Multi-Omics Analyses Identify Signatures in Patients with Liver Cirrhosis and Hepatocellular Carcinoma

SIMPLE SUMMARY: Gut dysbiosis with an impaired intestinal barrier is differentially associated with liver diseases and, therefore, alters the systemic immunological milieu through the gut–liver axis. As a result, it plays a prominent role in liver inflammation, fibrosis, and carcinogenesis. Here, a list of network features common to patients with liver cirrhosis or hepatocellular carcinoma (HCC), regardless of etiology, was identified. In addition, disease-specific signatures were identified. This study provides novel insights that suggest alterations in gut microbial/viral composition may either confer pre-HCC disorders or contribute to the metabolic reprogramming and/or inflammatory microenvironment for HCC development. ABSTRACT: Gut bacterial/viral dysbiosis, changes in circulating metabolites, and plasma cytokines/chemokines have been previously associated with various liver diseases. Here, we analyzed the associations between fecal microbial composition, circulating metabolites, and plasma cytokines/chemokines in patients with liver cirrhosis (LC) and hepatocellular carcinoma (HCC). We recruited 10 HCC patients, 18 LC patients, and 17 healthy individuals. Their stool samples were used for gene sequencing of bacterial 16S rRNA and viral genomes, while plasma samples were utilized for the determination of endotoxin, zonulin, metabolite, and cytokine/chemokine levels. Dysbiosis was observed among gut bacteria and viruses, with significant changes in abundance at the genus and species levels, respectively. However, no differences were found between cohorts in the alpha and beta diversity. Plasma lipopolysaccharides and zonulin, but not trimethylamine N-oxide, were progressively increased in LC and HCC subjects. Profiling plasma metabolites and selected cytokines/chemokines revealed differential changes in the LC and HCC cohorts. Following joint correlation and correlation network analyses, regardless of etiology, common network signatures shared by LC and HCC patients were characterized by the gut virus Stenotrophomonas virus DLP5 and the uncultured Caudovirales phage, plasma metabolites pyruvic acid and acetic acid, and plasma cytokines/chemokines eotaxin and PDGF-AB/BB, respectively. Additionally, LC- and HCC-specific correlation networks were also identified. This study provides novel insights into altered gut microbial/viral composition that may contribute to pre-HCC disorders, metabolic reprogramming, or inflammatory microenvironments for hepatocarcinogenesis.