Role of microbiota-derived metabolites, the short-chain fatty acids, on innate lymphoid cells

• Grant number: 18/10165-0
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• Start date: October 31, 2018
• End date: October 30, 2019
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Marco Aurélio Ramirez Vinolo
• Grantee: José Luís Fachi
• Supervisor: Marco Collona
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Institution abroad: University of Washington, United States
• Associated to the scholarship: 17/06577-9 - Mechanisms involved in the protective effect of short-chain fatty acids against Clostridium difficile-associated colitis, BP.DR

Abstract

The innate lymphoid cells (ILC) are a heterogeneous population of cells that, despite its morphological and effector similarities with T-lymphocytes, do not express T cell receptors and act in the first line of defense. These cells are found along the intestinal mucosa and play a fundamental role in the direct and indirect interactions between the microbiota and host cells. Bacterial metabolites, the short chain fatty acids (SCFAs), are produced during fiber fermentation in the gut. They are an important connection between microbiota and host affecting the development and activation of the immune system. Our hypothesis is that ILCs are key targets of SCFAs. In this context, we aim to analyze whether SCFAs, directly or indirectly (though their impact on intestinal epithelial cells), influence the maturation and function of ILCs, particularly, those of group 3. For that, we will test the direct effects of SCFAs on total and sorted-ILC3 from the lamina propria. Additionally, we intend to analyze the indirect effect of SCFAs on these cells activation. For that, we will co-cultivate intestinal organoids with ILC3 or their precursors. The intestinal organoids will be previously treated with SCFAs and then incubated with ILCs. Cytokine production (IL-17 and IL-22) by these cells will be analyzed in these experiments. For determining the molecular mechanisms by which SCFAs act on ILCs, we will evaluate the expression of molecular targets of these bacterial metabolites by qPCR and will use specific synthetic agonists of these pathways. In addition to that, we will analyze if the protective effect of SCFAs in the C. difficile infection depend on ILCs. For that, we will use Rag2 deficient (that lacks T/B lymphocytes but have intact ILCs) and Rag2/common gamma chain double knockout mice (lacks both T/B lymphocytes and ILCs) and an immunocompetent mouse model that lacks ILC3. (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)

CORREA, RENAN OLIVEIRA; CASTRO, POLLYANA RIBEIRO; FACHI, JOSE LUIS; NIRELLO, VINICIUS DIAS; EL-SAHHAR, SALMA; IMADA, SHINYA; PEREIRA, GABRIEL VASCONCELOS; PRAL, LAIS PASSARIELLO; PEREIRA ARAUJO, NATHALIA VITORIA; FERNANDES, MARIANE FONT; et al. Inulin diet uncovers complex diet-microbiota-immune cell interactions remodeling the gut epithelium. MICROBIOME, v. 11, n. 1, p. 25-pg., 2023-04-26. (16/23142-3, 21/06572-2, 19/06372-3, 19/16113-5, 19/02640-3, 18/15313-8, 20/02919-5, 17/16280-3, 20/14071-0, 21/00393-9, 17/06577-9, 20/13689-0, 21/05269-4, 20/02312-3, 18/10165-0, 20/00311-0)

WANG, QIANLI; ROBINETTE, MICHELLE L.; BILLON, CYRIELLE; COLLINS, PATRICK L.; BANDO, JENNIFER K.; FACHI, JOSE LUIS; SECCA, CRISTIANE; PORTER, SOFIA I.; SAINI, ANKITA; GILFILLAN, SUSAN; et al. Circadian rhythm-dependent and circadian rhythm-independent impacts of the molecular clock on type 3 innate lymphoid cells. SCIENCE IMMUNOLOGY, v. 4, n. 40, OCT 2019. (18/10165-0)