2.3.3. Liver Cirrhosis

Due to clinical associations with bacterial infection, microbial translocation is often examined in the context of liver cirrhosis. BT in cirrhosis has been identified using such methods as lymph node homogenate bacterial culture and bacterial DNA sequencing in cirrhotic patient blood [78,79]. Importantly, translocated bacteria, dominated by the Proteobacteria phylum, are abundant in the portal vein, as well as the hepatic and peripheral blood of decompensated cirrhotic patients [80]. When compared to healthy controls, SIBO is also significantly more common in patients with cirrhosis, particularly following decompensation [81,82]. Portal hypertension and abnormal small bowel motility are likely related to prevalent SIBO in decompensated cirrhosis [83].

Intestinal permeability as assessed by dual-sugar ingestion assays has been found to increase in both the small and large intestine of patients with decompensated/advanced cirrhosis [84–86]. Reduction in the expression of TJ proteins occludin and claudin-1 in cirrhotic patients may provide a mechanism for this increased permeability [87]. Nonetheless, electron microscopy experiments performed by Such et al. ten years prior demonstrated intact TJs in the duodenal epithelium of cirrhotic patients, but enlarged interspace between enterocytes [88]. More recently, an examination of cirrhotic mice treated with carbon tetrachloride (CCL4) showed a reduction of mucin (MUC)2 expression, mucus thickness, and goblet cell number, as well as an increase in intestinal permeability associated with bacterial overgrowth and translocation. The authors also suggested a modulatory role of the bile acid receptor Farnesoid X receptor (FXR), due to the restoration of TJ protein expression, goblet cell number, and bacterial translocation following FXR agonist treatment [89].

Although clinical associations have yet to be found, alterations in intestinal humoral and cellular immunity within gut-associated lymphoid tissues (GALT) have also been observed in cirrhotic models. An increase in bacterial translocation in cirrhotic rat models can activate monocytes and dendritic cells in GALT, releasing pro-inflammatory cytokines such as tumour necrosis factor (TNF)-α and

IL-12 [90,91] that have been shown to increase intestinal permeability by deregulating ZO-1 and claudin 1 within the TJs [92,93]. While dendritic cells have been shown to open TJs to allow microbial sampling of the lumen, an increased incidence of DC sampling has been measured in cirrhotic rats, and is associated with increased translocation of bacterial DNA [91].


**Table 1.** Intestinal barrier deficiencies in chronic liver disease.

ALD: alcohol liver disease; NAFLD: non-alcoholic fatty liver disease; NASH: non-alcoholic steatohepatitis; TJ: tight junction; ZO: zonula occludens; IFN: interferon; IL: interleukin; CD: cluster of differentiation; TNF: tumor necrosis factor; DC: dendritic cell.

Studies in recent years have provided sufficient evidence to suggest that microbial translocation can drive the development and exacerbation of chronic liver diseases. However, the detailed cellular and mechanisms implied by this association will need more efforts to elucidate.
