The first part of the human intestinal tract is the five to six meter long small intestine [48, 53- 55]. The small intestine is the major organ for nutrient absorption due to its length and surface (transit time 2 to 4 hr) [56]. The topography of its luminal surface is characterised by apical microvilli, crypts and villi as well as Keckring and half-moon folds which enlarge the contact surface to 200 m2 to enhance absorption [57, 58]. Peristalsis leads to a permanent movement and mixing of its contents [59].
As the epithelial cells of the small intestine form a permeable membrane, they are additionally protected by a mucus layer [54]. The thickest mucus layer is found in the early duodenum to protect against the highly acidic chyme coming from the stomach. The chyme is then mixed
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Figure 1.2: Schematic representation of the mucus coverage of the gastrointestinal tract [60].
Green layers represent expression of genes encoding the outer loose mucus (o) and inner stratified (s) layer, respectively. Red dots represent microorganisms in the outer mucus layer of the colon. Variation of mucus thickness and villi length along the GIT is not shown [60].
Figure 1.3: Schematic representation of the microbiota of the human gastrointestinal tract [18]
Schematic representation of the amount of bacteria per gram of intestinal contents, nutrient availability and bacterial fermentative activity typically found in different sections of healthy individuals.
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with sodium-bicarbonate, bile salts, phospholipids and enzymes in the duodenum [61]. Bile salts, amphipathic molecules synthesised in the liver [62], enable the diffusion of post-digestion emulsions through the (ex vivo porcine) intestinal mucus due to the high negative charge the
bio-surfactants impart to the droplets [63]. The lower parts of the small intestine are the jejunum, the main site of nutrient absorption and detection which has the most elongated villi, and the ileum for absorption of the remaining nutrients before passing the yet undigested food to the colon [64].
The small intestine has several functions [46], the major of which are absorption, barrier, and signal recognition and transduction. The combination of all processes is required to efficiently absorb nutrients while preventing harmful lumen contents, like bacteria or toxins, from entering the circulatory system [65]. Absorption, barrier, and signal recognition and transduction are illustrated in Figure 1.4 and are discussed below [66-68].
1.1.2.1 Absorption
The central function of the GIT is degradation of food and absorption of released nutrients [57]. The apical cell membrane has various transport systems for specific nutrients (e.g. glucose, amino acids or peptides) and also facilitates the uptake of non-nutrient food compounds. Membrane transport occurs mainly in three ways (Figure 1.4): (I) Paracellular transport is passive diffusion and utilises the gap at intercellular junctions between IEC [66]. This flexible and sometimes leaky (e.g. after interferon-γ treatment) pathway even allows transport of large solutes up to 10 kDa, including small proteins and bacterial lipopolysaccharides [69-71]. (II) Transcellular diffusion happens against an electrochemical gradient. It is the principal transport system for substances that can penetrate cell membranes, e.g. minerals [72]. (III) Intracellular vesicle transport is transcytosis of high molecular compounds like proteins [66].
Further, osmotic or electrochemical gradients can enable transport, e.g. water transport is related to osmotic processes (transcellular or paracellular) [45]. This is also linked to substance transport by solvent-drag whereby water carries off particles paracellularly [73, 74].
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Figure 1.4: Three major functions of the intestinal epithelial cell monolayer. Adapted from Shimizu [66].
Absorption Barrier Recognition
Transduction Response Xenobiotics Pathogens Stresses Nutrients Food components Efflux Shut-out Recognition Secretion of e.g. cytokines Transport Detoxification Signal transduction (biofactor production) TJ Food, nutrients Apical transporter Basal transporter Tight junctions Active xenobiotics Inactive xenobiotics Efflux pump Pathogens
Cell surface recognition sites Secreted signal molecules
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1.1.2.2 Barrier
The GIT interface is protected by several means: (I) a physical barrier that includes tight junctions which seal the IEC together [66, 75] and motility (peristalsis) to control the bacterial growth and to “clean off” chyme residues [57, 76]; (II) the biological barrier (innate immunity) including detoxification enzymes [77], secreted antiviral immunoglobulin A (IgA) antibodies and antimicrobial peptides [78-82]; (III) the harsh environment in the stomach and small intestine can also be considered a chemical barrier [83]; (IV) a last barrier is the commensal microbiota which deter exogenous bacteria from colonising the GIT surface[84].
1.1.2.3 Signal recognition and transduction
Signal recognition and transduction is carried out by the enteroendocrine cells which recognise food-derived nutrients [66] but also non-nutrient chemicals. The cells release hormones and paracrine factors to control digestion and food intake [85].
1.1.2.4 Duodenum as designated site for targeted delivery of nutrients
To date, the limited strategies that exist to control the release or retention of orally administered functional ingredients within the small intestine rely on pH (controlled release) or adhesion [59]. When moving from the stomach into the small intestine, the chyme is exposed to sudden changes in the environment, particularly an increase in pH-value from as low as 1 in the stomach up to 6.5 in the upper small intestine (Table 1.1). Further, glands attached to the duodenum start secreting digestive juices when food enters the small intestine, and this results for example in a 2-fold increase in bile salt concentration and changes in the ionic strength which also depend on the food. The combination of these milieu changes the chyme is exposed to, and a patchy mucus layer (Figure 1.2) make the duodenum the site of choice for studies of targeted delivery to the small intestine. The small intestine has only loose mucin coverage in discrete patches which are distributed along the villi. In-between the mucin islands, epithelial cells are exposed to the lumen contents to enable absorption of nutrients. In contrast, the mucin layers in the stomach and the colon are thick, two-layered blankets to protect the epithelial cells from hostile gastric conditions and dangerous food components or colonic microorganisms,
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respectively (Figure 1.2). The difference in mucin layer structure and thickness is only one of the physical and physiological changes observed through the GIT. These changes are summarised in Table 1.2 and are detailed in Section 1.1.4.