Metabolites of lactic acid bacteria present in fermented foods are highly potent agonists of human hydroxycarboxylic acid receptor 3

by Anna Peters, Petra Krumbholz, Elisabeth Jäger, Anna Heintz-Buschart, Mehmet Volkan Çakir, Sven Rothemund, Alexander Gaudl, Uta Ceglarek, Torsten Schöneberg, Claudia Stäubert

The interplay of microbiota and the human host is physiologically crucial in health and diseases. The beneficial effects of lactic acid bacteria (LAB), permanently colonizing the human intestine or transiently obtained from food, have been extensively reported. However, the molecular understanding of how LAB modulate human physiology is still limited. G protein-coupled receptors for hydroxycarboxylic acids (HCAR) are regulators of immune functions and energy homeostasis under changing metabolic and dietary conditions. Most mammals have two HCAR (HCA₁, HCA₂) but humans and other hominids contain a third member (HCA₃) in their genomes. A plausible hypothesis why HCA₃ function was advantageous in hominid evolution was lacking. Here, we used a combination of evolutionary, analytical and functional methods to unravel the role of HCA₃ in vitro and in vivo. The functional studies included different pharmacological assays, analyses of human monocytes and pharmacokinetic measurements in human. We report the discovery of the interaction of D-phenyllactic acid (D-PLA) and the human host through highly potent activation of HCA₃. D-PLA is an anti-bacterial metabolite found in high concentrations in LAB-fermented food such as Sauerkraut. We demonstrate that D-PLA from such alimentary sources is well absorbed from the human gut leading to high plasma and urine levels and triggers pertussis toxin-sensitive migration of primary human monocytes in an HCA₃-dependent manner. We provide evolutionary, analytical and functional evidence supporting the hypothesis that HCA₃ was consolidated in hominids as a new signaling system for LAB-derived metabolites.