Abstract
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.
Highlights
The interplay of microbiota and the human host is physiologically crucial in health and diseases
We provide evidence for such a unique example, where genetic events potentially improved the availability of a new food repertoire under changed ecological conditions that possibly triggered the fixation of a duplicated gene with new functions in hominids
Through analyses of the evolutionary history of the HCA receptor family, we show that HCA3, being absent in non-hominoid primates and all other vertebrates, resulted from a gene duplication that occurred before the split of gibbons from great apes (Fig 1B)
Summary
The interplay of microbiota and the human host is physiologically crucial in health and diseases. Lactic acid bacteria (LAB) are microorganisms present in many foods and the intestine of most mammals. There are extensive reports about the beneficial role of LAB on the immune system [1]. Short-chain fatty acids (SCFAs) and lactate are known metabolites of LAB that have been shown to play an important role in the maintenance of the gut barrier function [2]. SCFAs can induce effects in the host through activation of specific G protein-coupled receptors (GPCRs) expressed in intestinal epithelial cells and immune cells that are located in the intestinal mucosa [3]. The present study focuses on GPCRs belonging to the family of hydroxycarboxylic acid receptors (HCAR) which are regulators of immune functions and energy homeostasis under changing metabolic and dietary conditions. At least two HCAR subtypes are present in mammalian genomes
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