D- and L-Lactate enhance intestinal barrier function via activation of an apical HCAR1/Gαi pathway in a human colonic epithelial cell model - 04/02/26
, Aylin C. Hanyaloglu a, ⁎ 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 Gαi signalling in response to both L- and D -lactate, although L -lactate exhibited a more potent and rapid Gαi 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 Gαi-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.
Le texte complet de cet article est disponible en PDF.Graphical Abstract |
Speculative model for lactate-dependent changes in intestinal epithelial barrier. Apically expressed HCAR1, activated by lactate, signals through Gαi, in turn reducing cyclic AMP (cAMP) levels. This results in a decrease in p65 activation which promotes the tightening of tight junctions (TJs). LPS stimulation through toll-like receptor (TLR) increases p65 (NFκβ) activation to produce a pro-inflammatory response, weakening TJs. Lactate-mediated Gαi signalling reduces p65 activation limiting LPS-mediated damage to TJs. Figure created in Biorender.
Speculative model for lactate-dependent changes in intestinal epithelial barrier. Apically expressed HCAR1, activated by lactate, signals through Gαi, in turn reducing cyclic AMP (cAMP) levels. This results in a decrease in p65 activation which promotes the tightening of tight junctions (TJs). LPS stimulation through toll-like receptor (TLR) increases p65 (NFκβ) activation to produce a pro-inflammatory response, weakening TJs. Lactate-mediated Gαi signalling reduces p65 activation limiting LPS-mediated damage to TJs. Figure created in Biorender. Le texte complet de cet article est disponible en PDF.
Highlights |
• | D/ L -lactate induce distinct signaling profiles in human colonic epithelial cells. |
• | D/ L -lactate promote a ‘tighter’ gut barrier, in a polarity-dependent manner. |
• | Lactate treatment was able to rapidly reverse disruption in gut barrier function. |
Keywords : GPCR, HCAR1, Lactate, Gut barrier, Colon
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Vol 195
Article 119041- février 2026 Retour au numéro
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