*2.3. Bacterial Translocation in Chronic Liver Disease*

The intestinal mucosa represents the barrier protecting against luminal microbes while allowing the selective passage of digested nutrients into the circulation. This property, termed intestinal permeability, allows the intestinal tract to fulfill its absorptive function via two pathways [38]. The transcellular pathway enables macromolecules such as glucose, amino acids, or bacterial antigens to move through cells via enterocyte, M cell, and goblet cell transporter-mediated transcytosis or endocytosis. The paracellular pathway allows water and minerals to diffuse through the interspace between adjacent epithelial cells [39]. Passive transport in intestinal epithelium is, however, tightly controlled by the proteins making up the cell TJs [40]. Currently, intestinal permeability can be measured using in vivo or in vitro functional assays [39]. In vivo assays evaluate urinary or blood non-metabolized sugar such as lactulose/mannitol, polyethylene glycols (PEGs), Cr-labeled ethylenediaminetetraacetic acid (51Cr-EDTA), ovalbumin (OVA), or Fluorescein isothiocyanate dextran (FITC-dextran) following ingestion. In vitro assays indirectly measure intestinal permeability by detecting biomarkers such as bacteria, lipopolysaccharides (LPS), endotoxin antibodies, or bacterial fermentation products in lymph/blood or by histologically examining TJ protein localization and expression.

Even in the absence of disease, bacteria can be transported across the intestinal epithelium into the lamina propria where they can interact with mesenteric lymph nodes (MLN) and extra-intestinal organs via the blood [41]. This process was termed bacterial translocation by Berg and Garlington in 1979, and has since been expanded to include other luminal microbes such as viruses and fungi [42]. In fact, sequencing and culture methods have detected low levels of viable and non-viable microbes, microbial DNA, and antigens in the MLN as well as in other "sterile" organs, including the liver [43,44]. Bacteriophages have also been detected in various sites within the human body including the blood, kidney, and liver [45], however their immunogenicity remains uncertain.

Increased bacterial translocation (BT) is associated with gastrointestinal diseases and the extra-intestinal conditions of the liver, kidney, and brain, among others [46–48]. As early as 1995, Berg et al. identified three factors that contribute to BT: bacterial growth or dysbiosis, intestinal permeability, and immune deficiency [41]. These factors have been identified in various forms of chronic liver disease, and are outlined below and in Table 1.
