Metabolites of lactic acid bacteria present in fermented foods are highly potent agonists of human hydroxycarboxylic acid receptor 3
Although it has been known for 15 years that HCA3 is present in humans and other hominids but absent in all other mammals, no study so far aimed to understand why HCA3 was functionally preserved during evolution. Here, we take advantage of evolutionary analyses which we combine with functional assays of hominid HCA3 orthologs. In search for a reasonable scenario explaining the accumulated amino acid changes in HCA3 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 HCA3. Further, oral ingestion of Sauerkraut, known to contain high levels of D-PLA, caused subsequent plasma concentrations sufficient to activate HCA3. Our data interpreted in an evolutionary context suggests that the availability of a new food repertoire under changed ecological conditions triggered the fixation of HCA3 which took over new functions in hominids. These findings are particularly important because they unveiled HCA3, 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.