The gut-brain axis in GIPR KO mice: neuroprotective effect, immune function, and microbiota dependence

• Grant number: 23/06373-5
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate (Direct)
• Start date: November 30, 2023
• End date: November 29, 2024
• Field of knowledge: Biological Sciences - Immunology - Applied Immunology
• Principal Investigator: Alvaro Pacheco e Silva Filho
• Grantee: Eloisa Martins da Silva
• Supervisor: Daniel Drucker
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Institution abroad: Lunenfeld-Tanenbaum Research Institute, Canada
• Associated to the scholarship: 20/14388-4 - Incretin signal in tumor progression in the experimental model of Colorectal Cancer associated with Colitis, BP.DD

Abstract

Evidence suggests that Ulcerative colitis (UC) plays a role in the development of neuroinflammation, increasing the risk of developing cognitive diseases. The gut-brain-microbiota (GBA) is an intricate network connection among neural, microbial, endocrine, and immune systems, that could be mediated by many endocrine factors, including the incretin hormone glucose-dependent insulinotropic polypeptide (GIP). GIP acts in different tissues and cells, such as the gut, adipose tissue, pancreas, immune cells, and the brain. Indeed, GIP can be modulated by the microbiota and is associated with functions of the nervous system. New therapies targeting GIP have been studied in brain disorders, placing the hormone as a bridge that mediates the interaction between the gut and the brain. Given the broad action of GIP signaling, in this project, we hypothesize that deficiency in GIP- glucose-dependent insulinotropic polypeptide receptor (GIPR) signaling during gut inflammation may cause worse gut damage, favoring the development of brain disorders. To test this, we will induce acute colitis in wildtype and GIPR KO mice and measure gut permeability, cytokines productions, innate and adaptive immune cells (Th1, Th17, Treg, neutrophils, and macrophages), and brain (astrocytes and microglia) by FACS, qPCR, and the hormone GIP by Elisa. Moreover, to understand the microbiota modulation, we will perform a 16s rRNA gene sequencing to characterize the fecal microflora and transfer the changed gut microbiota into germ-free WT mice. We hope these findings uncover the GIP as a link between gut inflammation and dysbiosis and neuroinflammation paving the way for new possibilities for the treatment of inflammation-mediated diseases in the gut and the nervous system. (AU)