Analysis of the role of microbiota and TLRs signaling in epigenetic modifications of intestinal epithelial cells in DSS-induced inflammation

• Grant number: 21/10478-1
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: June 01, 2022
• End date: February 28, 2026
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Marco Aurélio Ramirez Vinolo
• Grantee: Mariane Font Fernandes
• Host 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
• Associated scholarship(s): 24/05509-3 - Deciphering the mechanism and biological consequences of histone crotonylation in the intestinal epithelium, BE.EP.DR

Abstract

The intestinal commensal microbiota, in a symbiotic relationship with the host, provides the necessary stimuli to promote the production of antimicrobial peptides, increased barrier function, and proliferation of Intestinal Epithelial Cells (IECs). This interaction, which can occur through the recognition of Pathogen-Associated Molecular Patterns (PAMPs) by Toll-Like Receptors (TLRs), is an essential component for the establishment of homeostasis. Disturbances in this environment are capable of initiating intestinal inflammation, in which Histone Post-Translational Modifications (HPTMs) known to induce a transcriptionally active profile (acetylation and crotonylation) are increased in IECs by mechanisms that are still unknown. In this same context, TLR signaling pathways are activated by microorganisms present in the altered microbiota, relying on the action of the adapter protein MyD88 and the activation of the transcription factor NF-kB, for example. Considering NF-kB can recruit HATs (p300 and CBP) and HDACs (HDAC1 and SIRT6) enzymes to alter the histone acetylation profile in its target genes, we hypothesized that MyD88 and NF-kB dependent TLR signaling in the epithelium is a key mediator for these HPTMs in the early stages of intestinal inflammation. Thus, we will analyze its signaling pathway in mice treated with DSS for three days, as well as in organoid cultures by activation of cell surface TLRs by agonists, in order to verify its ability to induce this same increased acylations pattern. Additionally, we will explore changes in the gut microbiota to predict which bacteria might be involved in this response. (AU)