TY - JOUR
T1 - Acetate coordinates neutrophil and ILC3 responses against C. difficile through FFAR2
AU - Fachi, José Luís
AU - Sécca, Cristiane
AU - Rodrigues, Patrícia Brito
AU - de Mato, Felipe Cézar Pinheiro
AU - Di Luccia, Blanda
AU - de Souza Felipe, Jaqueline
AU - Pral, Laís Passariello
AU - Rungue, Marcella
AU - de Melo Rocha, Victor
AU - Sato, Fabio Takeo
AU - Sampaio, Ulliana
AU - Clerici, Maria Teresa Pedrosa Silva
AU - Rodrigues, Hosana Gomes
AU - Câmara, Niels Olsen Saraiva
AU - Consonni, Sílvio Roberto
AU - Vieira, Angélica Thomaz
AU - Oliveira, Sergio Costa
AU - Mackay, Charles Reay
AU - Layden, Brian T.
AU - Bortoluci, Karina Ramalho
AU - Colonna, Marco
AU - Vinolo, Marco Aurélio Ramirez
N1 - Funding Information:
This study was supported by a research grant from Fundação de Amparo à Pesquisa do Estado de São Paulo (12/10653-9, 17/ 16280-3). The study was also financed by the Conselho Nacional de Desenvolvimento Científico e Tecnológico and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Finance Code 001. J.L. Fachi, P.B. Rodrigues, and L.P. Pral are recipient of fellowships from Fundação de Amparo à Pesquisa do Estado de São Paulo (2017/06577-9, 2019/14342-7, 2018/02208-1). M. Co-lonna was supported by Mucosal Immunology Studies Team, National Institute of Allergy and Infectious Diseases, National Institutes of Health (U01 AI095542). B.T. Layden is supported by the National Institutes of Health under award number R01DK104927-01A1; University of Chicago Diabetes Research and Training Center (P30DK020595); and Department of Veterans’ Affairs, Veterans Health Administration, Office of Research and Development, VA merit (grant no. 1I01BX003382-01-A1).
Publisher Copyright:
© 2019 Fachi et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
PY - 2020/3/2
Y1 - 2020/3/2
N2 - 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, acetateFFAR2 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.
AB - 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, acetateFFAR2 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.
UR - http://www.scopus.com/inward/record.url?scp=85077219688&partnerID=8YFLogxK
U2 - 10.1084/jem_20190489
DO - 10.1084/jem_20190489
M3 - Article
C2 - 31876919
AN - SCOPUS:85077219688
SN - 0022-1007
VL - 217
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 3
M1 - e20190489
ER -