Investigation of the molecular mechanisms involved in the interaction between microbiota-derived metabolites and host cells during inflammation

• Grant number: 18/15313-8
• Support type: Research Grants - Young Investigators Grants- Phase 2
• Duration: May 01, 2019 - April 30, 2024
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Marco Aurélio Ramirez Vinolo
• Grantee: Marco Aurélio Ramirez Vinolo
• Home Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated research grant: 12/10653-9 - Role of short chain fatty acids and their receptor (GPR43) in the immune response to anaerobic bacteria in vivo and in vitro, AP.JP
• Associated grant(s): 20/04583-4 - Impact of intestinal microbiota and its metabolites on SARS-CoV-2 infection, AP.R
• Associated scholarship(s): 20/02919-5 - Relevance of the FFAR2 receptor on the biological responses of stem cells and Intestinal Epithelial Cells (IECs) during inflammatory conditions, BP.PD; 20/02685-4 - Investigation of the effect of gut dysbiosis on histone post-translational modifications in neutrophils, BP.PD; 20/00465-7 - Relevance of SCFAs-induced histone acylation in neutrophils production of inflammatory mediators, BP.DD; + associated scholarships 20/02312-3 - Study of the effect of short-chain fatty acids on the tissue regeneration process during experimental colitis, BP.DD; 19/14342-7 - Role of GPR43 receptor in intestinal epithelial cells and neutrophils during gut inflammation, BP.DR; 19/11662-0 - Participation of the FFAR2 receptor in the inflammation in a DSS-induced colitis model, BP.MS - associated scholarships

Abstract

How the microbiota communicates with the host and contributes to health is a key question for progress in this research field. Bacterial metabolites called short chain fatty acids (SCFAs), which are generated by fermentation of non-digestible carbohydrates, constitute a link between microbiota and host cells. Previous studies demonstrated that these metabolites regulate host metabolism and immunity. However, the molecular mechanisms are not totally defined. The aim of this project is to investigate this by examining 1) activation of the SCFA receptor FFAR2 (GPR43) and 2) modification of the pattern of histone acylations (mainly, acetylation and crotonylation) in neutrophils and intestinal epithelial cells (IECs) and their biological relevance in inflammatory models. For this, we will 1) characterize, using cell-specific knockout mice, the role of FFAR2 in neutrophil and IEC functions, and its participation in inflammasome activation and relevance during intestinal inflammation and; 2) investigate the effect of SCFAs on the pattern of histone acylation in intestinal epithelial cells and neutrophils and how this affects their transcriptional and effector responses during inflammation. With this, we will contribute to the understanding of the molecular mechanisms of microbial-host interaction and identification of new biomarkers and therapeutic targets for inflammatory diseases. (AU)