**2. Structure and functions of the IB**

The mammalian IB is responsible for fulfilling two primary tasks: to absorb the ingested nutrients and to prevent the microorganisms, toxins, allergens, as well as luminal pro-inflammatory factors from passing through the luminal surface of the intestines into the circulatory system [6, 10–13].

The gastrointestinal tract, which consists of the mouth, esophagus, stomach, small and large intestines, calls for a single layer epithelial lining with its partners in crime, such as cells of innate and adaptive immune system, forming a multifunctional system to fulfill its barrier function [11].

In the name of intestinal homeostasis, "some" (capital S should be replaced with lowercase "s". ome of the complex functions should be performed alongside the absorption of the nutrients like to prevent the trespassing of the pathogens, toxins, or allergens limiting the pathogenic bacterial growth to maintain the balance of the luminal microbiota, detoxification of the endotoxins, and immune response on demand as it is the largest lymphoid organ of the body by a multilayer morphofunctional barrier [9, 14] (for a recent review, *see* reference [13]).

#### **2.1 First line of defense: commensal microbiota as the biological barrier**

Human beings are in a symbiotic relationship with millions of bacteria, fungi, and viruses colonized in our gastrointestinal tract [12, 15, 16]. This host-commensal relationship, which starts at birth, even in-utero [17–19], maintains the intestinal homeostasis as a biological barrier and responsible for the differentiation, growth, and integrity of the intestinal epithelium [12, 15, 16]. Most of the species of commensal bacteria are obligate anaerobes, and the rest are facultative anaerobes and aerobic bacteria (**Table 1**) [16, 20]. The majority of the anaerobic bacteria are found in the colon as the oxygen tension is relatively low, whereas the aerobic bacteria are prone to reside in the small intestines [21]. The bacterial population in the proximal small intestines and the colon are around 104 ml−1 and ∼107 ml−1, respectively [22].

These coexisting symbiotic bacteria demonstrate immunologic and metabolic functions and protect the intestines from pathogenic bacteria growth via alimentary competition and colonization suppression. They help ferment and digest carbohydrates and synthesize vitamin B and K, along with short-chain fatty acids, which will then become the energy source for the intestinal epithelium. They are also responsible for the deconjugation of bile acids which will then reenter the enterohepatic circulation [12, 16].


#### **Table 1.**

*The intestinal microbiota: Most common commensal anaerobic bacteria species in the human intestines (95% of them are obligate and 5% are facultative anaerobes) [16].*

*Intestinal Barrier Dysfunction, Bacterial Translocation and Inflammation: Deathly Triad… DOI: http://dx.doi.org/10.5772/intechopen.99554*

The intestinal immune system is modulated via the collaboration between the gut microbiota with the adaptive and innate immune systems, which is carried out by interacting pathogen-associated molecular patterns (PAMPs) with the specific receptors in the intestinal immune cells [12, 16].

#### **2.2 Second line of defense: intestinal alkaline phosphatase (IAP)**

IAP, one of four of the human alkaline phosphatase family, is an intestinal epithelial cell-derived enzyme constantly staying active intraluminally and in the mucosal lining to ease the gut's inflammatory response triggered by PAMPs. This way, it regulates the pH balance of the duodenal surface via bicarbonate secretion, helps the absorption of the long-chain fatty acids, defends the brush border membrane against the members of the intestinal microbiota. IAP also dephosphorylates bacterial endotoxin lipopolysaccharide (LPS) and pro-inflammatory nucleotides. Hence, it prevents the inhibition of the commensal microorganisms, as they are affected by the excessive luminal ATP by removing the phosphate groups from adenosine di- and triphosphate. LPS, which causes a systemic immune response and septic shock, is located on the wall of gram-negative bacteria and shows these effects by binding to toll-like receptor 4 (TLR4) thanks to its Lipid A moiety. TLR4 is expressed both in myeloid-borne immune cells (dendritic cells (DCs), macrophages, and monocytes) and in non-immune cells (i.e., endothelial cells) [23]. When dephosphorylated Lipid A moiety binds to TLR4, LPS shifts to a TLR4 antagonist, diminishes the pro-inflammatory cytokines, and activates nuclear factor-kappa-B (NF-κB), thereby minimizing the inflammatory response. It was previously shown that even being exposed to a lethal dose of E.coli, 80% of the mice survived with the help of IAP treatment. Thus, it was concluded that microbiota dysbiosis, intestinal inflammatory response, and transmigration of bacteria are inevitable in the absence of IAP [5, 14, 24, 25].

#### **2.3 Third line of defense: the mucous layer**

The first layer of the mechanical barrier is the mucosal layer which comprises water (95%), soluble glycoproteins (1–10%), nucleic acids, electrolytes, and antibodies. Mucin, a highly glycated protein, is secreted by goblet cells (specialized epithelial cells located in the villi), and with the help of other secreted proteins, they organize into a coherent mucus layer [11, 14].

Bacteria are responsible for the degradation of the mucus, and the balance between the secretion and the erosion of this layer determines the functionality of the IB. It was previously shown that this highly glycated structure of mucin feeds commensal bacteria, such as *Akkermansia muciniphila*, which is a gram-negative bacteria and gets protection from the potential pathogenic growth in return [26]. A previous study, in which bacterial adherence was coherently found to be elevated in the intestinal epithelia of the Mucin 2−/− mice leading to mucosal barrier dysfunction [14].

The outer intestinal mucosal layer is much looser and thicker in comparison with the inner layer. Therefore, the inner layer restrains the transmigration of the bacteria as it is tightly attached to intestinal epithelia to block the direct contact between epithelial cells and the bacteria. Contrarily, the outer layer retains the commensal microbiota elements to eliminate the opportunistic activity of pathogenic bacteria. For that reason, consistent usage of pro- and prebiotic preparations is reported to boost the number of commensal microbiota in order to promote mucosal barrier function [14].

Besides, the anionic residues like sialic acid or sulfate groups at the N-terminal of the mucin glycoprotein promote convergence of the cationic immune molecules, which serve as a chemical defense mechanism [27].

### **2.4 Fourth line of defense: physical barrier composed of the intestinal epithelial layer and submucosal capillary endothelial cells**

The second mechanical barrier is the polarized single layer of gut epithelial cells (enterocytes-responsible for the absorption, goblet-specialized in mucus production, enteroendocrine cells-responsible for the secretion of the intestinal hormones, Paneth cells-responsible for expressing the microbicidal proteins and peptides among other properties, and microfold cells (M cells)) besides submucosal capillary endothelial cells [21, 28, 29], which act as a selectively permeable interface allowing the transmigration of the essential nutrients, water, electrolytes, and immune factors, and preventing the transfer of luminal pathogenic microorganisms, antigens, and toxins to the circulatory system [4, 12–14, 30]. This feature of selectivity is coordinated by the paracellular pathway regulated by desmosomes, adherens junctions, and tight junctions (TJs), located at the apicolateral membrane junction, lateral membrane, and basolateral membrane, respectively, and the transepithelial pathway, which is maintained mainly by the selective transporters allowing the uptake of the nutrients [13, 14, 28, 31] (for a recent review about mechanobiology of TJs, see reference [32]).
