Hepatocellular Carcinoma is Associated with Gut Microbiota Profile and Inflammation in Non-Alcoholic Fatty Liver Disease

The gut-liver axis plays a pivotal role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD), which is the third cause of hepatocellular carcinoma (HCC) worldwide. However, the link between gut microbiota and hepatocarcinogenesis remains to be clarified. The aim of this study is to explore what features of the gut microbiota are associated with HCC in cirrhotic patients with NAFLD. A consecutive series of patients with NAFLD-related cirrhosis and HCC (group 1: 21 patients), NAFLD-related cirrhosis without HCC (group 2: 20 patients) and healthy controls (group 3: 20 patients) was studied for gut microbiota profile, intestinal permeability, inflammatory status and circulating mononuclear cells. We finally constructed a model depicting the most relevant correlations among these features, possibly involved in hepatocarcinogenesis. Patients with HCC showed increased levels of fecal calprotectin, whilst intestinal permeability was similar to cirrhotic patients without HCC. Plasma levels of interleukin (IL) 8, IL13, C-C motif chemokine ligand (CCL) 3, CCL4 and CCL5 were higher in the HCC group and were associated with an activated status of circulating monocytes. The fecal microbiota of the whole group of cirrhotic patients showed higher abundance of Enterobacteriaceae and Streptococcus, and a reduction in Akkermansia. Bacteroides and Ruminococcaceae were increased in the HCC group, while Bifidobacterium was reduced. Akkermansia and Bifidobacterium were inversely correlated with calprotectin concentration, which in turn was associated with humoral and cellular inflammatory markers. A similar behavior was also observed for Bacteroides.