Hepatic transcriptome, intestinal microbiome, and metabolite profiles associated with MASLD, MASH, and fibrosis in patients undergoing bariatric surgery

Metabolic dysfunction-associated steatotic liver disease (MASLD) is prevalent in obesity and can progress to steatohepatitis (MASH), fibrosis, cirrhosis and liver failure. The intestinal microbiome (IM) and metabolites may play a role in MASLD severity but their potential relationships with the hepatic transcriptome are not clear. We investigated these relationships in 93 patients undergoing bariatric surgery who provided blood and fecal samples prior to surgery for biochemical, metabolite (serum, fecal) and IM (metagenomics) measurements. A liver biopsy was obtained to assess histology and the hepatic transcriptome. Patients with MASH had higher expression of genes related to immune system, inflammation, cancer and apoptosis, higher Blautia species and lower Faecalibacterium prausnitzii , Bacteroides dorei , and Coprococcus species. Patients with severe fibrosis had higher expression of extracellular matrix-related genes and higher Collinsella stercoris . Significant associations were identified between differentially expressed genes in the liver, mainly related to growth, proliferation, metabolism and immune system, and bacterial taxa, especially B. dorei and F. prausnitzii , and fecal/serum metabolites (e.g. primary bile acids and acylcarnitines). Our findings demonstrate that fecal bacterial taxa as well as serum and fecal metabolites are associated with hepatic transcriptome according to MASLD severity. However, when adjusted for covariates known to be associated with MASLD definition or severity, these associations did not remain significant. Nonetheless, these interactions may suggest potential pathways and treatment targets requiring further study.