title: Bacterial short-chain fatty acid metabolites modulate the inflammatory response against infectious bacteria.
abstract: Short-chain fatty acids (SCFAs), predominantly acetic, propionic, and butyric acids, are bacterial metabolites with an important role in the maintenance of homeostasis due to their metabolic and immunomodulatory actions. Some evidence suggests that they may also be relevant during infections. Therefore, we aimed to investigate the effects of SCFAs in the effector functions of neutrophils to an opportunistic pathogenic bacterium, Aggregatibacter actinomycetemcomitans. Using a subcutaneous model to generate a mono, isolated infection of A. actinomycetemcomitans, we demonstrated that the presence of the SCFAs in situ did not affect leukocyte accumulation but altered the effector mechanisms of migrating neutrophils by downregulating the production of cytokines, their phagocytic capacity, and killing the bacteria, thus impairing the containment of A. actinomycetemcomitans. Similar effects were observed with bacteria-stimulated neutrophils incubated with SCFAs in vitro. These effects were independent of free-fatty acid receptor 2 (FFAR2) activation, the main SCFA receptor expressed on neutrophils, occurring possibly through inhibition of histone deacetylases because similar effects were obtained by using histone deacetylase inhibitors, such as SAHA, MS-275, and RGFP 966. Considering the findings of this study, we hypothesized that in an infectious condition, SCFAs may exert a detrimental effect on the host by inhibiting neutrophil's effector functions.
authors.affiliation: Laboratory of Immunoinflammation, Department of Genetics, Evolution and Bioagents, Institute of Biology, University of Campinas, Campinas, São Paulo, Brazil.
authors.forename: R O
authors.initials: RO
authors.lastname: Corrêa
authors.affiliation: Laboratory of Immunoinflammation, Department of Genetics, Evolution and Bioagents, Institute of Biology, University of Campinas, Campinas, São Paulo, Brazil.
authors.forename: A
authors.initials: A
authors.lastname: Vieira
authors.affiliation: Laboratory of Immunoinflammation, Department of Genetics, Evolution and Bioagents, Institute of Biology, University of Campinas, Campinas, São Paulo, Brazil.
authors.forename: E M
authors.initials: EM
authors.lastname: Sernaglia
authors.affiliation: Laboratory of Biotechnology, Department of Biochemistry, Institute of Biology, University of Campinas, Campinas, São Paulo, Brazil.
authors.forename: M
authors.initials: M
authors.lastname: Lancellotti
authors.affiliation: Immunopharmacology Group, Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: A T
authors.initials: AT
authors.lastname: Vieira
authors.affiliation: Anaerobe Laboratory, Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
authors.forename: M J
authors.initials: MJ
authors.lastname: Avila-Campos
authors.affiliation: Laboratory of Nutrients and Tissue Repair, School of Applied Sciences, University of Campinas, Limeira, São Paulo, Brazil.
authors.forename: H G
authors.initials: HG
authors.lastname: Rodrigues
authors.affiliation: Laboratory of Immunoinflammation, Department of Genetics, Evolution and Bioagents, Institute of Biology, University of Campinas, Campinas, São Paulo, Brazil.
authors.forename: M A R
authors.identifier: 0000-0003-1335-760X
authors.initials: MAR
authors.lastname: Vinolo
mesh_terms: D019342:Acetic Acid / Q000378:metabolism / Q000494:pharmacology*; D000178:Acrylamides / Q000494:pharmacology; D016976:Aggregatibacter actinomycetemcomitans / Q000276:immunology*; D000818:Animals; D002087:Butyrates / Q000378:metabolism / Q000494:pharmacology*; D016207:Cytokines / Q000096:biosynthesis; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism; D007249:Inflammation / Q000276:immunology; D007958:Leukocyte Count; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000276:immunology*; D009757:Nylons / Q000494:pharmacology; D016871:Pasteurellaceae Infections / Q000276:immunology* / Q000382:microbiology; D010587:Phagocytosis / Q000187:drug effects; D010655:Phenylenediamines / Q000494:pharmacology; D011422:Propionates / Q000378:metabolism / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology
chemical_list: D000178:Acrylamides; D002087:Butyrates; D016207:Cytokines; D056572:Histone Deacetylase Inhibitors; D009757:Nylons; D010655:Phenylenediamines; D011422:Propionates; D011758:Pyrroles; C000603861:RGFP966; C585734:SAHA-PIP-delta; D006655:Histone Deacetylases; C029658:propionic acid; D019342:Acetic Acid
keywords: Aggregatibacter actinomycetemcomitans; anaerobic bacteria; butyrate; histone deacetylases; neutrophils; propionate