The gut-liver axis plays a pivotal role in the pathogenesis of
nonalcoholic fatty liver disease (
NAFLD), which is the third leading cause of
hepatocellular carcinoma (HCC) worldwide. However, the link between gut microbiota and hepatocarcinogenesis remains to be clarified. The aim of this study was to explore what features of the gut microbiota are associated with HCC in patients with
cirrhosis and
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, while intestinal permeability was similar to patients with
cirrhosis but without HCC. Plasma levels of
interleukin 8 (
IL8),
IL13,
chemokine (C-C motif)
ligand (CCL) 3, CCL4, and CCL5 were higher in the HCC group and associated with an activated status of circulating monocytes. The fecal microbiota of the whole group of patients with
cirrhosis 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. Conclusion: Our results suggest that in patients with
cirrhosis and
NAFLD the gut microbiota profile and systemic
inflammation are significantly correlated and can concur in the process of hepatocarcinogenesis.