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

Author(s):Show less -

Fachi, Jose Luis ^{[1, 2]} ; Secca, Cristiane ^[1] ; Rodrigues, Patricia Brito ^[2] ; Pinheiro de Mato, Felipe Cezar ^[2] ; Di Luccia, Blanda ^[1] ; Felipe, Jaqueline de Souza ^[2] ; Pral, Lais Passariello ^[2] ; Rungue, Marcella ^[3] ; Rocha, Victor de Melo ^[3] ; Sato, Fabio Takeo ^[2] ; Sampaio, Ulliana ^[4] ; Pedrosa Silva Clerici, Maria Teresa ^[4] ; Rodrigues, Hosana Gomes ^[5] ; Saraiva Camara, Niels Olsen ^[6] ; Consonni, Silvio Roberto ^[7] ; Vieira, Angelica Thomaz ^[3] ; Oliveira, Sergio Costa ^[3] ; Mackay, Charles Reay ^[8] ; Layden, Brian T. ^{[9, 10]} ; Bortoluci, Karina Ramalho ^[11] ; Colonna, Marco ^[1] ; Ramirez Vinolo, Marco Aurelio ^{[2, 12]}

Affiliation:Show less -

^[1] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63130 - USA

^[2] Univ Estadual Campinas, Inst Biol, Dept Genet & Evolut Microbiol & Immunol, Lab Immunoinflammat, Campinas - Brazil

^[3] Univ Fed Minas Gerais, Inst Biol Sci, Dept Biochem & Immunol, Belo Horizonte, MG - Brazil

^[4] Univ Estadual Campinas, Sch Food Engn, Dept Food Technol, Campinas - Brazil

^[5] Univ Estadual Campinas, Sch Appl Sci, Lab Nutrients & Tissue Repair, Limeira - Brazil

^[6] Univ Sao Paulo, Inst Biomed Sci, Dept Immunol, Sao Paulo - Brazil

^[7] Univ Estadual Campinas, Inst Biol, Dept Biochem & Tissue Biol, Campinas - Brazil

^[8] Monash Univ, Dept Immunol, Melbourne, Vic - Australia

^[9] Univ Illinois, Dept Med, Div Endocrinol Diabet & Metab, Chicago, IL - USA

^[10] Jesse Brown Vet Med Ctr, Chicago, IL - USA

^[11] Univ Fed Sao Paulo, Ctr Cellular & Mol Therapy, Sao Paulo - Brazil

^[12] Expt Med Res Cluster, Campinas - Brazil

• Document type: Journal article
• Source: JOURNAL OF EXPERIMENTAL MEDICINE; v. 217, n. 3 MAR 2020.
• Web of Science Citations: 0

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-1 beta; in ILC3s, acetate-FFAR2 augments expression of the IL-1 receptor, which boosts IL-22 secretion in response to IL-1 beta. We conclude that microbiota-derived acetate promotes host innate responses to C. difficile through coordinate action on neutrophils and ILC3s. (AU)

• FAPESP's process: 17/06577-9 - Mechanisms involved in the protective effect of short-chain fatty acids against Clostridium difficile-associated colitis
• Grantee: José Luís Fachi
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 19/14342-7 - Comparison of gamma variant tropism and pathogenicity versus original SARS CoV-2 in humanized K18-ACE2 mice: role of gut microbiota
• Grantee: Patrícia Brito Rodrigues
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 12/10653-9 - Role of short chain fatty acids and their receptor (GPR43) in the immune response to anaerobic bacteria in vivo and in vitro
• Grantee: Marco Aurélio Ramirez Vinolo
• Support Opportunities: Research Grants - Young Investigators Grants
• FAPESP's process: 18/02208-1 - Effect of short chain fatty acids on the function of type 3 innate lymphoid cells: involvement of the FFAR2 receptor in this process
• Grantee: Laís Passariello Pral
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 17/16280-3 - Role of the interaction between HIF-1 and the short chain fatty acids in the colon in physiological and pathologycal conditions (intestinal inflammation)
• Grantee: Marco Aurélio Ramirez Vinolo
• Support Opportunities: Regular Research Grants