Multi-omic profiling and pathways related to changes in liver histology after Roux-en-Y gastric bypass: a longitudinal study

BACKGROUND: Roux-en-Y gastric bypass (RYGB) improves metabolic dysfunction-associated steatotic liver disease (MASLD). However, the impact of RYGB on hepatic transcriptome, faecal microbiome and serum/faecal metabolome remain understudied. Our objective was to investigate the change in these omics and their relationships with changes in liver histology. METHODS: In this prospective cohort study, patients undergoing RYGB were recruited between 2013 and 2020 and followed for 12 months. Anthropometrics, biochemistry, hepatic transcriptome, faecal microbiome (shotgun metagenomics) and serum/faecal metabolomes were measured. Liver histology and NAFLD Score (NAS) were assessed. FINDINGS: Thirty-eight patients completed the study. Anthropometrics, biochemical and histological parameters improved post-RYGB (p < 0.05). Hepatic transcriptome analysis revealed a co-expression module enriched in fatty acid metabolism which correlated with changes in NAS post-RYGB (ρ = 0.38, p = 0.019). The core enrichment genes in this pathway were involved in mitochondrial and peroxisomal β-oxidation (ACADVL, ACOX1, and EHHADH) and the tricarboxylic acid (TCA) cycle (SUCLG2, SDHC, and SERINC1). There was an increase in TCA cycle gene expression associated with the resolution of ballooning, while upregulation of β-oxidation genes correlated with less reduction in NAS, ballooning, and inflammation. Metabolomic changes related to the identified co-expression module and pathways reveal a significant increase in faecal acylcarnitines, likely due to malabsorption from RYGB, with a significant reduction in circulating acylcarnitines which correlated positively with SUCLG2 expression and resolution of ballooning. Additionally, the increase in faecal acylcarnitines positively correlated with the bacterial species utilising acylcarnitines. In network analysis, ballooning of hepatocytes was associated with faecal/serum acylcarnitines and TCA metabolites while SUCLG2 was the hub gene associated with these changes. INTERPRETATION: These findings provide insight on how post-RYGB changes in the transcriptome, metabolome, and microbiome could be associated with improvement in liver histology and may inform the development of future strategies for MASLD management. FUNDING: Canadian Institutes of Health Research and American College of Gastroenterology.