Potential therapeutic strategies to target gut microbiota in hepatocellular carcinoma

The gut microbiota (GM) is an assorted ecosystem, composed of viruses, fungi, protozoa, archaea, and especially bacteria, which exist in a definite symbiosis between each other and the host (human) as well. Increasing data document that GM plays key parts in human physiology, taking part in the digestive process, vitamin B synthesis, promotion of angiogenesis and nerve functionality, and notably in the maturation and modulation of the immune system. In addition, it is commonly known and accepted that the GM has an impacting role in different pathological disorders, such as gastrointestinal, hepatic, respiratory, cardiovascular and endocrine . In fact, different studies confirmed that the GM is involved in the pathogenesis of different pathologies, including inflammatory and irritably bowel syndrome, autism, depression, obesity, atherosclerosis, colorectal carcinoma, infectious and noninfectious chronic liver diseases. The GM as a “virtual metabolic organ” makes axis with various extra-intestinal organs, such as brain (the most relevant), lung, cardiovascular, kidneys and the liver. The gut-liver axis is the result of a close (anatomical and functional) bidirectional interaction of the gastrointestinal tract and liver, primarily by the portal circulation. Moreover, an intricate network of interactions, which encompass metabolic, immune, and neuroendocrine crosstalk between them, controls the symbiotic connection between the liver and the GM (2). The gut-liver axis has been associated with the pathogenesis of numerous chronic liver diseases, comprising liver cirrhosis, chronic hepatitis B/C (CHB and CHC), non-alcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), and the hepatocellular carcinoma (HCC) (8), that is the third most common cause of cancer-related mortality worldwide (9). To date, numerous data from animal models and human studies suggest a GM role in the HCC development. In particular, intestinal dysbiosis was found in patients with liver cirrhosis and HCC and in mice after diethylnitrosamine (DEN) administration.