*2.2. Physical and Chemical Barriers of the Intestinal Mucosa*

To maintain a healthy coexistence with commensal microbes and prevent bacterial dissemination, the gastrointestinal tract is lined by a cellular epithelium. This physical barrier is composed primarily of epithelial cells, with the addition of specialized cell types that differ between the small and large intestine. While all epithelial cells arise from intestinal epithelial stem cells (IESC) at the base of crypts, they differentiate into a variety of cells, including enterocytes (colonocytes in the large intestine), goblet cells, Paneth cells, tuft cells, and Microfold cells (M cells) [32]. Apart from hormone-secreting enteroendocrine cells and nutrient-absorbing enterocytes, the remaining epithelial cells are largely responsible for defending against microbial invasion (Figure 1).

Goblet cells secret mucin proteins to form a highly glycosylated mucus layer over the vast epithelial surface, and this layer is significantly thinner in the small intestine compared to the colon due to a lower goblet cell density and bacterial colonization [33]. IgA secreted across the intestinal epithelium also comprises a significant component of the chemical defense. IgA is secreted by plasma cells in lymphoid follicles of the lamina propria, and transported via polymeric immunoglobulin receptors (pIgR) on the basolateral surface of epithelial cells into the lumen [34].

Epithelial integrity is maintained by junctions between intestinal epithelial cells (IECs) that provide selective nutrient permeability while preventing microbial translocation. There are three major types of cell junction that typically form near the apical end of the cells' side walls: tight junctions (TJs), gap junctions, and adherens junctions [35]. Among them, TJs form the most rigid and impenetrable

seal, hence their name. This junction is a complex of more than 50 proteins, most of which are transmembrane proteins such as occludin, claudin, and the junctional adhesion molecule (JAM) family proteins such as zonula occludens (ZO)-1, which connect with the cytoskeleton and form fibrils with adjacent cells [36,37].

**Figure 1.** Intestinal mucosal barriers in health and chronic liver disease. (**A**) Several physical and chemical defenses make up the intestinal mucosa, which serves to protect us from luminal microbes. Intestinal epithelial stem cells (IESCs) located at the base of crypts give rise to all epithelial cells. Goblet cells secrete mucins to form a thin mucus layer in the small intestine and two thick layers in colon, the innermost of which is devoid of bacteria. Enterocytes/colonocytes and Paneth cells secrete antimicrobial peptides (AMPs) primarily in the small intestine, while mast cells secrete IgA, which travels through the epithelium and is concentrated in the colon. Underlying the epithelium, dendritic cells and macrophages continuously surveil luminal contents using trans-epithelial dendrites. (**B**) Disruption of these physical barriers can lead to intestinal permeability and increased microbial translocation in chronic liver disease. These include the reduction of secreted mucus, AMPs, and IgA, permitting microbial access to the epithelial layer. Downregulation, altered localization, or rearrangement of tight junction components can also significantly impact intestinal permeability, allowing microbial translocation into the portal circulation where they are transported into the liver.
