Epithelial Barrier Function in Gut-Bone Signaling

Abstract

The intestinal epithelial barrier plays an essential role in maintaining host homeostasis. The barrier regulates nutrient absorption as well as prevents the invasion of pathogenic bacteria in the host. It is composed of epithelial cells, tight junctions, and a mucus layer. Several factors, such as cytokines, diet, and diseases, can affect this barrier. These factors have been shown to increase intestinal permeability, inflammation, and translocation of pathogenic bacteria. In addition, dysregulation of the epithelial barrier can result in inflammatory diseases such as inflammatory bowel disease. Our lab and others have also shown that barrier disruption can have systemic effects including bone loss. In this chapter, we will discuss the current literature to understand the link between intestinal barrier and bone. We will discuss how inflammation, aging, dysbiosis, and metabolic diseases can affect intestinal barrier-bone link. In addition, we will highlight the current suggested mechanism between intestinal barrier and bone.

Figure 1. Schematic representation of the intestinal tight junctions proteins and their location

Tight junctions are protein complexes that span between epithelial cells to form a tight barrier. They are comprised of transmembrane proteins, such as occludin (red) and claudins (purple) and they are connected to the actin cytoskeleton via a zona occludens (ZO-1 and ZO-2 (grey)). The transmembrane receptor JAM (junctional adhesion molecule (blue)) is also found at tight junctions complexes. Abbreviations: JAM, junctional adhesion molecule; ZO, zona occludens.

Figure 2. Schematic representation of the gut epithelial layer in healthy gut vs dysbiosis

In the normal state, the mucus layer prevents the interaction between the gut microbiota and the intestinal epithelial barrier. Underneath the epithelial layer is the lamina propria. The lamina propria is composed of connective tissue and cells of the innate and adaptive immune system: mast cells, macrophages, dendritic cells, and lymphocytes (T and B). The composition of the intestinal epithelial layer can be influenced by many factors including antibiotic treatment, psychological and physical stress, radiation, age, and diet. This can lead to alterations in bacterial metabolism as well as overgrowth of potential pathogenic bacteria. This dysbiosis is associated with increased levels of permeability, bacterial translocation and inflammation.

Figure 3. Model of intestinal epithelial disruption signals that can regulate bone density

Many factors such as aging, menopause and metabolic diseases are known to disrupt the intestinal epithelial layer. They can modulate gut microbiota composition and activity, increase intestinal permeability, inflammation and decrease nutrient absorption. These changes can result in local and systemic responses that can affect bone density.