Impairment of the intestinal epithelium barrier through alteration of proliferation and differentiation balance in alcohol use disorder

doi:10.3748/wjg.118458

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World Journal of Gastroenterology

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1007-9327

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Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA

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Copyright: ©Author(s) 2026. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution-NonCommercial (CC BY-NC 4.0) license. No commercial re-use. See permissions. Published by Baishideng Publishing Group Inc.

World J Gastroenterol. Jul 28, 2026; 32(28): 118458
Published online Jul 28, 2026. doi: 10.3748/wjg.118458

Impairment of the intestinal epithelium barrier through alteration of proliferation and differentiation balance in alcohol use disorder

Ami G Toulehohoun, Jérôme Ambroise, Bouchra Illiyas, Luca Maccioni, Joaquim Lupianez, Rita Manco, Laure-Alix Clerbaux, Caroline Bouzin, Bernd Schnabl, Peter Stärkel

Ami G Toulehohoun, Bouchra Illiyas, Luca Maccioni, Joaquim Lupianez, Rita Manco, Laure-Alix Clerbaux, Peter Stärkel, Laboratory of Gastroenterology (GAEN), Institut de Recherche Expérimentale et Clinique, UCLouvain, Brussels 1200, Belgium

Jérôme Ambroise, Centre de Technologies Moléculaires Appliquées Platform, Institut de Recherche Expérimentale et Clinique, UCLouvain, Brussels 1200, Belgium

Caroline Bouzin, IREC Imaging Platform Belgium (2IP, RRID: SCR_023378), Institut de Recherche Expérimentale et Clinique, UCLouvain, Brussels 1200, Belgium

Bernd Schnabl, Department of Medicine, University of California San Diego, La Jolla and VA San Diego Healthcare System, California City, CA 92093-0063, United States

Peter Stärkel, Department of Hepato-Gastroenterology, Cliniques Universitaires Saint-Luc, UCLouvain, Brussels 1200, Belgium

Co-corresponding authors: Ami G Toulehohoun and Peter Stärkel.

Author contributions: Toulehohoun AG and Stärkel P carried out the conceptualization as co-corresponding authors; Toulehohoun AG and Ambroise J performed data curation and executed software analysis; Toulehohoun AG, Ambroise J, and Stärkel P performed the formal analysis; Toulehohoun AG and Maccioni L implemented the methodology; Stärkel P supervised the manuscript; Toulehohoun AG, Illiyas B, Maccioni L, and Lopianez J carried out research validation; Toulehohoun AG, Stärkel P, Bouzin C, and Manco R performed visualization; Toulehohoun AG wrote the original draft; Stärkel P, Bouzin C, Manco R, Ambroise J, Maccioni L, Clerbaux LA, and Schnabl B undertook writing, reviewing and editing. All authors approved the final version to publish.

Supported by Fond National de Recherche Scientifique Belgium, No. T.0217.18, No. J.0195.24, and No. T.0195.22; and Action de Recherche Concertée, Université Catholique de Louvain, Belgium by National Institutes of Health, No. 5R01AA024726-08, No. 5R01AA020703-05, No. 5U01AA026939-05, No. 1R01AA031710-01A1, and No. 5P30DK120515-07.

Institutional review board statement: This study protocol was approved by the Institution’s Human Research and Ethical Committee (Comité Ethique Hospitalo-facultaire, Cliniques Universitaires Saint Luc), No. B403201422657. Written informed consent was obtained from all patients and controls. Patients hospitalized for selective alcohol withdrawal in a dedicated alcohol withdrawal unit and controls undergoing out-patient upper gastro-intestinal endoscopy for dyspepsia or reflux symptoms were recruited. Control patients were only retained for the study if they had a normal gastro-intestinal endoscopy and no histological changes on the biopsy samples.

Conflict-of-interest statement: Schnabl B has been consulting for Ambys Medicines, Ferring Research Institute, Gelesis, HOST Therabiomics, Intercept Pharmaceuticals, Mabwell Therapeutics, Patara Pharmaceuticals, Surrozen, and Takeda; Schnabl B’s institution UC San Diego has received research support from Axial Biotherapeutics, BiomX, ChromoLogic, CymaBay Therapeutics, Intercept Pharmaceuticals, NGM Biopharmaceuticals, Prodigy Biotech, and Synlogic Operating Company. Schnabl B is founder of Nterica Bio.

Data sharing statement: sharing statement: The raw data that support the findings of this study are available from the corresponding authors upon request. Raw 16S sequencing reads are available in the National Center for Biotechnology Information Sequence Read Archive under BioProject accession PRJNA705611 and BioSample IDs SAMN18094194-SAMN18094231.

Corresponding author: Ami G Toulehohoun, Laboratory of Gastroenterology (GAEN), Institut de Recherche Expérimentale et Clinique, UCLouvain, Avenue Mounier 52, Brussels 1200, Belgium. ami.toulehohoun@uclouvain.be

Received: January 4, 2026
Revised: February 17, 2026
Accepted: April 7, 2026
Published online: July 28, 2026
Processing time: 188 Days and 11.8 Hours

Abstract

BACKGROUND

Alcohol use disorder (AUD) profoundly affects human health, yet its direct impact on the intestinal epithelium and stem cell niche remains insufficiently understood.

AIM

To characterize alcohol-induced alterations in intestinal epithelial morphology, proliferation, differentiation, and barrier-related functions in AUD patients.

METHODS

Duodenal biopsies from healthy and AUD patients were analyzed for epithelial architecture, proliferation, differentiation activity, and lineage composition using histological, immunofluorescence, proteomic, and transcriptomic approaches. Findings were complemented by studies in human-derived enteroids exposed to 40- or 70-mM ethanol to assess its direct effects on epithelial proliferation and signaling pathways.

RESULTS

A subset of AUD patients exhibited marked epithelial remodeling, including increased crypt depth, shortened villi, and expanded proliferation in the crypt base and transit-amplifying zone. Ki67⁺ cells and OLFM4⁺ stem-like compartment were increased, with CD44 identified as a potential driver of crypt-base proliferation. Moreover, a higher number of Ki67⁺ crypts co-expressed the enteroendocrine cells marker CHGA⁺ and the stem cell marker OLFM4. Ki67⁺ Kruppel-like factor 4⁺ cells were elevated in transit-amplifying zone, correlating with higher MUC2, MUC5AC, and anterior gradient-2 expression, alongside reduced antimicrobial peptides DEFA5, DEFA6, and REG3A. Nutrient absorption markers MTTP, FABP2, and SLC1A5 were dysregulated. Ethanol-exposed enteroids showed increased Ki67⁺ cells and cyclin B1 mRNA without changes in CD44 or Axin2 indicating a proliferative effect independent of canonical Wnt signaling.

CONCLUSION

Heavy alcohol consumption induces profound alterations in intestinal epithelial morphology, stem cell niche dynamics, and functional barrier properties. Together, these findings suggest that ethanol disturbs the intestinal proliferation-differentiation balance.

Keywords: Alcohol use disorder; Intestinal epithelium; Intestinal barrier; Stem cell niche; Intestinal organoids; Enteroids

Core Tip: The effects of alcohol on the human intestinal epithelium are poorly understood, as existing studies are limited, inconsistent, and largely based on animal models that incompletely reflect human pathology. Human-based analyses reveal that heavy alcohol consumption disrupts intestinal epithelial homeostasis by altering stem cell niche and lineage commitment. Duodenal crypts displayed increased depth and expanded proliferation driven by enlarged OLFM4⁺ stem-like compartments and elevated Ki67⁺ and CD44⁺ cells. Ethanol induced aberrant proliferation, impaired secretory lineage commitment, antimicrobial defense and nutrient transport. Using human intestinal organoids, we confirm a direct, Wnt-independent proliferative effect of ethanol on epithelial cells.