Gut Microbiota in Inflammatory Bowel Diseases: A Possible Role in the Development of Rapidly Evolving Chronic Hepatitis and Endothelial Dysfunction with Increased Cardiovascular Risk

It is known that in various liver disorders such as hepatic steatosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) and cirrhosis, there is a qualitative and quantitative alteration of the gut microbiota. Indeed, in such pathologies, normal intestinal flora, which is made up of lactobacilli in the healthy subject, is replaced by quantitatively significant gram-positive bacteria, probably due to the reduction of endoluminal concentration of long chain fatty acids (LCFAs). Therefore, the intraluminal production of various endotoxins increases, and among them the role of lipopolysaccharide (LPS) is notable. This results in the activation of inflammatory cells of the intestinal layer that begin to produce Tumor Necrosis Factor-alpha (TNF-a). The TNF-a alters and destroys the tight junctions of the intestinal mucosa epithelium, so allowing translocation of intestinal bacteria and their endotoxins to the intestinal blood vessels. Through the portal circulation, endotoxins are transported to the liver and bounded to the Toll-like receptors (TLRs) present on the cytoplasmic membrane of hepatocytes, bile duct epithelial cells, Kupffer’s cells, and intrahepatic stellate cells. Kupffer’s cells, thus stimulated, produce pro-inflammatory interleukins (IL-1, IL-6, IL-8, IL-10), TNF-a, PDGF, MCP-1, while the stellate cells become able to produce collagen, that is, to trigger liver fibrogenesis. It’s intuitive to understand that the whole process produces an inflammatory and pro-fibrotic liver microenvironment that is capable of causing a rapid evolution of the liver damage to necro-inflammation, fibrosis, cirrhosis and also hepatocarcinoma (HCC) at certain percentage (5 - 10%)