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bioRxiv · 10.1101/2025.10.28.685091

D- and L-Lactate enhance intestinal barrier function via activation of an apical HCAR1/Giα pathway in a human colonic epithelial cell model

Milner, A.·Anujan, P.·Frost, G.·Hanyaloglu, A.
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Abstract

The stereoisomers of lactate, L- and D- are not only metabolic substrates but also signalling molecules, capable of activating and signalling through its G protein-coupled receptor, Hydroxycarboxylic acid receptor 1 (HCAR1). These stereoisomers are both produced by the gut microbiota at millimolar concentrations creating a physiological environment for lactate-sensing unique to the gut yet, poorly understood. Here we identify a role for D-/L-lactate on intestinal barrier function. A human colonic epithelial cell model, Caco2, activated Gi signalling in response to both L- and D-lactate, although L-lactate exhibited a more potent and rapid Gi signal profile. When differentiated, apically but not basally treated D-/L-lactate enhanced tight junctions and reduced cell permeability, consistent with the apical localization of HCAR1. This improved barrier function occurred in a Gi-dependent manner. In addition, apical lactate rescued the reduced intestinal barrier function induced by lipopolysaccharides. This work highlights the potential for D-/L-lactate supplementation in improving gut health. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/685091v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@28fa82org.highwire.dtl.DTLVardef@56a75borg.highwire.dtl.DTLVardef@10578c6org.highwire.dtl.DTLVardef@3c3cd2_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Milner, A., Anujan, P., Frost, G., Hanyaloglu, A.. 2025-10-29. D- and L-Lactate enhance intestinal barrier function via activation of an apical HCAR1/Giα pathway in a human colonic epithelial cell model. https://doi.org/10.1101/2025.10.28.685091

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