Dietary d‐Lactate Intake Facilitates Inflammatory Resolution by Modulating M1 Macrophage Polarization

Scope Given the d ‐lactate dehydrogenase (D‐LDH) deficiency, L‐ but not d ‐lactate is assumed to be the physiological isomer in mammals. Paradoxically, many fermented foods (e.g., yogurt, sauerkraut, cheeses) often contain substantial amounts of d ‐lactate. In the present study, dietary d ‐lactate may be a previously unrecognized nutrient aiding in inflammatory resolution is hypothesized. Methods and results The anti‐inflammatory properties of d ‐lactate are evaluated in experimental colitis and endotoxemia. Oral administration of d ‐lactate favorably affects acute inflammation in two different mouse models. Analysis of lactate—the lactate receptor (the hydroxycarboxylic acid receptor 1 HCA1, formerly GPR81) signal axis in inflammation is performed in primary peritoneal macrophages and wild‐type (WT) or GPR81 knockout (KO) mice. GPR81 KO mice are susceptible to endotoxic shock than WT mice, while d ‐lactate exerts its anti‐inflammatory activities in a GPR81‐dependent manner. Mechanistically, the activation of lactate‐GPR81 axis may suppress LPS‐TLR4 signaling to modulate M1 macrophage polarization. Although D‐LDH deficiency in mammals impairs d ‐lactate clearance, it might prolong its plasma terminal half‐life, and thus provide a pharmacokinetic advantage of d ‐lactate over l ‐lactate. Conclusion This study highlights housekeeping function of the lactate‐GPR81 axis in inflammation control, and suggests that dietary intake of d ‐lactate may underlie Metchnikoff's probiotic yogurt theory of life prolongation.