Mucosa enterocyte

It has been known for some time that the enteric nervous system does not simply regulate smooth muscle contraction, but is intimately involved in the control of transport processes in enterocytes. Nerve fibres in the mucosa terminate subjacent to the basement membrane of epithelial and entero-endocrine cells, on which muscarinic acetylcholine receptors (mAChRs)... 

Although infection with C. parvum is considered predominantly secretory, histopathologic studies have revealed varying degrees of villous atrophy and infiltration of inflammatory cells beneath the epithelial mucosa [85, 86], Prostaglandins, which are known to induce cAMP-mediated apical chloride secretion and inhibit electroneutral sodium chloride and water absorption in enterocytes, have been demonstrated to be elevated in a porcine model of cryptosporidiosis [87], Inflammatory cytokines such as IL-1, IL-8 and TNF-a are induced in intestinal epithelial cell lines infected with Cryptosporidium and in animal models of cryptosporidiosis and have been postulated to play a role in pathogenesis [88, 89], Expression of TNF-a and IL-1 mRNA in the majority of jejunal biopsies of adult volunteers after experimental infection were also observed, although this did not correlate with the enteric symptoms [90]. 

Figure 8.1 (A) Cross-sectional view of the organization of the small intestine, illustrating the serosa, the longitudinal and circular muscle layers (=muscularis externa), the submucosa, and the intestinal mucosa. The intestinal mucosa consists of four layers, the inner surface cell monolayer of enterocytes, the basal membrane, the lamina propria (connective tissue, blood capillaries), and the muscularis mucosae, (B) Schematic representation of an enterocyte (small intestinal epithehal cell) (according to Tso and Crissinger [151], with permission).

When a drug has dissolved in the GI fluids and is present in solution at the site of absorption it has to pass a biological barrier, that is, the enterocytes lining the gut wall, in order to be absorbed into the body. The absorptive flux (J) can be described as a function of the permeability of the intestinal mucosa to the drug (Peff), the surface area available for absorption (SA), and the concentration gradient (AC) across the mucosa (e.g., [6], Eq. 2)... 

As mentioned above, the villi of the small intestine (Figure 1.2) house a dynamic, self-renewing population of the epithelial cells that includes absorptive cells (enterocytes), secretory cells, and endocrine cells. The thin lining (height 25 p,M height of the microvilli is 1.5 pM) of the columnar enterocytes is the only barrier between the intestinal lumen and the muscularis mucosa, which represents, in this context, the entire body interior. The entire epithelial lining of the intestine replaces itself every 3-5 d [128], It is the enterocyte and its neighboring cells where absorption processes occur and it will therefore be the focus of the mechanistic discussions below. 

Figure 1.1 shows the major sites of enzyme activity in the GI tract, and we will consider each of these in turn. While most of the enzymes that hydrolyse macromolecules enter the gut in the pancreatic fluid and hence are found in the lumen of the gut, there is significant peptidase activity located on the membranes of the intestinal cells, the so-called brush border. Consideration should also be given to the enzymes that are located inside the cells of the intestinal mucosa, namely, the epithelial cells or enterocytes. This is for two reasons first, the intestinal mucosa has a turnover of 3-6 days in humans and this means that the enterocytes are constantly being sloughed-off into the lumen of the gut. Thus intracellular enzymes and brush border enzymes will be found in the lumen of the gut, though the precise quantity is difficult to assess (see later in Section 1.6). 

Considerable evidence has accumulated indicating that macromolecules and microparticulates can be taken up by the intestinal enterocytes, generally via pinocytosis. In some cases, transcytosis, i.e. passage through the cells, has been observed, with microparticles subsequently gaining access to the lymphatics of the mucosa. For example, studies have shown that receptor-mediated endocytosis via enterocytes is a major pathway for the internalization of certain antisense oligonucleotides. 

At least part of the impairment of iron absorption in riboflavin deficiency is a result of morphological changes in the intestinal mucosa, with hyperproliferation, an increased rate of enterocyte transit along the villi and a reduced number of (longer) villi and deeper crypts (Williams et al., 1996). 

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