The gastrointestinal tract

The various segments of the gastrointestinal tract cooperate to acquire and modify food, extract nutrients from it. and prepare the residue for excretion. This makes it elcar that the organs assisting in digestion, such as pancreas and liver, are as important as the intestines.

Oral cavity and esophagus Solid foods are chewed which increases the surface area for digestion and facilitates mixing with saliva. Several glands (sublingual, submandibular. parotid, v on l-.bners and other glands) empty ing ¡mo the oral cavity normally produce about 1500ml saliva. Salivation is almost exclusively under neural control and can be stimulated by odors, tastes, as well as tactile and chemical manipulation. Images of foods can also stimulate saliv ation very potently (Drummond. 1995).

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Tannins bind salivary proline-rich proteins and thereby reduce viscosity, increase lubricant characteristics of saliva. and convey the perception of asiringency, Tannin-rich beverages (tea, coffee, and red wine) reduce adhesion of food panicles to the oral mucosa allowing their rapid oral clearance (Prinz and Lucas. 2000).

Saliva is a thin secretory fluid that contains minerals, enzymes, antibacterial compounds (such thiocyanate, hydrogen peroxide, and secretory immunoglobulin A), and numerous other substances (Table 1). Actual concentrations strongly depend on the flow rate (Dennebaum. 1992). Healthy people produce about 1.51 saliva per day

Stomach

Anatomical structure: The luminal surface of the stomach folds into deep glandular recesses. The mucosa consists mainly of parietal (oxyntic) cells (secretion of hydrochloric acid and intrinsic factor), chief (peptic, zymogenic) cells (secretion of enzymes), and mucus-secreting cells. The neck area near the opening of the gastric gland ducts contains stem cells that are the source for replacement cells. The much smaller number of interspersed enteroendocrine cells (Bordi a al.. 2000) includes LC'L cells (histamine production), D cells (somatostatin production), EC cells (enterochromaffme cells for serotonin production), A cells (glucagon). C cells (gastrin production), and cells that release motilin-relaicd peptide.

Secretory function: The stomach adds hydrochloric acid, digestive enzymes, and spccilic binding proteins (e.g. intrinsic factor for the binding of vitamin B12) to ingested food. About 1-31 arc secreted per day containing about 0.1 moll hydrochloric acid (pH 1 1.5). The presence of food in the stomach, even the sight or thought of appetizing foods, gets the juices flowing. Low intragastric pH and fullness of the terminal ileum and colon inhibit secretion. The latter effect, often called the 'ileal brake', is at least partially mediated by peptide YY (Yang. 2002). The acid-stimulating effect of several hormones, including gastrin and cholecystokinin (CCK). is mediated by histamine release from ECL cells. Stimulation of histamine-2 (112) receptors, gastrin receptors, cholinergic receptors (parasympathetic innervation), and the divalent ion-sensing iabk; 4 J Typ«" aJ composition of xthva

Volume 1500 ml

Sodium 2-21 mmol/l

Potassium 10-36 mmol/1

Magnesium D.Oß-0,5 mmol/l Cortisol

Immunoglobulin A

«•amylase (EC3 2,1.1) Salivary actd phosphatases A^ B {EC3.1.3.2) N-acetylmuramyl-L»alanine amidase [EC3.5.1 28) NAD(P)H d ehyd roge nase- q u i n one (EC1 6.99.2) Glutathione transferases it, fi, IT (EC2.5.1.1H) Gass 3 aldehyde dehydrogenase (Etil.2,1.3) G lue ose-6-phosphate i som erase (EC 5 3 1 9}

Chloride 5-40mmol/l Bicarbonate 2-13mmol/l Phoipfiaie 1.4-39 mmol/l Thiocyanate 0,4-1.2 mmo!/l Hydrogen peroxide Uctoferrin

Ungual lipase (EC3.1.1.3) Lysojtyme (EC3.2 1 17) Salivary (actoperomdase (EC1.11.1.7) Superoxide dtsmucase (EC 1.15.1.1 ) Tissue Itallikrein (EC3.4.21.35)

receptor SCAR (Gctbel et al„ 2001J on parietal cells stimulates gastric acid output directly. Hormones including gastrin and CC'K induce histamine release by ECL cells. Stimulation of G cells by the presence of protein-rich foods and alcoholic bev erages in the stomach increases gastrin production.

The hydrochloric acid inactivates potential pathogens, denatures dietary proteins, and prov ides the optimal pH for protein digestion by pepsin. The hydration of carbon dioxide by the isoforms I and 11 of carbonate dehydratase (carbonic anhydrase: EC4.2.1.1, zinc-dependent l generates bicarbonate, a prolific source of protons, in parietal cells of the stomach. The protons are then pumped across the secretory canalicular membrane in exchange for potassium ions into the glandular lumen by-hydrogen potassium-exchanging ATPase (EC3.6.3.10. magnesium-dependent). The parallel export of chloride ions via the chloride channel 2 (C1C2) completes gastric acid synthesis (Sherry et a!.. 2001), The basolateral sodium.potassium chloride «transporter (NKCCI. SLC12A2) and the bicarbonate chloride exchanger 2 (SLC4A2) provide chloride from pericapillary fluid to parietal cells. This cell type also produces intrinsic factor, whose production diminishes whenever acid output decreases.

The chief cells produce pepsinogen A (F.C3.4.23.1) and gastricsin (pepsinogen C; EC3.4.23.3), which are activated when they come in contact with gastric acid. Both enzymes cleave with broad specilicity and break down most proteins to small- to medium-sized peptides. Other products include gastric lipase (EC3.1.1.3 ) and vitamin 1312-binding haptocorrins (R proteins).

Motility: The stomach retains solids for some time. Segmental contraction of its muscles (peristalsis especially of the distal portions, contributes to the mixing and grinding of ingested foods. Some nutrients (including alcohol, molybdenum, nicotinate. and nicotinamide) can be absorbed from the stomach. Small portions of the stomach contents are propelled into the small intestine by peristalsis while the distal (antral) lumen is open. Hormonal signaling stimulated by acidity, sugars, specific amino acids, and

Figure 4.1 The production ofgasinc acid depends on an abundant supply of chloride

monoglyeerides in the duodenum regulates such periodic release of gastric contents (Meyer, 1994),

Small intestine

Gross anatomical structure: The distal (pyloric) end of the stomach connects to a tubular organ of about 500-600 cm in length - the small intestine. The initial 30 cm-long segment is called the duodenum. The next segment, the jejunum, is approximately 200cm long. There is no clear transition to last 3(K)em. the ileum. The intestines are attached on one side to a mesenteric stem that carries blood vessels and lymph ducts. The mesentery is cov ered with folds of adipose tissue that may account for a third or more of total body fat in obese people (abdominal obesity). The main function of the small intestine is the digestion and absorption of most nutrients from the food mixture coming from the stomach,

The small intestine is characterized by the numerous folds that protrude into the lumen and greatly expand the surface area available for digesting and absorbing the food chyme. The luminal surface is interspersed with small (1 mm diameter) accumulations of lymphatic tissue (Peyer's plaques). Brunner's glands in the submucosa of the proximal duodenum produce mucin, bicarbonate, protective peptides, growth factors, and other compounds that help to protect the lining of the small intestine where it is most exposed to the corrosive effects of gastric acid pancreatic enzymes, and bile constituents (Krause. 2000).

MicroanatomyI features: Throughout, the small intestine is composed of discernible layers. The mucosa is the layer of epithelial cells that form the luminal surface and are directly responsible for local digestion and absorption. The major cell types of the smal! intestinal mucosa are enterocytes (95%). goblet cells, enteroendoerine cells, and Pancth cells. The luminal surface of the small intestine is arranged in a folded pattern. At the bottom of the folds are the crypts of Lieberkuhn and the lips of the folds are the villi. New enterocytes continuously arise from the dividing mult ¡potent stem cells at the base of the crypts. A new cell rises toward the tip of its vilous and is shed after 3-5 days. Small intestinal enterocy tes are the major site of terminal digestion, uptake, processing, and transport into circulation for most nutrients. The luminal (apical) side of individual cells is covered with numerous protrusions that greatly increase the surface area. This luminal surface is called the brush border membrane because of its bristle-like appearance. The individual protrusions are called microvilli. (These ultramicroscopic structures should not be confused with the v illi. which are much larger structures comprising numerous cells and barely visible w ith the naked eye.)

Paneth cells are located at the bottom of the crypts. Paneth cell secretions are critically important to maintain gut wall integrity and antimicrobial defense. They serve these functions partly by secreting peptides with antimicrobial, trophic, and paracrine properties into the intestinal lumen. The secretory granules of the Paneth cells contain defensins (crypt ¡dins) and other peptides packaged together with matrilysin (EC3.4.24.23 requires zinc and calcium), a matrix metalloproteinase thai cleaves and thereby activ ates the propeptides upon release of the granules into the crypts.

The mucosa also contains a small number of mueus-secrcting goblet cells, interspersed between the enterocytes.

The cnteroendocrine cells of the smal! intestine include at least ten distinct types, including secret in-producing S cells, choleeystokinin-producing 1 cells. L-cells (peptide YY. glucagon, glucagon-1 ike peptides GLP-1 andGl.P-2). D cells (somatostatin), K-cells (glucose-dependent insulinotropic peptide), and enterocliromaflin cells (serotonin). Counteracting stomach acidity; The food chyme coming from the stomach into the small intestine is strongly acidic. Secretions from the intestinal wall and from pancreas rapidly raise the pH to 6. Much of ¡he neutralizing action is attributable to the putative anion transporter (PAT 1. SLC26A6) that moves bicarbonate into the proximal intestinal lumen ( Wang et al., 2002), Since chloride ions arc taken up in return, this exchanger (which is not at all putative, the name just stuck) neutralizes the acidity and recovers chloride at the same time and in a tightly coordinated fashion. The sodium hydrogen exchangers 2 (NHE2. SLC9A2) and 3 (NHE3, SLC9A3) also contribute to bicarbonate transport and pH adjustment (Repishti et ui. 2001). The duodenal mucosa typically produces 1 21 of fluid with about 250mmol bicarbonate (Gullo et al., 1987). A lirmly adhering layer of mucus gel from the goblet cells provides additional protection against the corrosive effects of stomach acidity and food contents (Atuma et til., 2001). This protective layer is present throughout the intestines. Pancreatic secretions: The pancreas is a glandular organ that lies adjacent to the curvature of the duodenum and below the stomach. The secretory ducts join with the bile duct shortly before leading into the duodenum. The opening of the joint duct into the duodenal lumen is called the papilla of Vater (papilla Vateri). An additional smaller duct carries only pancreatic secretions. The pancreas is both an endocrine organ (output into the bloodstream) and an exocrine organ (output into the intestines). The endocrine products include insulin, glucagon and other hormones with direct bearing on nutrient utilization and disposition. The exocrine secretions contain, among other minor ingredients, sodium, bicarbonate, chloride, and a diverse set of digestive enzymes. Trypsin (EC3.4.21.4). chymotrypsin B (EC3.4.2I.I). chymotrypsin C (EC3.4.21.21, carboxypcptidases Al and A2 (EC3.4.2.I). elastascs I1A and III) (EC3 4.2l.711, lipase and lipase-related proteins 1 and 2 (EC3.1.I.3). carboxylester lipase (EC3.1.1.13), and phospholipasc A2 (EC3.I.1.4) are secreted as proenzymes that have to be cleaved before they become effective. The other enzymes are active as secreted. Bicarbonate output of the pancreas is stimulated by the peptide hormone secretin from Seel Is in the small intestinal wall that respond to low pi I and fatty acids. The peptide hormone eholecystokmin (identical to pancreozymin) front I entcroen-docrine cells increases the output of pancreatic enzymes in response to the presence of fat and protein in the small intestine.

Digestion: At this point, much of the ingested food has been broken down mechanically (by chewing and by grinding action of the stomach) to small particles, denatured by concentrated acid and predigested by a-amylase, proteases, and lipases from saliva and stomach. With the movement of small portions of this mixture into the duodenum, digestion can start in earnest.

First, a cascade of proteases must remove the lead sequences from the newly secreted pancreatic proenzymes to remove their lead sequence. Duodenase (no EC number

Volume 1000-3000 ml 120 mmol,I bicarbonate 70 m mol/1 chloride pH 7.2-7.4 I40mmol/I sodium 5mmol/l potassium 2 mmol. I calcium a-amylase (EC3.2.U) Prochymotrypsin C (EO.4.21 2i Proelastases MA. B (EC3.4.21.71)

Volume 1000-3000 ml 120 mmol,I bicarbonate 70 m mol/1 chloride pH 7.2-7.4 I40mmol/I sodium 5mmol/l potassium 2 mmol. I calcium a-amylase (EC3.2.U) Prochymotrypsin C (EO.4.21 2i Proelastases MA. B (EC3.4.21.71)

Trypsin (EC3.4.21.4) Pro «-chymotrypsin (EC3.4.21.1) Procarboxypeptidases At/2 (EC3,4.2,1) Endopepudases EL3A, B (EC3.4.21.70) Pancreatic prolipase (EC3.1.1.3) Upase-related proteins 1/2 (EC3.1.1.3) Pro-carboxylestcrlipase (EC3.1.1.13) Prophospholipase A2 (EC3.1.1.4) Pancreatic nbonuctease (EC3,1.27,5)

Col i pase

Prophospholipase 8 (EC3.1.V5) Deo*ynbonuclease I (EC3.1.21,1)

assigned. Zamolodch¡kova el a}., 200Ü) from duodenal glands cleaves and thereby activates the brush border protease entcropcptidasc (enterokinase; EC3.4.21.9). Enterokinase then activates trypsin (EC3.4.21.4). and trypsin finally activates the other proenzy mes.

Carbohydrates are broken up into oligosaccharides by «-amylase, and other secreted enzymes act on their targets.

A particular feature of the digestion and absorption of fat and many tat-solubie compounds is the need to first create an emulsion. The liver produces 0.5 I 1 of bile with around 12% bile acids and 4% phospholipids that can spontaneously form mixed micelles with fat. Prcdigestion of fat by lingual and gastric lipase generates mono-glycerides, which act as additional cmuisifiers. Lipase action then gradually cleaves the triglycerides in the micelles and makes them available for absorption. Bile also contains alkaline sphingomyelinase (no EC number assigned), which cleaves ceramides (Duan and Nilsson. 1997).

Most of the enzymes that render the half-digested nutrient molecules lit for absorption reside on the brush border membrane of the small intestine (Table 4.3). Some of the enzymes cluster near the channels and transporters for uptake, as found with lactase and the associated sodium-glucose transporter I (Mizuma and Avvazu, 1998).

Entero hepatic circulation

Bile flows into the small intestine just a few centimeters below the pylorus and has the benefit of the digestive and absorptive activities of the entire length of the small and large intestine. Recovery of water, minerals, bile acids, and phospholipids is nearly complete. Bile acids and bile acid conjugates are taken up from the jejunum mainly by an anion exchange mechanism, and from the ileum by sodium-mediated transport (Amelsberg el al„ 1999). The taurine that is cleaved in the terminal ileum from bile acid conjugates by bacterial enzymes is also recovered with high efficiency by the chloride-dependent taurine transporter (TAUT. SLC6A6).

This cycling of bile constituents between liver and intestines exposes those bile constituents that reach the terminal ileum to bacterial modification. An important

Tabic 4.3 tfliymo at the brush bonder membrane which prepare nutri«H molecules for ahsotpnon

Enterolcinase (EC3.4.21.9)

Membrane alanine a m mope pi id as e (aminopeptidase N) (EC3.4.11.2)

Leucine aminopepudase (LAP) (EC3 4.11.1)

Aminopeptidase A (EC3 4.11.7)

Dipepudyl peptidase IV (EC3.4 14,5)

y-glutamyl transpeptidase (g,imma-CT) (EC2.3.2.2)

Angiotensin I-converting enzyme (ACE) (EC3.4.15.1)

Carboitypeptidase P (EC3 4,17.16}

Folyipolyy-glutamate carboxypeptidase (glutamate carbcutypeptidase M) (EC3.4 19,8) Nepnlystn (neutral cndopeç>tidasr)(EC3A 24.11) X-pro aminopeptidase (aminopeptidase P) (EC3.4.11.9) Membrane dîpeptidase (EC3.4.13.19)

Meprin A ( N-be nzoyl-L-ryrosyl-p-a mi no benzoic acid hydrolase. EC3.4.24.18)

rc-glucosldase (EC3.2.1.20)

Sucrose-n-glucosIdase (EC3.2.1.10/EC3.2.1.48)

Lactase phlorhizin hydrolase (EC3.21.108)

Trehalase (EC3.2.1.28)

Alkaline phosphatase (EC3.1.3.1 )

5-nucleotide phosphodiesterase (EC3.1.4,1 )

Phospholipase B (EC3.1.1.5)

example is the intestinal conversion of the primary bile acid (directly synthesized in the liver) chenodesoxycholate to the secondary bile acid (derived from a primary bile acid by bacterial action) lithocholate.

The importance of hepatobiliary circulation is also highlighted by v itamin 1312, of which several micrograms are secreted into bile every day. The recycling of this nutrient is so efficient that normal liver stores last for decades. The benefit is that it eliminates corrinoids without vitamin 1312 activity. If reabsorption becomes less effective, usually due to a lack of intrinsic factor, biliary stores can be depleted w ithin a few months.

Large intestine

The colon is a tubular organ of 1.2-1.5 m in length that connects to the distal end of the small intestine. A valve (the Bauhinian valve) limits the backflow of fecal mailer from the colon into the small intestine. The smalt portion (about 7cm) of the colon that extends below the valve is called the cecum; it ends in a much narrower, worm-shaped portion, the appendix. This appendix contains lymphatic tissue.

The main function of the colon is the recovery of fluid and electrolytes from the intestinal contents. Some micronutrients. such as biotin, pantothenate, and vitamin k. may be absorbed from bacterial production.

In contrast to the small intestine, the mucosa of the colon is relatively smooth without villi, and the enterocytes of the colon (colonocytes) do not have microv illi. The colon contains a much larger number of mucin-producing goblet cells than the small intestine. Because of this the mucous layer covering the colonic mucosa is also much thicker, close to I mm, The absence of folds, crypts, and villi, and better lubrication.

obviously facilitates the mov ement of feces through the colon even when it becomes relatively solid.

Movement of food through the Gl tract

Movement of food through the mouth and esophagus proceeds largely by voluntary movements, assisted by reflexes that prompt swallowing of ingested foods and prevent aspiration. Coordinated contractions (peristalsis) propel small portions of chyme (the slurry of food and digestive juices) through the pylorus into the duodenum.

Segments of small intestinal segments that arc a few centimeters in length can contract in a coordinated fashion and thereby generate slow peristaltic waves. The propulsive motion is essential to push the chyme through the small intestine. In healthy subjects, food takes about 290 minutes after ingestion to reach the colon (Geypens et at., 1999). This interval is often called the orocecal transit time. Digestion and absorption of most bioavailable compounds in the intestinal content proceeds while the chyme moves through the small intestine. Fecal matter is moved through the colon by a series of concerted contractions about once a day. usually triggered by food intake.

[t is important to remember that a large proportion of chyme constituents, such as w ater and electrolytes, bile acids, lipids, and proteins, are of endogenous origin and need to be recovered. The fecal mass remains for another few hours to several days in the large intestine where most of the remaining water and electrolytes are extracted.

Intestinal microflora

Normally, the upper small intestine contains few. if an>. bacteria. Most ingested microorganisms are inactivated by the acidity of the stomach, digestive secretions (containing lysozyme. proteases, lipases, DNAses. RNAscs. and many other enzymes), and the intestinal immune defense system I antibodies, lymphocytes and macrophages from Peyer's plaque, and other intestinal structures). Colonization of the intestine by aerobic and anaerobic bacteria becomes significant only in the terminal ileum, and is extensive throughout the colon. In those segments the intestinal flora show s considerable diversity: typically E. colt, bifidobacteria, lactobacilli, Clostridia, and bacteroides species arc present in significant numbers. Many of these physiological microorganisms produce compounds that contribute to the nutriture of the host. Bacteria that break down some types of dietary fiber generate short-chain fatty acids (mainly acetic, propionic, and butyric acid) which are important energy fuels for the local enterocytes and may influence hepatic lipid metabolism. Bacteria of the lower intestine also are important sources of pantothenate (Said et at.. 1998). biotin (Said et al.. 1998). queuine (Morris et al., 1999), and to some extent vitamin K, How much vitamin K actually is available from the terminal ileum and the colon is uncertain (Lipsky, 1994).

"flic elaboration of potentially toxic bacterial product* is dependent on both the pattern of the microflora and on the presence of microbiologicial nutrients in the colon. Fermentable carbohydrates including dietary fiber lend to suppress the production of various indols, phenols, and heterocyclic amines (Maclarlane and Macfarlane, 1997: Kassie et al.. 2001).

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