# Paneth Cell, Gut Microbiota Dysbiosis and Diabetes Mellitus
## 3 Innate Immunity of the Small Intestine
### Gut Microbiota and Innate Immunity in the Small Intestine  
The gut lumen contains numerous species of bacteria, viruses, fungi, parasites and archaea [100]. Around \(10^{14}\) bacteria reside in the colon, but the small intestine contains fewer microorganisms [78]. Colonisation of the gut starts in utero and increases during childbirth [101; 102]. Further changes in the gut microbiota composition occur during breastfeeding and weaning [101; 102]. The normal gut flora of an individual is established during early childhood or adolescence. Once established, the gut microbiota is involved in the regulation of the physiological function and innate immunity of the small intestine [101; 103]. The gut microbiota also influences the proliferation and differentiation of the Lgr5+ ISCs and assists with the digestion of food [28]. Some of the commensals in the microbiota help process nutrients such as vitamins and short-chain fatty acids (SCFAs) like acetate and butyrate [3; 28]. Complex dietary fibres would be difficult to digest and absorb without the assistance of commensal bacteria [3; 28]. Figure 3: Schematic diagram showing the mechanism of action of HD-5 and HD-6. HD-5 kills bacteria and other microorganisms by creating pores on the cell membrane, while HD-6 forms nanonets to entrap pathogens (created using BioRender.com on 9 of February 2023). Certain species of bacteria help sustain the prevailing anti-inflammatory state to prevent damage to the intestinal epithelium, increased permeability, translocation of endotoxins and chronic systemic inflammation [32]. The other roles of the commensal organisms include preventing excessive production of ROS or RNS [30]. Furthermore, some of the commensal bacteria in the microbiota possess quorum sensors and secrete bacteriocins to kill the pathogenic species [70]. In addition, several species of bacteria can influence the cells involved in adaptive immunity in the lamina propria of the small intestine [30]. Several bacteria can modulate the hormonal milieu in the GIT and the entire body by participating in the microbiota-gut-brain axis. In return, commensal organisms depend on the nutrients in the diet, residue following digestion of nutrients and mucins secreted by goblet cells [104]. More than 80% of the bacteria in a healthy adult human belong to the Firmicutes and Bifidobacterium phylum [105]. Changing diet, use of antibiotics, chronic illness and excisional or bypass surgery in the GIT may lead to dysbiosis [106; 107]. Dysbiosis may involve the entire length or certain niches along the GIT. Dysbiosis commonly leads to a reduction in the diversity of the microbial species and the dominance of pathogenic organisms like the Bacteroides [3; 27; 30; 32; 78]. Dysbiosis not only involves bacteria but may also include the virome [100]. Dysbiosis and the emergence of pathogenic species may lead to an increase in the production of ROS [108]. High levels of ROS in the lumen of the gut can damage the intestinal epithelium [108]. Concomitantly, pathogenic gram-negative or gram-positive bacteria may initiate an inflammatory response by releasing pro-inflammatory lipopolysacchariderades or peptidoglycan, respectively [32; 109] (Figure 4). Inflammation of the epithelium of the small intestine increases its permeability, leading to the translocation of bacteria and their products [29]. Ongoing translocation of bacteria and endotoxins causes endotoxin and chronic systemic inflammation [4]. Chronic systemic inflammation creates an environment that is obesogenic and diabetogenic [106]. Chronic systemic inflammation also increases the generation of ROSINS from mitochondria in tissues and organs throughout the body [34; 78]. Some cells in organs throughout the body such as the \(\beta\)-cells of the islets of Langerhans in the pancreas have a limited capacity to neutralise reactive species, which can perpetuate the damage to their mitochondria [30].