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.
News published in Agência FAPESP Newsletter about the scholarship: