# Paneth Cell, Gut Microbiota Dysbiosis and Diabetes Mellitus
## 3 Innate Immunity of the Small Intestine
### Intestinal Epithelial Cells and Innate Immunity
#### 3.1.1 The Role of Paneth Cells in the Innate Immunity of the Small Intestine  
Paneth cells are among the derivatives of the Lgr5\({}^{+}\) ISCs in the small intestine and the small intestine's major source of antimicrobial peptides and proteins [62]. Paneth cells control the microbiota in the lumen of the small intestine and the proximal parts of the large bowel. The antimicrobial peptides from Paneth cells bathe and sterilise the area where the rapidly dividing and highly vulnerable Lgr5\({}^{+}\) ISCs are found [2; 64; 73]. Matured Paneth cells are found at the base of the intestinal crypt of Lieberkuhn in the entire small intestine from the duodenum to the terminal ileum [74; 75]. Paneth cells start appearing in the small and large intestines of embryos at the end of 12 weeks, and their number increases significantly in the small intestine after 36 weeks [73; 76]. The adult colon contains few, if any, Paneth cells. Goblet cells and other cells, instead of Paneth cells, are responsible for the antimicrobial activities in the colon [76]. Metaplastic Paneth cells may appear in the colon and other sites in patients who have, for example, IBD [77]. The number of Paneth cells increases during childhood and a full complement for an individual is reached later in life [78]. Each intestinal crypt in an adult ultimately contains around 5-15 Paneth cells [79]. The number of Paneth cells per intestinal crypt is, however, variable, as their density increases downwards. The highest density of Paneth cells in a healthy state is found in the ileum [80]. The HD-5 is responsible for most of the antimicrobial activities in the small intestine [13; 14; 74; 81]. The other antimicrobial peptides and proteins that are secreted by the Paneth cells include human \(\alpha\)-defensin 6 (HD-6), lysozyme and phospholipase [13; 82]. Although the other IECs such as the absorptive enterocytes, goblet cells and tuft cells survey and regulate the gut microbiota, Paneth cells are the most critical for innate immunity in the small intestine, as they secrete the largest amount of the most potent antimicrobial peptides and proteins [16; 78]. In addition, the localisation of matured Paneth cells at the base of the intestinal crypts ensures the maximal concentration of antimicrobial peptides for the defence of the highly active but most vulnerable Lgr5 ISCs [78] (Figure 1). Paneth cells are pyramidal in shape. They have a broader base where their nucleus is situated [82]. Paneth cells are among the secretory derivatives of the Lgr5\({}^{+}\) ISCs, and their cytoplasm contains several organelles, which include the endoplasmic reticulum and Golgi apparatus. The apical area of Paneth cells has eosinophilic granules that contain, among other constituents, HD-5, HD-6, lysosome, growth factors, Wnt signals and cytokines [74; 82]. Paneth cells release their constituents after the detection of pathogens through their pathogen recognition receptor system. Paneth cells continually sample the microbiota in the lumen of the small intestine to prevent dysbiosis [82; 83; 84]. Paneth cells also secrete antimicrobial peptides and other products following a stimulus from the brain via the cholinergic system. The mere sight or smell of food may also lead to the activation of the Paneth cells. Additionally, Paneth cells sample the composition of nutrients in the food following ingestion [7] (Figure 2). Some of the antimicrobial proteins and peptides secreted by the Paneth cells are stored as zymogens in the cytoplasmic granule and are activated just before release [82]. Once activated, HD-5 can kill all bacteria, fungi and parasites and some viruses [85]. Paradoxically, HD-5 can enhance proliferation of certain viruses [12; 82]. Human defensin 5 is lipophilic and kills pathogenic bacteria by creating pores on the cell membrane, which increases the permeability, thus making the bacteria swell up and subsequently burst [12; 17; 19].