# Paneth Cells and Lgr5+ Intestinal Stem Cells in Radiation Enteritis
## 2 The Structure and Functions of the Small Intestine
### The Lgr5 Intestinal Stem Cells  
The derivatives of the Lgr5+ ISCs are divided into absorptive and secretory cells, and more than 80% of IECs are absorptive enterocytes [31; 46]. The majority of the remaining IECs is made up of goblet cells and Paneth cells, which are secretory [10; 12; 17]. The other secretory IECs are the enteroendocrine cells and the tuft cells [10; 15; 40; 48; 49] (Figure 1). Whereas all the other derivatives of the Lgr5+ ISCs are found throughout the entire small intestine from the duodenum to the terminal ileum, the M-cells are specialized enterocytes which are found only in regions where there are lymphoid follicles such as the Peyer's patches in the terminal ileum [50]. Although the enterocytes are primarily responsible for digestion and absorption of nutrients they also, like the other IECs, play a role in the maintenance of the structural integrity and innate immunity in the small intestine [31]. The robust innate immunity in the small intestine is dependent on the maintenance of the physical integrity of surface epithelial cells, quality of the junctional proteins, active surveillance of the gut microbiota, secretion of antimicrobial peptides predominately by the Paneth cells, good quality of mucins which are secreted by the goblet cells, and an adequate supply of nutrients [51]. High-dose ionizing radiation affects the structure, physiology, and immunological function of the entire wall of the small intestine. Figure 1: Schematic illustration of the structure of the intestinal crypt showing Lgr5+ ISCs in intimate contact with the Paneth cells at the base of the crypt, enterocytes with microvilli, goblet cells, and enteroendocrine cells. The sketch also shows some of the cells which are critical for the maintenance of normal structure and function of the small intestine that include dendritic cells, endothelial cells, nerve cells, and smooth muscle cells (The illustration was created using BioRender.com). All the IECs, bar the M-cells, possess pathogen recognition receptors that include the Toll-like receptors (TLRs) which they use for sampling of luminal contents in the small intestine [52]. Sampling of the intestinal contents by the IECs is continuous to prevent dysbiosis, increased intestinal permeability, and gut inflammation [28; 53; 54; 55]. Dysbiosis, increased intestinal permeability, and gut inflammation are the initiating events in several gastrointestinal and extra-gastrointestinal such as inflammatory bowel disease, type 2 diabetes mellitus, obesity, cancer, and radiation enteritis [56; 57; 44; 58]. The dysbiosis which is seen in chronic RE is superimposed on the damage from the direct and indirect effects of ionizing radiation on the Lgr5\({}^{+}\) ISCs, Paneth cells, other IECs, junctional proteins, and mesenchymal cells in the lamina propria. The Lgr5\({}^{+}\) ISCs are rapidly dividing cells and therefore highly sensitive to genotoxins and ionizing radiation [19]. The response of the Paneth cells and the other IECs may include de-differentiation and acquisition of stemness to replace the Lgr5\({}^{+}\) ISCs if they have been irreversibly damaged following ionizing radiation [21; 22; 37; 45; 58; 59; 60; 61; 62]. There are several tiers of the ISCs which are distributed along the crypt-villous axis. The Lgr5\({}^{+}\) ISCs are the most rapidly dividing and therefore the most sensitive to ionizing radiation. The Lgr5\({}^{+}\) ISCs are found intermingled with Paneth cells at the base of the intestinal crypt [47; 63]. The reserve ISCs are quiescent and get activated if the Lgr5\({}^{+}\) ISCs have been destroyed as is seen in RE [19; 47]. The high sensitivity of the Lgr5\({}^{+}\) ISCs is necessary to prevent an accumulation of radiation-induced non-fatal DNA damage which would later increase the risk of cancer.