Gut lactate increases circulating <scp>l</scp>-Lac-Phe and key metabolites linked to GLP-1 and human health

Lactate, a small organic acid related to short-chain fatty acids, is emerging as a key energy metabolite, although much remains unknown about its actions in the gut. In the current study, we specifically tested how oral and parenteral (IV) lactate affects lactoylation of amino acids in humans and whether these clinical results could be reproduced in a perfused rat intestine model. Furthermore, using targeted and untargeted metabolomics, we globally investigated how oral and IV lactate impacts the circulating metabolome to delineate potential circulating messengers and obtain additional mechanistic insights into how oral lactate may potentially induce glucagon-like peptide-1 secretion as well as alternative metabolites correlated to human health. Our findings provide a better understanding of the general effects of lactate in the gut and how it potentially signals to increase satiety in humans.<b>NEW & NOTEWORTHY</b> By investigating the effects of oral versus IV lactate administration, we find that oral lactate elevates plasma l-lactate and strongly increases circulating l-Lac-Phe and l-Lac-Val, potentially via an alternative mechanism than exercise-induced formation. Furthermore, we find that GLP-1 secretion is not directly induced by lactate but may be mediated via increased bile acids and SCFAs in the gut.