Acetate coordinates neutrophil and ILC3 responses against C. difficile through FFAR2
José Luís Fachi1,2, Cristiane Sécca2, Patrícia Brito Rodrigues1
1Laboratory of Immunoinflammation, Department of Genetics and Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, Brazil.
The Journal of Experimental Medicine
|December 27, 2019
Summary
Short-chain fatty acid acetate, a metabolite from gut bacteria, significantly reduces disease severity in a mouse model of Clostridium difficile infection. Acetate enhances innate immunity by boosting neutrophil and ILC3 cell responses via FFAR2 signaling.
Area of Science:
- Microbiology
- Immunology
- Gastroenterology
Background:
- Antibiotic use disrupts gut microbiota, leading to dysbiosis and increasing susceptibility to Clostridium difficile infections (CDIs).
- CDIs manifest as intestinal diseases, from mild diarrhea to severe pseudomembranous colitis.
- Microbiota-derived metabolites play crucial roles in host-microbe interactions and immune modulation.
Purpose of the Study:
- To investigate the therapeutic potential of acetate, a short-chain fatty acid, in an acute mouse model of Clostridium difficile infection.
- To elucidate the underlying mechanisms by which acetate influences the host's innate immune response against C. difficile.
Main Methods:
- An acute mouse model of Clostridium difficile infection was established.
- Acetate was administered to mice to assess its effect on disease amelioration.
- Immune cell responses, specifically neutrophils and innate lymphoid cells (ILC3s), were analyzed.
- The role of the free fatty acid receptor 2 (FFAR2) in mediating acetate's effects was examined.
Main Results:
- Administration of acetate significantly reduced the severity of Clostridium difficile infection in mice.
- Acetate enhances innate immune responses by acting on neutrophils and ILC3s through the FFAR2 receptor.
- In neutrophils, acetate promotes recruitment, inflammasome activation, and IL-1β release.
- In ILC3s, acetate upregulates IL-1 receptor expression, enhancing IL-22 secretion.
Conclusions:
- Microbiota-derived acetate is a beneficial metabolite that ameliorates Clostridium difficile infection.
- Acetate promotes host innate immunity through a coordinated action on neutrophils and ILC3s via FFAR2 signaling.
- Targeting acetate metabolism or FFAR2 signaling may represent a novel therapeutic strategy for managing CDI.
