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

• Published in: The Journal of experimental medicine Vol. 217; no. 3
• Main Authors: Fachi, José Luís, Sécca, Cristiane, Rodrigues, Patrícia Brito, Mato, Felipe Cézar Pinheiro de, Di Luccia, Blanda, Felipe, Jaqueline de Souza, Pral, Laís Passariello, Rungue, Marcella, Rocha, Victor de Melo, Sato, Fabio Takeo, Sampaio, Ulliana, Clerici, Maria Teresa Pedrosa Silva, Rodrigues, Hosana Gomes, Câmara, Niels Olsen Saraiva, Consonni, Sílvio Roberto, Vieira, Angélica Thomaz, Oliveira, Sergio Costa, Mackay, Charles Reay, Layden, Brian T, Bortoluci, Karina Ramalho, Colonna, Marco, Vinolo, Marco Aurélio Ramirez
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 02.03.2020
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.20190489

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.