# Paneth Cells and Lgr5+ Intestinal Stem Cells in Radiation Enteritis
## 2 The Structure and Functions of the Small Intestine
### Paneth Cells  
Paneth cells make up around 5% of the IECs and are found throughout the small intestine from the duodenum to the terminal ileum. Paneth cells start appearing in the small intestine and colon of a human fetus at 12 weeks gestational age [12]. Matured Paneth cells are found at the base of the intestinal crypts where they are in direct contact with the Lgr5+ ISCs [15; 62; 70]. The life span of the Paneth cells is 3-7 weeks which is 3-4 times longer than that of the other IECs [12; 17; 40; 74; 75]. Paneth cells influence the proliferation and differentiation of the Lgr5+ ISCs through the release of niche factors or their ligands such as Wnt and Notch, cytokines, and growth-enhancing factors in collaboration with mesenchymal and immune active cells which reside in the lamina around the base of the intestinal crypts [17; 24; 60]. The other role of the Paneth cells is to regulate the microbiota in the lumen of small intestine. Paneth cells are the main producers of the antimicrobial peptides and proteins which sterilize the area around the Lgr5+ ISCs and the luminal surface of the IECs [29; 62; 75; 76; 77; 78]. The main antimicrobial peptides which are secreted by the Paneth cells are human \(\alpha\)-defensin 6, human \(\alpha\)-defensin 6, and lysosome [12; 75; 78; 79]. Human \(\alpha\)-defensin 5 can kill bacteria, parasites, fungi, and most pathogenic viruses [14; 29; 30; 54; 77; 78].  
Paneth cells together with cells which located in the lamina propria are critical for the maintenance of the structural, physiological, and immunological integrity of the small intestine and are activated following a damage to the gut mucosa or emergence of dysbiosis [12; 62; 74; 77; 79; 80]. Paneth cells are involved in the initiation of the repair process after bowel injury such as following radiation injury. Like the other IECs, Paneth cells can de-differentiate into Lgr5+ ISCs if they themselves are not fatally damaged. Paneth cells and the reserve ISCs lead the process of de-differentiation if they themselves are still viable. Dysbiosis is a common feature of radiation that is also linked to the dysfunction of Paneth cells [39]. Failure of the Paneth cells to regulate the microbiota leads to dysbiosis, increased permeability of the intestinal epithelium, translocation of bacteria and their products, and local inflammation. The inflammation in the wall of the small intestine may spill over and become systemic. Dysbiosis and systemic inflammation are the main drivers of some of the complications associated with acute and chronic RE [33]. The other important functions of the Paneth cells which may be disrupted following ionizing radiation are nourishment of the Lgr5+ ISCs, sampling of nutrients and phagocytosis of the other IECs if they have been damaged or are apoptotic IECs [81].  
The quality of Paneth cells and their potency is assessed by studying their morphological appearance, position along the crypt-villous axis, and their overall number per crypt [82]. More objective analysis of their capabilities includes checking the position, size, and the intensity of staining of their apical cytoplasmic granules on immunohistochemistry [70; 75; 83]. Matured Paneth cells are found at the base of the intestinal crypts where the most radio-sensitive Lgr5+ ISCs which need the most protection are found. Paneth cells have intense and uniform staining of apical cytoplasmic granules. Genomics, transcriptomics, or metabolomics-based studies can determine the level of expression of genes or concentration of protein which are synthesized by the Paneth cells [23; 64].