Metabolite-Mediated Crosstalk Between Neutrophils, Commensal Bacteria, and Dendritic Cells Is Associated with Intestinal Immune Responses.

The intestinal immune system relies on coordinated interactions between innate immune cells and commensal bacteria. How metabolites integrate host-microbe communication in the gut remains incompletely understood. Using neutrophil activation assays, bacterial chemotaxis analysis, short-chain fatty acid profiling, and imaging of inflamed intestinal tissue, we examined how neutrophil-derived metabolites regulate commensal behavior and immune cell function. Activated neutrophils released lactate, which was associated with selective chemotaxis of commensal Escherichia coli but not pathogenic Acinetobacter or Salmonella. This response required bacterial lactate dehydrogenase, suggesting that lactate metabolism may contribute to commensal localization within the intestinal mucosa. Commensal-derived short-chain fatty acids suppressed neutrophil activation by inhibiting neutrophil extracellular trap formation and reactive oxygen species generation, consistent with a potential feedback mechanism that may attenuate neutrophil activation. Neutrophil-derived soluble factors were associated with phenotypic changes in dendritic cells, as reflected by increased dendrite formation and modest elevation of major histocompatibility complex class II expression. Imaging revealed close spatial proximity between neutrophils and dendritic cells within inflamed villi, supporting spatial association consistent with potential crosstalk in vivo. These findings are consistent with a model of metabolite-mediated communication in which neutrophil-derived lactate may attract commensal bacteria, commensal-derived metabolites restrain neutrophil effector activity, and neutrophil-derived soluble factors are associated with phenotypic changes in dendritic cells rather than definitive functional maturation, collectively suggesting potential contributions to immune regulatory processes within the intestinal mucosa.