Gut-liver axis is defined as a functional entity that establishes the intimate connection and the strict cooperation between the gut and the liver. It has been observed that the integrity of intestinal barrier is vital for the maintenance of liver homeostasis, in which liver acts as a second firewall towards potentially harmful substances translocated from the gut. Plethora of evidence have supported the significance of increased intestinal permeability (IP) and subsequent bacterial translocation in the development of liver injury. Recent studies highlights impairment of IP, diet and gut dysbiosis as the primary pathogenic trigger in patients with non-alcoholic fatty liver disease. This IP further gets enhanced by portal hypertension in advanced liver disease which in turn, increases bacterial translocation that precipitates liver damage. This pathogenic mechanism is involved in majority of liver cirrhosis complications, such as spontaneous bacterial peritonitis, hepatorenal syndrome, portal vein thrombosis, hepatic encephalopathy, and hepatocellular carcinoma. 

Increased IP is the result of multiple disorders that affect the homeostasis of the barrier in liver diseases. Several studies showed that an association exists between liver damage and dysfunction to alterations of the gut microbiota composition, mucus quality and quantity, gastrointestinal motility, intestinal epithelial barrier and tight junction, and the immune system. The disruption of the intestinal barrier at any level leads to an increase in IP and harmful substances, such as microorganisms and microbial- and pathogen- associated molecular patterns (MAMPs and PAMPs), metabolic products, and whole bacteria tremendously reach local mesenteric lymph nodes (MLNs), that are unable to provide an adequate clearance. This increased concentration in variable amount is delivered to the liver through the mesenteric and portal circulation. The damage is restored by triggering a systemic inflammatory response, developing from the liver, which is mainly mediated by Kupffer cells.

 The interaction between pathogen-associated molecular patterns and toll-like receptors (TLRs) activate intracellular molecular pathways, which further result in the activation of NF-κB and the expression of inflammatory cytokines, chemokines, vasoactive factors [nitric oxide (NO)] and reactive oxygen species (ROS). When equilibrium of detrimental effect of species and antioxidant elements gets deranged, ROS can negatively affect both sides of the gut-liver axis and contributes to intestinal barrier damage. Additionally, diet, alcohol, infectious and primary inflammatory diseases, and drugs are able to disturb the balance in the redox state in the gut, resulting in increased IP. 

The researchers have also supported these observations with studies reporting a positive relationship between altered IP and liver inflammation and fibrosis in a population of children with non-alcoholic fatty liver disease (NAFLD). A meta-analysis also showed that altered IP was seen in patients with NAFLD, especially those with increased liver injury markers, indicative a pathogenic mechanism that determines liver damage through the alteration of the gut barrier.

Source: Nicoletti A, Ponziani FR, Biolato M, et al. Intestinal permeability in the pathogenesis of liver damage: From non-alcoholic fatty liver disease to liver transplantation. World J Gastroenterol. 2019;25(33):4814-4834.