Alcohol consumption in metabolic dysfunction-associated steatotic liver disease (MASLD): understanding the gut–liver crosstalk for clinical translation
Year: 2026
Type: article
Abstract: Objective In the present study, we investigated the role of the gut–liver crosstalk in the pathogenesis of steatotic liver disease (SLD) induced by the compounding and deleterious effects of alcohol and metabolic risk factors, and explored the potential translational aspects of microbiome-based interventions.Design The effects of combined exposure to alcohol and a high-fat, high-cholesterol diet (HFHC) Western diet (WD) were tested in a dietary mouse DUAL model and compared to mice fed only with WD. Liver and gut phenotypes were evaluated via histochemistry, flow cytometry, gene expression, proteomic, and metabolomic analyses. The effects on the gut microbiota were studied in both DUAL mice and MASLD patients with a history of alcohol consumption. Antibiotic-induced microbiota depletion (AIMD) and microbiota modulation therapies (probiotics and fecal microbiota transplant (FMT)) were performed in mice. Primary human hepatocytes and HepG2 cells were used to study the underlying mechanisms. Zebrafish larvae exposed to alcohol and a HFHC diet were used as a validation model.Results Alcohol in combination with WD synergistically exacerbated SLD. DUAL-diet-induced disruption of the intestinal barrier led to LPS leakage into the bloodstream and subsequent TLR4-mediated hepatic inflammation. This, together with enhanced intestinal fat absorption, and impaired intrahepatic lipid oxidation – particularly due to insufficient CPT-1 activity – contributed to prominent steatohepatitis. The DUAL-induced changes in the gut microbiota showed similarities to human dysbiosis in MASLD patients who consumed alcohol, including an increase in Bacteroides and Alistipes. AIMD improved pathology, indicating a causal role of the microbiota in the pathophysiology of DUAL steatohepatitis, whilst early microbiome modulation via FMT induced mild improvements in liver and gut physiology.Conclusions These results indicated that the microbiota‒gut‒liver axis plays a crucial role in the progression of SLD intensified by alcohol and concurrent metabolic risk factors, thus providing a promising translational target for potential therapeutic interventions.
Source: Gut Microbes
Authors: Raquel Benedé-Ubieto, Olga Estévez-Vázquez, Rana Acar, Hector Leal-Lassalle, Alejandro H. Gutierrez, Ana Redondo-Urzainqui, Salvador Iborra, Vera E. Odintsova, Alexander Tyakht, José María Herranz, Zehra Firat, Merve Basol, Busra Korkmaz, Carlos Sanz-García, Oriol Juanola, Esther Caparrós, Rubén Francés, Andreea Ciudin, Juan M. Pericàs, Beatriz Gómez-Santos, Patricia Aspichueta, Nicole Treichel, Thomas Clavel, Johanna Reißing, Tony Bruns, Matthias Bartneck, Marina S. Mazariegos, Justina Clarinda Wolters, Gonzalo Jorquera, Christian Liedtke, Javier Vaquero, Rafael Bañares, Gulcin Cakan-Akdogan, Matías A. Ávila, Ozlen Konu, Francisco Javier Cubero, Yulia A. Nevzorova
Institutions: Universidad Complutense de Madrid, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Instituto de Investigación Sanitaria Gregorio Marañón, Bilkent University, Spanish National Centre for Cardiovascular Research, Inmunotek (Spain), Max Planck Institute for Biology, Vall d'Hebron Hospital Universitari, Vall d'Hebron Institute of Oncology, Centro de Investigación Médica Aplicada, Universidad de Navarra, Dokuz Eylül University, Izmir Biomedicine and Genome Center, Universitat de Miguel Hernández d'Elx, Hospital General Universitario de Alicante Doctor Balmis, Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL), Vall d'Hebron Institut de Recerca, University of the Basque Country, Universitätsklinikum Aachen, RWTH Aachen University, DWI – Leibniz Institute for Interactive Materials, Lund University, University Medical Center Groningen, University of Groningen, University of Chile, University of Valparaíso, Hospital General Universitario Gregorio Marañón, Navarre Institute of Health Research, National Nanotechnology Research Center, Universidad Nacional Autónoma de México
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,060
OpenAlex ID: W7130933420