity and T2DM. We hypothesize that theingestion of LL-GLP-1/GLP-2 has the potential to combat and prevent obesity and T2DM bypromoting functional and molecular changes that are preventive and/or protective, primarily in theintestine and intestinal microbiota, consequently reducing the adverse effects of obesity and T2DMon peripheral tissues. To this end, we will combine current methodologies and technologies todevelop LL-GLP-1/GLP-2 and investigate its potential impacts on preventing and treating body mass gain and glucose regulation. We seek to understand whether the effects of LL-GLP-1/GLP-2 can be attributed to the intestine and the microbiota. We will gather anthropometric andfunctional analyses; plasma and serum assessments and feces; as well as cellular and molecularanalyses, RT-qPCR, and Western blotting of tissues, which will be distinctly applied acrossdifferent preclinical experimental models. Our findings will shed light on a new, cost-effectivestrategy for the prevention and/or treatment of obesity and T2DM in Brazil and worldwide