Probiotic Lactobacilli activate Formyl-Peptide Receptor 2

Abstract Changes in the composition of the human microbiota can negatively impact human health. Probiotic bacteria like many lactobacilli help prevent or repair dysbiosis but it is largely unclear which molecules of these bacteria mediate the probiotic effects. Given the extensive crosstalk between the immune system and microbiome members, we investigated whether lactobacilli activate the formyl-peptide receptor 2 (FPR2), a pattern recognition receptor that is expressed on the surface of intestinal epithelial cells and known to promote wound healing and immune homeostasis. Probiotic strains of Lacticaseibacillus paracasei, Lactiplantibacillus plantarum , and Lacticaseibacillus rhamnosus were isolated from probiotic compounds and sequenced. Calcium influx experiments in FPR1 or FPR2 overexpressing HL60 cells, and primary human neutrophils, along with pharmacological inhibition of FPR2, revealed that culture filtrates of the isolated lactobacilli strongly activate FPR2, promote killing of the methicillin resistant S. aureus USA300 and induce neutrophil chemotaxis. Pretreatment of culture filtrates with proteinase K reduced FPR2 activity, indicating that the FPR2 ligands are peptides. In silico analysis of the amphipathic properties of the signal peptides of lactic acid bacteria identified selected signal peptides of L. plantarum with the ability to predominantly activate FPR2 in vitro . Thereby, via targeted activation of FPR2, peptides released by some lactobacilli are likely to positively influence the outcome of inflammatory gut diseases and could be used to treat inflammatory diseases.