Alcohol consumption in metabolic dysfunction-associated steatotic liver disease (MASLD): understanding the gut-liver crosstalk for clinical translation.
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Benedé-Ubieto Raquel, Estévez-Vázquez Olga, Acar Rana, Leal-Lassalle Hector, Gutierrez Alejandro H, Redondo-Urzainqui Ana, Iborra Salvador, Odintsova Vera E, Tyakht Alexander, Herranz José María, Firat Zehra, Basol Merve, Korkmaz Busra, Sanz-García Carlos, Juanola Oriol, Caparrós Esther, Francés Rubén, Ciudin Andreea, Pericàs Juan M, Gómez-Santos Beatriz, Aspichueta Patricia, Treichel Nicole, Clavel Thomas, Reißing Johanna, Bruns Tony, Bartneck Matthias, Mazariegos Marina S, Wolters Justina Clarinda, Jorquera Gonzalo, Liedtke Christian, Vaquero Javier, Bañares Rafael, Cakan-Akdogan Gulcin, Ávila Matías A, Konu Ozlen, Cubero Francisco Javier, Nevzorova Yulia A
Аннотация
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.