Persistent changes in liver methylation and microbiome composition following reversal of diet-induced non-alcoholic-fatty liver disease

• Published in: Cellular and molecular life sciences : CMLS Vol. 76; no. 21; pp. 4341 - 4354
• Main Authors: Kim, Hyejin, Worsley, Oliver, Yang, Edwin, Purbojati, Rikky Wenang, Liang, Ai Leng, Tan, Wilson, Moses, Daniela I. Drautz, Hartono, Septian, Fan, Vanessa, Lim, Tony Kiat Hon, Schuster, Stephan C., Foo, Roger SY, Chow, Pierce Kah Hoe, Pettersson, Sven
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.11.2019; Springer Nature B.V
• Subjects: Animals; Biochemistry; Biomedical and Life Sciences; Biomedicine; Cell Biology; Cholesterol; Composition; Deoxyribonucleic acid; Diet; Diet, High-Fat - adverse effects; Dietary Fats - adverse effects; Dietary Fats - pharmacology; Digestive system; DNA; DNA methylation; DNA Methylation - drug effects; Epigenetics; Fatty liver; Fructose; Gastrointestinal Microbiome - drug effects; Genes; Genomes; Glucose; Glucose tolerance; High cholesterol diet; High fat diet; Intolerance; Life Sciences; Lipids; Liver; Liver - drug effects; Liver - metabolism; Liver diseases; Male; Medicin och hälsovetenskap; Mice; Mice, Inbred C57BL; Microbiomes; Microbiota; Non-alcoholic Fatty Liver Disease - etiology; Non-alcoholic Fatty Liver Disease - genetics; Non-alcoholic Fatty Liver Disease - metabolism; Non-alcoholic Fatty Liver Disease - microbiology; Obesity - genetics; Obesity - metabolism; Obesity - microbiology; Original; Original Article; Phenotypes; Priming; DNA methylation; Epigenetics; NAFLD; Gut microbiome; High-fat diet
• ISSN: 1420-682X; 1420-9071; 1420-9071
• DOI: 10.1007/s00018-019-03114-4

Non-alcoholic fatty liver disease (NAFLD) is a metabolic liver disease that is thought to be reversible by changing the diet. To examine the impact of dietary changes on progression and cure of NAFLD, we fed mice a high-fat diet (HFD) or high-fructose diet (HFrD) for 9 weeks, followed by an additional 9 weeks, where mice were given normal chow diet. As predicted, the diet-induced NAFLD elicited changes in glucose tolerance, serum cholesterol, and triglyceride levels in both diet groups. Moreover, the diet-induced NAFLD phenotype was reversed, as measured by the recovery of glucose intolerance and high cholesterol levels when mice were given normal chow diet. However, surprisingly, the elevated serum triglyceride levels persisted. Metagenomic analysis revealed dietary-induced changes of microbiome composition, some of which remained altered even after reversing the diet to normal chow, as illustrated by species of the Odoribacter genus. Genome-wide DNA methylation analysis revealed a “priming effect” through changes in DNA methylation in key liver genes. For example, the lipid-regulating gene Apoa4 remained hypomethylated in both groups even after introduction to normal chow diet. Our results support that dietary change, in part, reverses the NAFLD phenotype. However, some diet-induced effects remain, such as changes in microbiome composition, elevated serum triglyceride levels, and hypomethylation of key liver genes. While the results are correlative in nature, it is tempting to speculate that the dietary-induced changes in microbiome composition may in part contribute to the persistent epigenetic modifications in the liver.