Immunology of Gut-Bone Signaling

Abstract

In recent years a link between the gastrointestinal tract and bone health has started to gain significant attention. Dysbiosis of the intestinal microbiota has been linked to the pathology of a number of diseases which are associated with bone loss. In addition modulation of the intestinal microbiota with probiotic bacteria has revealed to have both beneficial local and systemic effects. In the present chapter, we discuss the intestinal and bone immune systems, explore how intestinal disease affects the immune system, and examine how these pathologic changes could adversely impact bone health.

Fig 1. Regions of the Intestine

The intestine is composed of two main segments: the small intestine and the large intestine. The small intestine is further divided into the duodenum, jejunum and ileum while the large intestine consists of the cecum, colon and anus. These regions are specialized with regard to the digestion and absorption of nutrients required to maintain homeostasis.

Fig 2. Layers of the Intestinal Tract

A cross section of the intestine displaying the different layers. The serosa, the outermost layer, covers the intestine. The muscular layer (muscularis externa) consists of two types of muscle, the inner circular muscle and the outer longitudinal muscle; coordinated contraction of these muscles, known as peristalsis, moves chime / feces through the intestinal tract. The submucosa consists of dense and irregular connective tissue containing blood vessels, lymphatics and nerves that branch into the mucosa. The mucosa is the inner most layer of the intestine and consists of the epithelium (in contact with the lumen), the lamina propria and the muscularis mucosae.

Fig 3. Simplified Schematic Representation of the Intestinal Layers and Epithelial Barrier of the Small (left) and Large (right) Intestine

The small intestine consists of projections in to the lumen known as villi. These vastly increase the absorptive surface area. In contrast, the colon is relatively smooth and contains crypts. The epithelial barrier is made up of numerous cell types. Enterocytes, found in the small intestine, are the absorptive cell and have microvilli on their apical surface further increasing the surface area involved in digestion. Interspersed between the enterocytes are goblet cells and intraepithelial lymphocytes (IELs). Goblet cells produce mucus that forms a protective layer over the epithelial barrier. In the small intestine this mucus layer is loosely adherent while in the large intestine the mucus layer is split into two sections; a loose outer layer and an adherent inner layer. IELs have numerous functions including but not limited to; forming a frontline of defense against pathogens in the lumen, suppressing excessive inflammation and ensuring the integrity of the epithelium. Within the intestinal crypt Paneth cells produce antimicrobial peptides, defensins and lysozymes. These Paneth cells are interspersed between stem cells which renew the intestinal epithelium. Adapted from Mowat et al. (1).

Fig 4. Simplified Schematic Diagram of the Peyer's Patch

Peyer's patches are lymphoid structures visible on the anti-mesenteric side of the small intestine and are composed of B cell germinal centers surrounded by T cells. Peyer's patches are characterized by the presence of the follicle-associated epithelium which contains M cells. M cells transport the antigens present in the lumen into the Peyer's patch where they are up taken by DCs. DCs present these antigens to the lymphocytes which initiate the adaptive immune response. Adapted from Mowat et al. (23).

Fig 5. Immune Cells of the Lamina Propria

The lamina propria is comprised of loosely packed connective tissue that forms a supportive structure for the villi and contains the mucosa blood supply, lymph drainage and nervous system. The lamina propria cell population is variable containing cells of the innate immune system: DCs, macrophages, eosinophils and mast cells, and adaptive immune system: T lymphocytes (CD4⁺ T_h1, T_h2, T_h17, T_reg and T_R1; CD8⁺) and B lymphocytes (B cells and IgA and IgM producing plasma cells). Adapted from Mowat et al. (1).

Fig 6. Osteoblast and Osteoclast Cross Talk

Osteoblasts regulate osteoclast differentiation and activity through the expression of three critical cytokines: macrophage colony stimulating factor (MCSF receptor activator of nuclear-factor kappa B ligand (RANKL) and osteoprotegerin (OPG) a soluble decoy receptor for RANKL. Conversely, osteoclasts can modulate osteoblast differentiation through expression of the osteogenic factors Wnt10b and bone morphogenic protein (BMP)-6.

Fig 7. Lymphocyte Modulation of Bone Remodeling

Bone marrow lymphocytes can modulate the differentiation and function of osteoclasts and osteoblasts through the expression of pro- and anti-inflammatory cytokines as well as RANKL and OPG.

Fig 8. Role of Myeloid Cells in Osteoclast Differentiation

Under inflammatory conditions neutrophils upregulate expression of RANKL which can stimulate osteoclast differentiation. Furthermore, following stimulation with RANKL and MCSF, immature dendritic cells can transdifferentiate into functional osteoclasts.