Role of the high-fiber diet on the function of the intestinal stem cells and their niche

• Grant number: 19/02640-3
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• Effective date (Start): May 28, 2019
• Effective date (End): May 27, 2020
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Marco Aurélio Ramirez Vinolo
• Grantee: Renan Oliveira Corrêa
• Supervisor: Omer Yilmaz
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Research place: Massachusetts Institute of Technology (MIT), United States
• Associated to the scholarship: 16/23142-3 - Interaction between HIF-1 and short-chain fatty acids in the intestine: what is the role of HIF-1 acetylation? , BP.DR

Abstract

Dietary fibers are fermented by the intestinal microbiota generating important metabolites known as short-chain fatty acids (SCFAs). These molecules act differently on various cell lineages through three main pathways: activation of G protein-coupled receptors (GPCRs), HIF-1± stabilization and inhibition of histone deacetylases (HDACs). Recently, it has been shown that specifically on intestinal epithelial cells, SCFAs regulate the pattern of histone modifications, an effect that is related to cell proliferation and cancer. The intestinal epithelium is a single-layer barrier composed by several cell types, all originated from the intestinal stem cells (ISCs) located at the bottom of the intestinal crypts. Although some studies demonstrated that different diet approaches regulate the function of the ISCs, the impact of diets enriched in fiber on these cells is still unclear. Thus, the aim of this project is to elucidate the role of a diet enriched with inulin (a soluble fiber) on the ISCs and their niche. For that, we will keep mice on a control or high-fiber diet for 30 days and then we will analyze the number of ISCs and progenitor cells in the small intestine and colon and test the capacity of these cells to generate intestinal organoids. RNA-Seq and metabolomics analysis of these cells will also be performed, as well as ex vivo experiments with SCFAs and HDACs inhibitors to elucidate the mechanisms that account for the observed effects. Formation of primary and metastatic colon tumors will be done by orthotopic transplantation of ISCs and progenitor cells isolated from control/high-fiber diet and injected to a mice lineage without cancer predisposing mutations. (AU)