Short-Chain Fatty Acids Promote Intracellular Bactericidal Activity in Head Kidney Macrophages From Turbot (Scophthalmus maximus L.) via Hypoxia Inducible Factor-1α

Abstract

Short-chain fatty acids (SCFAs) are mainly produced by microbiota through the fermentation of carbohydrates in the intestine. Acetate, propionate, and butyrate are the most abundant SCFA metabolites and have been shown to be important in the maintenance of host health. In this study, head kidney macrophages (HKMs) were isolated and cultured from turbots. We found that the antibacterial activity of HKMs was increased after these cells were incubated with sodium butyrate, sodium propionate or sodium acetate. Interestingly, our results showed that all three SCFAs enhanced the expression of hypoxia inducible factor-1 α (HIF-1α) in HKMs, and further study confirmed that butyrate augmented the oxygen consumption of these cells. Moreover, HIF-1α inhibition diminished the butyrate-promoted intracellular bacterial killing activity of macrophages, and SCFAs also raised the gene expression and activity of lysozymes in HKMs via HIF-1α signaling. In addition, our results suggested that butyrate induced HIF-1α expression and the bactericidal activity of HKMs through histone deacetylase inhibition, while G protein-coupled receptors did not contribute to this effect. Finally, we demonstrated that butyrate induced a similar response in the murine macrophage cell line RAW264.7. In conclusion, our results demonstrated that SCFAs promoted HIF-1α expression via histone deacetylase inhibition, leading to the enhanced production of antibacterial effectors and increased bacterial killing of macrophages.

Acetate Improves the Killing of Streptococcus pneumoniae by Alveolar Macrophages via NLRP3 Inflammasome and Glycolysis-HIF-1α Axis

“…In line with our finding, butyrate was shown to improve the killing ability of macrophages via HIF-1a activation (46). However, while we propose that acetate does so by modulating glycolysis and NO production, butyrate seems to activate HIF-1a through inhibition of histone deacetylase (HDAC) leading to increased activity of lysozymes, which boost bacterial killing (46). Another study showed that butyrate inhibits HDAC3 activity, leading to reprogramming during the monocyte-to-macrophage differentiation, ultimately resulting in enhanced production of antimicrobial peptides and high bactericidal activity.…”

“…In parallel, acetate relied on NLRP3 inflammasome to increase IL-1b secretion which enhanced NO production in an autocrine manner, leading to bacterial killing (Figure 7). Despite the described role of SCFAs to improve the killing ability of macrophages, the mechanisms of action are only described for butyrate (16,(42)(43)(44)(45)(46)(47). In line with our finding, butyrate was shown to improve the killing ability of macrophages via HIF-1a activation (46).…”

“…Despite the described role of SCFAs to improve the killing ability of macrophages, the mechanisms of action are only described for butyrate (16,(42)(43)(44)(45)(46)(47). In line with our finding, butyrate was shown to improve the killing ability of macrophages via HIF-1a activation (46). However, while we propose that acetate does so by modulating glycolysis and NO production, butyrate seems to activate HIF-1a through inhibition of histone deacetylase (HDAC) leading to increased activity of lysozymes, which boost bacterial killing (46).…”

Novel Insight Into Nutritional Regulation in Enhancement of Immune Status and Mediation of Inflammation Dynamics Integrated Study In Vivo and In Vitro of Teleost Grass Carp (Ctenopharyngodon idella): Administration of Threonine

“…Macrophages executed the basic role of phagocytosis and immune system motivation ( 106 ). The activated macrophages could be mainly characterized as canonical M1 and M2 types, which were in charge of the pro- and anti-inflammation responses, respectively.…”

Development and Validation of a LC-MS/MS Technique for the Analysis of Short Chain Fatty Acids in Tissues and Biological Fluids without Derivatisation Using Isotope Labelled Internal Standards

“…As well as providing energy for colonic cells important for gut barrier integrity, SCFAs have emerged as energy substrates for colonic and liver cells and as signalling molecules influencing a range of metabolic and physiological pathways in the liver, brain, kidney, and the immune system [3,9]. Additionally, due to their low pH, SCFA are critical in preventing the colonization of pathogenic microbes [10].…”