Gut-liver axis in liver cirrhosis: How to manage leaky gut and endotoxemia

Figure 1 Mechanism of lipopolysaccharide clearance in the blood and LPS-toll like receptors-MyD88 signal transduction. LBP enhances cell responses to LPS by accelerating the binding of LPS to CD14. LBP can also inhibit cell responses to LPS; It transfers LPS to plasma lipoproteins and it combines with LPS aggregates to form large LPS-LBP complexes that are internalized[176]. sCD14 can remove, or divert, LPS from mCD14 and transfer it to plasma lipoproteins, where LPS is inactivated[176]. Albumin is essential during the interaction of LBP with LPS aggregate to produce a LBP: LPS aggregate and the efficient transfer of LPS from the aggregate to a molecule of sCD14[177]. Albumin stabilizes LPS: CD14 complexes for cell activation. Mechanism of inhibitory effect of albumin on LPS is still unknown. It may directly inactivate minute amount of LPS and may also enhance LPS transport to lipoproteins. LPS: Lipopolysaccharide; LBP: Lipopolysaccharide binding protein; TNF-α: Tumor necrosis factor α; TLR4: Toll-like receptors 4; NF-κB: Nuclear factor kappa B; TRAF6: TNF receptor-associated factor.

Figure 2 Mechanism of endotoxemia and its consequences in advanced liver cirrhosis (hypothesis). Depressed elimination of endotoxin by Kupffer cells (KCs) is considered to induce spillover endotoxemia and processing of endoxin by extrahepatic macrophages which secrete larger amount of TNF than KCs. The excessive cytokine response to endotoxin by splenic and alveolar macrophages may be important in the pathogenesis of ARDS and multiple organ failure. Endotoxemia enhances vascular NO production, which is the primary stimulus for the development of vasodilatation. Enhanced vasoconstrictive factors in response to vasodilatation and endotoxemia are responsible for ascites and hepatorenal syndrome. Hepatic encephalopathy is also closely related to inflammatory reaction attributable to leaky gut amd endotoxemia. RAA: Renin-angiotensin-aldosterone system; SN: Sympathetic nerves; ADH: Antiduretic hormone (vasopressin); SBP: Spontaneous bacterial peritonitis; NO: Nitric oxide; LBP: Lipopolysaccharide binding protein; HDL: High-density lipoprotein.