Composition of gut microbiota and altered gut immune response in steatohepatitis and steatohepatitis related liver cancer

The gut liver axis has been attracted much attention in the pathogenesis of nonalcoholic steatohepatitis and steatohepatitis-related hepatocellular carcinoma (HCC). Although many animal models are used, comparison of gut microbiota and immune response in the gut has not yet performed. We used a high fat (HF) diet and a choline deficient amino acid-defined (CDAA) diet to induce steatohepatitis, and hepatocyte-specific PTEN deficient (PTEN KO) mice as a steatohepatitis-related HCC model. Composition of gut microbiota was analyzed by pyrosequencing. Levels of IL-17 were examined as an immune modulator in the gut. WT mice on the CDAA diet exhibited steatohepatitis while the HF diet induced simple steatosis. Lactate-producing bacteria and anti-inflammatory bacteria such as Parabacteroides distasonis were decreased in the CDAA diet group. These alteration of bacteria resulted in an increase of IL-17 in the CDAA diet group. Chemokines, downstream targets of IL-17, were increased in the liver, leading to accumulation of inflammatory cells. PTEN KO mice exhibited steatohepatitis and subsequent tumor development in the liver. Compared with control mice, the abundance of lactate-producing bacteria was decreased in the PTEN KO mice. On the other hand, the abundance of phylum Proteobacteria was increased in the PTEN KO mice. In conclusion, alteration of gut microbiota may modulate IL-17 expression in the small intestine and affect the severity of steatohepatitis and subsequent HCC development.