EXTERNAL MEMBRANE VESICLES (OMVS) OF AKKERMANSIA MUCINIPHILA AS A THERAPEUTIC INTERVENTION IN TYPE 2 DIABETES EXPERIMENTAL

• Grant number: 21/14793-9
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Effective date (Start): January 01, 2023
• Effective date (End): February 28, 2023
• Field of knowledge: Health Sciences - Nutrition
• Principal Investigator: Daniela Carlos Sartori
• Grantee: Caroline Bertoncini Silva
• 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

The etiology of type 2 Diabetes Mellitus (DM2) is multifactorial, linked to genetic, environmental, dietary and metabolic factors. The gut microbiota plays an important role in intestinal homeostasis through the expression of microorganism-associated molecular patterns (MAMPs), production of metabolites, and secretion of outer membrane vesicles (outer membrane vesicles or OMV). Through interaction with innate immunity leukocytes and intestinal epithelial cells via pattern recognition receptors (PRR), the gut microbiota contributes to the regulation of the intestinal barrier and control of meta-inflammation in metabolic diseases. Our group of research found an association between meta-inflammation and reduced abundance of probiotic bacteria Akkermansia muciniphila during the progression of DM2. A. muciniphila has been shown to increase the number of goblet cells in the intestine, thereby restoring the mucus layer that is damaged in the high-fat diet-induced obesity (HFD) model. In addition, A. muciniphila OMVs (AmOMV) act to maintain the integrity of the epithelial barrier by increasing the expression of cell junction proteins, such as occludin, claudin-4 and reducing toll-like receptors (toll-like receptors or TLR) such as TLR2 and TLR4. Furthermore, AmOMV promotes the reduction of pro-inflammatory cytokines TNF-± and IL-6 and potentiates IL-4, so our hypothesis is that their administration in obese mice is able to control meta-inflammation via induction of M2 macrophages and prevent/slow DM2 progression. Given this scenario, we intend to assess whether the in vitro stimulation of bone marrow-derived macrophages with AmOMV promotes, directly or indirectly, the differentiation of type 2 (M2) macrophages in vitro. In parallel, we will test whether the administration of AmOMV promotes a resolving/anti-inflammatory microenvironment of M2 macrophages in the visceral adipose tissue (VAT) with the ability to attenuate the inflammatory and metabolic changes that occur with DM2 induced by HFD. The results obtained in this project may show the use of AmOMV as a potential adjuvant therapeutic approach in the treatment of DM2.