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Role of GPR43 receptor in intestinal epithelial cells and neutrophils during gut inflammation

Grant number: 19/14342-7
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): October 01, 2019
Effective date (End): February 28, 2023
Field of knowledge:Biological Sciences - Immunology - Cellular Immunology
Principal Investigator:Marco Aurélio Ramirez Vinolo
Grantee:Patrícia Brito Rodrigues
Home Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
Associated research grant:18/15313-8 - Investigation of the molecular mechanisms involved in the interaction between microbiota-derived metabolites and host cells during inflammation, AP.JP2

Abstract

Antibiotic-induced dysbiosis is a key factor to predispose to Clostridium difficile (Cd) infection. Cd colonizes the intestine and triggers intestinal epithelial damage by the action of its toxins A and B and intestinal inflammation. Short-Chain Fatty Acids (SCFAs) are metabolites of the intestinal microbiota from the fermentation of dietary fibers and, as shown in our previous work, protect the intestinal epithelium from damage caused by Cd toxins, as well as attenuate the inflammatory process and the systemic effects of infection. The GPR43 receptor also known as FFAR2 (Free Fatty Acid Receptor-2) is highly expressed in myeloid and intestinal epithelial cells and when activated by SCFAs it regulates important biological activities including immune and intestinal barrier functions. However, the relationship between GPR43 receptor activation in these cells and their role in controlling Cd infection has not been explored. Therefore, our goal is to identify the contribution of tissue-specific GPR43 expression during intestinal inflammation caused by Cd. For this, we will use GPR43-deletion mice in intestinal epithelial cells (VilcreFFAR2fl/fl) or in neutrophils (S100creFFAR2fl/fl), which will be infected with Cd and treated with acetate (FFAR2 linker) or placebo in drinking water; other groups will be treated with diets containing different amounts of soluble fibers with intent of analyze the effect of the endogenous production of SCFAs on the infection. Parameters including mortality, development of Colitis, intestinal barrier and immune response will be evaluated in vivo. In order to complement and deepen our study, we will also perform in vitro analyzes on neutrophils and intestinal organoids isolated from animals deficient or not for FFAR2. With the present project, we will understand the involvement and cell-specific effects of FFAR2 receptor activation, which is relevant not only for a better understanding of the microbial-host interaction, but also, potentially, for the development of new therapeutic strategies. (AU)

Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
FACHI, JOSE LUIS; SECCA, CRISTIANE; RODRIGUES, PATRICIA BRITO; PINHEIRO DE MATO, FELIPE CEZAR; DI LUCCIA, BLANDA; FELIPE, JAQUELINE DE SOUZA; PRAL, LAIS PASSARIELLO; RUNGUE, MARCELLA; ROCHA, VICTOR DE MELO; SATO, FABIO TAKEO; SAMPAIO, ULLIANA; PEDROSA SILVA CLERICI, MARIA TERESA; RODRIGUES, HOSANA GOMES; SARAIVA CAMARA, NIELS OLSEN; CONSONNI, SILVIO ROBERTO; VIEIRA, ANGELICA THOMAZ; OLIVEIRA, SERGIO COSTA; MACKAY, CHARLES REAY; LAYDEN, BRIAN T.; BORTOLUCI, KARINA RAMALHO; COLONNA, MARCO; RAMIREZ VINOLO, MARCO AURELIO. Acetate coordinates neutrophil and ILC3 responses against C. difficile through FFAR2. JOURNAL OF EXPERIMENTAL MEDICINE, v. 217, n. 3 MAR 2020. Web of Science Citations: 0.

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