The effect of microbial metabolites from colonic protein fermentation on bacteria-induced cytokine production in dendritic cells

Compared to the well-defined immune-modulating effect of butyrate, the understanding of the effect of other protein fermentation metabolites is limited. This study aimed to investigate the impact of protein-derived metabolites (valerate, branched-chain fatty acids, ammonium, phenol, p-Cresol, indole, and hydrogen sulfide) on cytokine production in murine bone marrow-derived dendritic cells (BMDCs) stimulated with lipopolysaccharides (LPS), Lactobacillus acidophilus NCFM, or Staphylococcus aureus USA300. Some of the metabolites, but not the short-chain fatty acids (SCFAs), strongly affected cell viability. After short-term treatment and depending on the microbial stimulus, SCFAs affected the cytokine profile similarly but weaker than butyrate, as reflected by inhibition of IL-12p70 and IL-10 but enhanced IL-23 (LPS and S. aureus USA300) and IL-1β production. Compared to butyrate, valerate exhibited a weaker and slower effect on cytokine expression. Two-day treatment with valerate and butyrate resulted in similar effects, that is, LPS-induced IL-12 abrogation and IL-10 enhancement, increased aryl hydrocarbon receptor (Ahr) expression, and after LPS stimulation, increased expression of dual specificity phosphatase 1 (Dusp1). In conclusion, SCFAs exhibited low toxicity and modulated microbially stimulated BMDCs. Valerate and butyrate showed the strongest effect, which was dependent on the specific microbial stimulation and the course of the SCFA treatment. Our work adds knowledge regarding the role of protein-derived metabolites from gut bacterial fermentation on the immune system.