Acetate coordinates neutrophil and ILC3 responses against C. difficile through FFAR2

José Luís Fachi, Cristiane Sécca, Patrícia Brito Rodrigues, Felipe Cézar Pinheiro de Mato, Blanda Di Luccia, Jaqueline de Souza Felipe, Laís Passariello Pral, Marcella Rungue, Victor de Melo Rocha, Fabio Takeo Sato, Ulliana Sampaio, Maria Teresa Pedrosa Silva Clerici, Hosana Gomes Rodrigues, Niels Olsen Saraiva Câmara, Sílvio Roberto Consonni, Angélica Thomaz Vieira, Sergio Costa Oliveira, Charles Reay Mackay, Brian T. Layden, Karina Ramalho BortoluciMarco Colonna, Marco Aurélio Ramirez Vinolo

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6 Scopus citations

Abstract

Antibiotic-induced dysbiosis is a key predisposing factor for Clostridium difficile infections (CDIs), which cause intestinal disease ranging from mild diarrhea to pseudomembranous colitis. Here, we examined the impact of a microbiota-derived metabolite, short-chain fatty acid acetate, on an acute mouse model of CDI. We found that administration of acetate is remarkably beneficial in ameliorating disease. Mechanistically, we show that acetate enhances innate immune responses by acting on both neutrophils and ILC3s through its cognate receptor free fatty acid receptor 2 (FFAR2). In neutrophils, acetate-FFAR2 signaling accelerates their recruitment to the inflammatory sites, facilitates inflammasome activation, and promotes the release of IL-1β; in ILC3s, acetate-FFAR2 augments expression of the IL-1 receptor, which boosts IL-22 secretion in response to IL-1β. We conclude that microbiota-derived acetate promotes host innate responses to C. difficile through coordinate action on neutrophils and ILC3s.

Original languageEnglish
JournalThe Journal of experimental medicine
Volume217
Issue number3
DOIs
StatePublished - Mar 2 2020

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    Fachi, J. L., Sécca, C., Rodrigues, P. B., Mato, F. C. P. D., Di Luccia, B., Felipe, J. D. S., Pral, L. P., Rungue, M., Rocha, V. D. M., Sato, F. T., Sampaio, U., Clerici, M. T. P. S., Rodrigues, H. G., Câmara, N. O. S., Consonni, S. R., Vieira, A. T., Oliveira, S. C., Mackay, C. R., Layden, B. T., ... Vinolo, M. A. R. (2020). Acetate coordinates neutrophil and ILC3 responses against C. difficile through FFAR2. The Journal of experimental medicine, 217(3). https://doi.org/10.1084/jem.20190489