Effect of methyl donor supplementation on gut microbiota and hepatic expression of key miRNAs in a murine model of MAFLD

Abstract

Introduction and Objectives: Metabolism-associated fatty liver disease (MAFLD) is the most common liver disease worldwide, and intestinal dysbiosis is associated with its development. Methyl donor supplementation has shown beneficial effects for MAFLD treatment; however, its role on the intestinal microbiota and miRNAs hepatic expression has been poorly studied. The aim of this study was to evaluate the effect of methyl group donor supplementation on gut microbiota and hepatic expression of key miRNAs in a murine model of MAFLD. Materials and Patients: Twenty-four male C57BL/6J mice were divided into three groups: 1) Control: Conventional diet. 2) HF/FS: Diet rich in fats and sugars for 18 weeks. 3) HFMS: HF/FS diet for the first 10 weeks, followed by a HF/FS diet plus orogastric supplementation with methyl group donors for the last 8 weeks. Results: The intestinal microbiota was characterized by 16S rRNA gene sequencing; supplementation with methyl donors modified microbial composition analyzed by beta diversity. In addition, HFMS group strongly tended to increase alpha diversity and induced enrichment of six genus: Acinetobacter, Anaeroplasma, Pseudomonas, Stenotrophomonas, Tuzzerella, and Moraxellaceae family. HFMS group significantly increased SCFAs fecal concentration and restored intestinal permeability dysfunction by increasing Ocln and Cldn1 expression; consequently, a decrease in liver inflammation was observed due to a decrease in Tnf-a expression. On the other hand, HFMS group significantly increased hepatic expression of miR-122 and decreased miR-33a expression. Conclusions: This study offers valuable insights into the role of methyl donors as microbiota modifiers, highlighting their ability to promote restoration of intestinal health and liver metabolism. These findings contribute to the proposition that methyl donors could be a promising strategy for treating MAFLD and hepatic related conditions.