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.

The definition of neutrophil extracellular traps and the concentration of short-chain fatty acids in salmonella-induced inflammation of the intestine against the background of vancomycin and Bacteroides fragilis

“…Thus, scientists, who used a subcutaneous model of opportunistic infection, caused by pathogenic microorganisms A. actinomycetemcomitans, demonstrated that the presence of SCFA did not affect the number of leukocytes, but they reduced significantly the production of cytokines, phagocytic activity and caused the death of bacteria, but did not lead to a change in effector mechanisms of neutrophils. A similar effect that was not associated with the activation of FFAR2 and the main SCFA receptor expressed on the surface of neutrophils was also observed in the stimulation of neutrophils by bacteria, which may have been due to the inhibition of histonedeacetylases [57][58][59]. Of particular interest are the results of studies obtained by Brinkmann (2004), who showed that the infection of S. typhimurium and S.enteritidis, the main agents of gastroenteritis development, against the background of the dysbiotic changes in the intestinal microflora, can enhance the formation of NETs due to the action of superoxidedismutase [60][61][62].…”

HDAC inhibitors modulate innate immune responses to micro-organisms relevant to chronic mucocutaneous candidiasis

“…RGFP966 is a specific HDAC3 inhibitor linked to down‐regulation of phagocytic function of neutrophils in an Acinetobacter actinomycetemcomitans in‐vitro assay, whereas cytokine production by neutrophils was largely unaffected, except for lower levels of TNF‐α []. Earlier this year another study assessed the effect of RGFP966 on primary microglia and found that immune pathways linked to the TLR signalling and STAT‐3 and STAT‐5 were impacted strongly by RGFP966 [].…”

Deciphering interactions between the gut microbiota and the immune system via microbial cultivation and minimal microbiomes

“…SCFA promote neutrophil activation and migration via upregulation of adhesion molecules and increased chemokine production (151, 152). However, they can also dampen neutrophil effector functions such as phagocytosis, bacterial killing and cytokine production (153). …”

“…151,152 However, they can also dampen neutrophil effector functions such as phagocytosis, bacterial killing, and cytokine production. 153 Many reports in the literature also describe the profound impact of SCFA on the adaptive immune system, particularly T-cell phenotypes.…”