Evaluation of the therapeutic potential of Lactococcus lactis expressing IL-17 in Obesity-induced type 2 Diabetes

• Grant number: 21/13597-1
• Support Opportunities: Scholarships in Brazil - Doctorate
• Effective date (Start): July 01, 2022
• Effective date (End): August 31, 2025
• Field of knowledge: Biological Sciences - Immunology - Applied Immunology
• Principal Investigator: Daniela Carlos Sartori
• Grantee: Sara Cândida Barbosa
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 18/14815-0 - Evaluation of the intestinal microbioma profile and of the therapeutic potential of intervention strategies in the immunopathogeny of type 1 and 2 Diabetes, AP.JP2

Abstract

Obesity is a chronic disease with a multifactorial etiology that predisposes to other comorbidities, such as Type 2 Diabetes Mellitus (T2D), being capable of altering energy homeostasis due to the excessive accumulation of lipids and influx of inflammatory cells into the adipose tissue. T2D is characterized by hyperglycemia due to insufficient insulin secretion or insulin resistance, which can result in the death of pancreatic cells, changes in the composition and functionality of the intestinal microbiota, associated with high intestinal permeability. It has been described that Obesity induced by a High Fat Diet (HFD) decreases TH17 lymphocytes in the intestine and that the adoptive transfer of these cells to obese mice attenuated the metabolic and inflammatory dysfunction in the Visceral Adipose Tissue (VAT). Our research group demonstrated that NOD2 receptor deficiency provided rapid progression of T2D in the model of Obesity induced by HFD, in addition to intestinal dysbiosis, bacterial translocation in VAT and loss of intestinal epithelial integrity. Additionally, there was a reduction in TH17 lymphocytes and an increase in TH1 in the intestinal mucosa of the ileum of these animals, inferring that the prevalence of TH17 lymphocytes in the intestine contributes to the maintenance of the epithelial barrier and limits the metainflammation in VAT, which precedes the onset of T2D. Thus, this work aims to investigate the therapeutic use of the probiotic Lactococcus lactis that expresses IL-17 in the control of Obesity-induced T2D, due to the ability of this bacterium to function as a localized and transient expression vector of heterologous IL-17 in the intestine. In parallel, we intend to evaluate the direct effect of L. lactis expressing IL-17 on the integrity, regeneration and permeability of epithelial cells using intestinal organoids. (AU)