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

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 (HCA(1), HCA(2)) but humans and other hominids contain a third member (HCA(3)) in their genomes. A plausible hypothesis why HCA(3) function was advantageous in hominid evolution was lacking. Here, we used a combination of evolutionary, analytical and functional methods to unravel the role of HCA(3) 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 HCA(3). 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 HCA(3)-dependent manner. We provide evolutionary, analytical and functional evidence supporting the hypothesis that HCA(3) was consolidated in hominids as a new signaling system for LAB-derived metabolites. Author summary Although it has been known for 15 years that HCA(3) is present in humans and other hominids but absent in all other mammals, no study so far aimed to understand why HCA(3) was functionally preserved during evolution. Here, we take advantage of evolutionary analyses which we combine with functional assays of hominid HCA(3) orthologs. In search for a reasonable scenario explaining the accumulated amino acid changes in HCA(3) of hominids we discovered D-phenyllactic acid (D-PLA), a metabolite produced by lactic acid bacteria (LAB), as the so far most potent agonist specifically activating HCA(3). Further, oral ingestion of Sauerkraut, known to contain high levels of D-PLA, caused subsequent plasma concentrations sufficient to activate HCA(3). Our data interpreted in an evolutionary context suggests that the availability of a new food repertoire under changed ecological conditions triggered the fixation of HCA(3) which took over new functions in hominids. These findings are particularly important because they unveiled HCA(3), which is not only expressed in various immune cells but also adipocytes, lung and skin, as a player that transfers signals of LAB-derived metabolites into a physiological response in humans. This opens up new directions towards the understanding of the versatile beneficial effects of LAB and their metabolites for humans.