Starring role of toll-like receptor-4 activation in the gut-liver axis

Figure 1 The results of intestinal disorders that are associated with impaired motility. A: Normal conditions with intestinal mucosa tolerance; B: In the presence of microbiota imbalance, intestinal mucosa is characterized by a leak and mild inflammatory infiltrate. The subsequent passage of modest quantities of lipopolysaccharides (LPS) induces activation of resident macrophages (MΦ) with the release of inflammatory mediators, such as prostaglandins (PGs) and nitric oxide (NO). LPS can also reach the muscle layer and bind to smooth muscle cell (SMC) toll-like receptor 4 (TLR-4). Both conditions cause morpho-functional changes of SMCs. The reduced intestinal motility further induces intestinal microbiota imbalance, which leads to dysbiosis; C: Dysbiosis induces barrier damage and relevant bacterial and LPS translocation. The large amount of translocated LPS reaches the blood vessels through the portal vein and reaches the liver.

Figure 2 Hepatic cell types express toll-like receptor-4. In the presence of the loss of lipopolysaccharides (LPS) tolerance, such as during non-alcoholic fatty liver disease, non-alcoholic steatohepatitis or HCV chronic hepatitis, TLR-4 is activated by gut-derived LPS and overexpressed. An altered balance of known miRNAs (miR155, miR21, let-7i) and chemokine receptors (CXCR4, CXCR7) could promote this condition. Then, activation and recruitment of inflammatory cells, ductular reaction and activation of endothelial and stellate cells drive liver inflammation and fibrosis. On the right, the mediators mainly involved in the fibrosis are presented (TGF-β, IGF-1, TNF-α, IL-6), on the left, mediators related to the inflammation are shown (TNF-α, IL-6, IL-1α, IL-8, GM-CSF, IFN-γ). TLR-4: Toll-like receptor-4; TNF-α: Tumor necrosis factor alpha; IL: Interleukin; GM-CSF: Granulocyte-macrophage colony-stimulating factor; IFN: Interferon; HCV: Hepatitis C virus; MMPs: Matrix metalloproteinases; NAFLD/NASH: Nonalcoholic fatty liver disease/nonalcoholic steatohepatitis.