A DISTINCT FECAL MICROBIAL SIGNATURE PREDICTS HEPATOCELLULAR CARCINOMA

Objective: To investigate the clinical relevance of fecal microbial dysbiosis in HCC development
Design: A case-control study. Fecal microbial composition and predicted genetic function inferred from high-throughput 16S ribosomal RNA sequencing were analyzed between HCC (n=53) and age-, gender- and body mass index-matched non-HCC subjects (n=53). The predicting performance of microbial dysbiosis index (MDI) of selected contrasting taxa was examined in the testing dataset and validation dataset. Further animal studies were conducted by transplantation of feces containing the selected contrasting taxa.
Results: A significant alteration of fecal microbial diversity and composition were found in HCC patients. HCC patients with early stage and liver cirrhosis had higher fecal microbial diversity but not richness. We identified the subset of 4 species (Ruminococus gnavus, Bifidobacteirum longum, Eubacteirum dolicum, and Rothia mucilaginosa)-based biomarker which achieved a great association with HCC development (area under the curve [AUC] 0.916). The AUC value increased up to 0.966 when combined with AFP values. This fecal microbial signature performed well in the validation cohort (AUC 0.920). The fecal microbiota signature in HCC was predicted to be associated with enhanced signaling pathways involving L-arginine biosynthesis, urea-cycle, heme biosynthesis, and nicotinamide adenine dinucleotide (NAD) salvage pathways; and reduced signaling pathways involving allantoin degradation and pyrimidine deoxyribonucleotide. Fecal microbial transplantation study demonstrated a significantly increased tumor growth in mice receiving feces containing the 4-species signature.
Conclusion: A distinct gut microbial profile was found in HCC patients. The specific fecal microbial signature may involve tumorigenesis and predict HCC development.