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

Annabelle J. Milner; Priyanka Anujan; Gary S. Frost; Aylin C. Hanyaloglu

doi:10.1016/j.biopha.2026.119041

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

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

Annabelle J. Milner, Priyanka Anujan, Gary S. Frost and Aylin C. Hanyaloglu

Biomedicine & pharmacotherapy, Vol.195, 119041

2026

DOI: https://doi.org/10.1016/j.biopha.2026.119041

PMID: 41616468

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Abstract

Colon

GPCR

Gut barrier

HCAR1

Lactate

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. 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.

Details

Title: D- and L-Lactate enhance intestinal barrier function via activation of an apical HCAR1/Gαi pathway in a human colonic epithelial cell model
Authors/Creators: Annabelle J. Milner - Imperial College London
Priyanka Anujan - Imperial College London
Gary S. Frost - Imperial College London
Aylin C. Hanyaloglu - Imperial College London
Publication Details: Biomedicine & pharmacotherapy, Vol.195, 119041
Publisher: Elsevier Masson SAS
Identifiers: 991005884851207891
Murdoch Affiliation: Centre for Computational and Systems Medicine
Language: English
Resource Type: Journal article

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