Physiological Functions of the Small Intestine:The 3 main functions are: I.

Digestion & Absorption of nutrients via: Bilio-pancreatic secretions Large Absorptive Surface Area Motility Function II.Endocrine Function III.Immune Function

Digestion and Absorption

The main functions of the small intestine: digestion and eventual absorption of nutrients, water, electrolytes, vitamins and minerals. . The stomach initiates the process of digestion with the breakdown of solids to particles 1 mm or smaller, which are then delivered to the duodenum, where pancreatic enzymes, bile, and brush border enzymes continue the process of digestion and eventual absorption through the small intestinal wall The intestinal epithelium is the interface through which absorption and secretion occur; it has the characteristic features of absorptive epithelia including epithelial cells with cellular membranes possessing distinct apical (luminal) and basolateral (serosal) domains demarcated by intercellular tight junctions, and an asymmetric distribution of trans-membrane transporter mechanisms that promotes transport of solutes and nutrients across the epithelium.

Nutrients and Solutes traverse intestinal mucosal surface by either Active Or Passive Transport: Passive transport occurs by simple diffusion; driven by existing electrochemical gradients through either
trans-cellular (through the cell), or para-cellular pathways (in-between cells through the tight junctions).

Active transport :is the energy-dependent net transfer of solutes and nutrients in the absence of or against
an electrochemical gradient .Active Transport occurs through trans-cellular pathways (through the cell).

Trans-cellular transport : requires solutes and nutrients to traverse the cell membranes through specialized
membrane transporter proteins,( such as channels, carriers, and pumps). The molecular characterization of transporter proteins is evolving rapidly, with different transporter families, each containing many individual genes encoding specific transporters, now identified.

Para-cellular transport: it is becoming apparent that paracellular permeability is substrate specific, dynamic,
and subject to regulation by specific tight junction proteins.

Carbohydrates: Average daily carbohydrate Intake: is 350-400 G; kcal (4 kcal/g of carbohydrate).) Carbohydrates are present in three main digestible forms: Providing about 50% of caloric supply/day (1,600

A) Complex starches- (50%) Amylopectin and Amylose: derived from cereals and plants B) Disaccharides- (sucrose and lactose 40%) : (lactose derived from milk ; sucrose derived from purified
sugar cane or beets). Fruits and vegetables contain (fructose, glucose, and sucrose).

C) Simple sugars: glucose; fructose ; galactose . Processed foods contain a variety of sugars including fructose, oligosaccharides, and polysaccharides Glycogen derived from meat - contributes only a small fraction of dietary carbohydrate. Carbohydrate Digestion :

The complex starches ( amylopectin and amylose) are digested with the aid of salivary and pancreatic amylase. Salivary amylase contributes a small amount to this process as it is inactivated by gastric acid, leaving the remainder of this process to be completed by pancreatic amylase. This process yields oligosaccharides (maltose, malt-triose, -dextrins. ) .This digestive process is usually completed before the carbohydrate bolus leaves the duodenum.

These small oligosaccharides along with ingested disaccharides, typically sucrose and lactose, are then further digested by the brush border enzyme saccharidases in the jejunum; charide moieties, such as glucose, galactose, and fructose. The three major monosaccharides that represent the terminal products of carbohydrate digestion are glucose, galactose, and fructose into their component monosac-

Carbohydrate Absorption:-

These monosaccharides can be transported across the enterocytes apical cell membrane: . Glucose and galactose utilize the same transporter ( sodium-dependent hexose transporter (SGLUT-1) . The co-transportation of these monosaccharides with sodium is dependent on the Na +-K+-ATPase pump on the basolateral membrane(This pump provide the necessary energy to move three Na+ ions out of the cell while transporting two K+ ions into the cell against an electrical gradient. This process maintains a negatively charged low Na+ intracellular environment) .This pump maintains sodium electro-chemical gradient allowing for this influx.

Fructose is transported in a carrier-mediated diffusion-dependent manner by GLUT5 and does not require sodium as a cotransporter The movement of these monosaccharides into the cellular cytoplasm provides an additional gradient by which water is absorbed by the enterocytes from the intestinal lumen into ECF. All of these monosaccharides are then transported across the basolateral membrane by GLUT2. This hexose transporter allows for the diffusion of all three monosaccharides into the extracellular space and ultimately into the portal blood flow

There is evidence of overexpression of hexose transporters specifically SGLT1, in disease states such as diabetes .Several approaches aimed at down-regulation of these transporters are being investigated as a novel therapy for disease states such as diabetes and obesity Dietary fiber: ( Non-digestible; Non-fermentable complex carbohydrates) such as cellulose present in

grains, vegetables, and pulpy fruits.It helps to increase the faecal bulk by absorbing water in the intestinal and colonic lumen. In addition, fiber can absorb organic materials such as lipids and bile salts and inorganic minerals such as zinc, calcium, and magnesium. These actions of fiber are thought to play a role preventing carcinogenesis and in helping to maintain normal serum lipid profiles.

Protein:

An average adult requires : 0.75 g/kg of protein per day, although this requirement may be significantly
increased during childhood, pregnancy, and times of significant illness./Trauma

The ingested daily protein from dietary sources(Exogenous) is: 70 to 100 g/day; while the protein load that enters the small intestine; derived from( Endogenous sources including; salivary and GI secretions and desquamated intestinal epithelial cells is 50 to 60 g of protein per day). Nearly 90% of this protein load is metabolized in a similar fashion to dietary proteins.

Protein provides an important caloric energy source (10-15% of total caloric requirments) essential building blocks for production of new proteins.

as well as the

Protein Digestion

In the stomach :( small part of overall protein digestion.) The initial digestion of protein begins with the activation of
pepsinogen to pepsin in the acid environment . Pepsin hydrolyzes protein into its component of polypeptides. Patients who are achlorhydric,(Atrophic gastritis) or had total or subtotal gastrectomy are still able to successfully digest proteins.

In the small intestine: The majority of protein digestion occurs by pancreatic peptidases. Pancreatic enzymes flow into the
duodenum are initially released as inactive proenzymes.Activation of pancreatic peptidases is initiated by the brush border enzyme enteropeptidase (enterokinase) in the duodenum; which cleaves trypsinogen into the active enzyme trypsin; trypsin, in turn, activates itself and other peptidases.

Pancreatic Peptidases are: Endopeptidases : Trypsin; Chymotrypsin; Elastase

Hydrolyze interior peptide bonds of polypeptides and proteins

Exopeptidases :

Carboxypeptidase A; Carboxypeptidase B

Hydrolyze external peptide bonds of polypeptides and protein .

The final products of intraluminal protein digestion consist of: 30% single amino acids

70% short oligopeptides (two to six amino acids);

Additional digestion of short oligopeptides occurs through the actions of peptidases that exist in the enterocyte brush border and cytoplasm into dipeptides; tripeptides and AA. ( Single amino acids , dipeptides, and tripeptides are only able to diffuse through the microvilli of apical membrane into the cytoplasm.)

PROTEIN ABSORPTION

Single amino acids: are cotransported into the cytoplasm with sodium along an electrochemical gradient. ; which is maintained by the Na+-K+-ATPase pump on the basolateral cell membrane. At least four separate transporter mechanisms exist for the various electrochemical properties of amino acids that are transported (neutral, dibasic, acidic, and imino).

Dipeptides and tripeptides: are transported into the cytoplasm along with H+ by a cotransporter PepT1, where they are
hydrolyzed by specific peptidases (in the cytoplasm of enterocytes) into their component amino acids.

Transport of amino acids into the cytosol provides an osmotic gradient by which water is further absorbed from the intestinal lumen. The vast majority of the processed AA are shuttled into the portal blood flow via amino acid transporters on the basolateral membrane of the enterocytes. A small portion is utilized by the enterocyte, glutamine appears to be a unique, major source of energy for enterocytes. Active glutamine uptake into enterocytes occurs through both apical and basolateral transport mechanisms

Normally; digestion and absorption of proteins are usually 80% to 90% completed in the jejunum.

Fat:
The average daily Fat Intake(in adult):is (60 to 90 g); constitute 40% of the daily caloric intake. The ingested dietary fats :90% Triglycerides; 10% cholesterol, cholesterol esters, phospholipids, and fat-soluble vitamins.

Fat Digestion and Absorption:

The majority of dietary fat is processed and absorbed in the duodenum and upper jejunum

Emulsification:

This is initiated by the mechanical actions of mastication and antral peristalsis causing breakdown of fat globules into smaller sizes.

Emulsification: is the solubilization of water insoluble ingested fats into an emulsion to facilitate further breakdown by
water-soluble digestive enzymes. This process is facilitated by bile salts and the phospholipid lecithin (the fat-soluble portions of bile salts and lecithin dissolve in the surface layer of the fat globules ;while the water- soluble polar portions, projecting outward into the surrounding aqueous fluids. This arrangement renders the fat globules more accessible to fragmentation by agitation in the intestinal lumen; and readily attacked by pancreatic lipase

Long-chain Triglycerides; Cholesteroles; Phospholipids; Fat-Sol.Vit.

CCK: is stimulated by the presence of fatty acids on the duodenal mucosa. CCK in turn stimulates pancreatic secretion of
lipase and its cofactor colipase.

Colipase: binds to the surface of fat globules ;displacing the emulsifying agents to allow action of lipase enzyme. Lipolysis: Gastric Lipase (initiates lipolysis in the stomach)
Pancreatic Lipase (complete the process in the upper jejunum) Lipase: hydrolyzes triglycerides :yielding two fatty acids and a monoglyceride (a fatty acid esterified to glycerol);. Cholesterol and fat-soluble vitamins are hydrolyzed by pancreatic cholesterol esterase; and phospholipids by phospholipase A2.

Micelle Formation: Micelles are water-soluble polymolecular aggregates;formed by the products of lipolysis interacting
with bile salts.They consist of hydrophobic core of fat (FA;Monoglycerides;Cholesteroles Phospholipides; fatsol.vitamines), and a hydrophilic shell of bile salts that act as shuttles; delivering the products of lipolysis to the

enterocyte brush border membrane, where they are absorbed. Absorption of fat-components of the Micelles: Micelles are able to interact with the enterocyte brush border membrane,
and empty their contents into the cytoplasm. This occurs by the process of dissolution of the micelles into the lipid bilayer of the mucosal cell; in a thin layer of water with an acidic microenvironment immediately adjacent to the brush border called the unstirred water layer. The bile salts, however, remain in the bowel lumen and travel to the terminal ileum, where they are actively reabsorped. They enter the portal circulation and are resecreted into bile, thus completing the enterohepatic circulation. Fatty acid binding proteins located on the brush border membrane, facilitating diffusion of long-chain fatty acids across the brush border membrane into the cytoplasm. Cholesterol crosses the brush border membrane through an active process

Chylomicrons Formation: , long-chain fatty acids and -monoglycerides are carried by cytosolic fatty acidbinding
proteins to the smooth endoplasmic reticulum (SER). In the SER, resynthesis of triglycerides occurs. These triglycerides and cholesterol esters are further processed in the Golgi apparatus where a phospholipid and an apoprotein coat are added to form a chylomicron..Chylomicrones are formed of core of Triglycerides and cholesterol esters(90%) ; and shell of phospholipids and apoproteins(10%). The chylomicrons are packaged into secretory vesicles; before exiting the

Golgi apparatus; then exit the cell membrane by exocytosis and enter the central lacteal of the villus and the intestinal lymphatic system.They are transported into the thoracic duct;then into the systemic venous blood.

Very-low-density lipoproteins: In addition, enterocytes also synthesis smaller lipoprotein particles which contain a higher
cholesterol /triglyceride ratio and provide the major route of entry for dietary cholesterol into the lymphatic system.

Short-chain and Medium-chain triglycerides:

These are more hydrophilic and are absorbed without undergoing intraluminal hydrolysis, micellular solubilization, mucosal re-esterification, and chylomicron formation. Instead, they are directly absorbed simple diffusion into the enterocyte and then enter the portal venous circulation rather than the lymphatics.

The entero-hepatic circulation of the bile salts:

This is process of recycling bile salts; where approximately 95% of the bile salts secreted into the intestine are reabsorbed and returned to the liver through the portal circulation. Once in the liver, these bile salts are reprocessed and secreted and stored in the gallbladder in preparation for the next meal. This reabsorption occurs by both passive and active means. A small amount of bile salts are passively reabsorbed along the entire length of the small intestine. The majority of bile salts, however, are reabsorbed though an active Na+-dependent transport mechanism in the terminal ileum.. Bile, which is not reabsorbed, passes into the colon where it is deconjugated by the enteric flora.

Patients who have undergone resection of their ileum may suffer from diarrhea due to high concentrations of bile salts within the colon; inhibiting sodium and water reabsorption, resulting in diarrhea. These patients may be treated with the bile-binding resin (cholestyramine )to help alleviate their symptoms.

Absorption AND Secretion of Water and Electrolytes:

Approximately; 9 L of fluid enter the small intestine daily. (Oral intake; salivary, gastric, biliary, pancreatic, and intestinal secretions. Under normal conditions, the small intestine absorbs over 80% of this fluid, leaving approximately 1.5 L that enters the colon .

This dynamic process is accomplished by a rapid bidirectional movement of fluid in the intestinal lumen. This ebb and flow of fluid in the intestinal lumen is critical in maintaining normal homeostasis. Minor changes in intestinal permeability or rate of flow of the intestinal contents can result in net secretion and diarrheal states. Water Absorption and Secretion:

The tonicity of the intraluminal intestinal contents determines the overall net movement of water.

Water absorption is believed to be driven by osmotic gradients created primarily by active trans-cellular Na+ absorption(also by glucose and amino acids absorption).

Intestinal water secretion, in contrast, is believed to be driven by osmotic gradients created primarily by transcellular Cl secretion.

Sodium(Na) Absorption:

Intestinal trans- epithelial Na+ absorption: depends upon the activity of the Na+/K+ ATPase pump, which is located in the basolateral membrane .(This pump utilizes the hydrolysis of ATP to provide the necessary energy to move three Na+ ions out of the cell while transporting two K+ ions into the cell against an electrical gradient).This process, generates the electrochemical gradient that drives the transport of Na+ from the intestinal lumen into the cytoplasm of enterocytes.

Na+ ions traverse the apical membrane of enterocytes through several distinct transporter mechanisms:

a) Nutrient-coupled sodium co transport (e.g., sodium-glucose cotransporter-1, SGLT1)

b) Electroneutral absorption of sodium chloride: occurs through counter transport mechanisms .(Na/ H & Cl/Hco3 counter transport) Na+ is exchanged for H+ and Cl- is exchanged for HCO3-, resulting in no net change in intracellular charge (allows for intracellular pH regulation). This process provides an influx(Absorption) of NaCl in exchange for H+/HCO3- efflux. c) Sodium channels : Simple absorption of sodium of Na+ ions down the electro-chemichal gradient ( from the sodiumrich intestinal lumen into the negatively charged low-sodium intracellular environment.)

Absorbed Na+ ions are then extruded from enterocytes through the Na+/K+. ATPase located in the basolateral membrane.

Chloride Absorption:
a) Electroneutral absorption through: counter-transport mechanism.(Na/ H & Cl/Hco3 counter transport) of Cl absorption). b) Passive diffusion: in a para-cellular fashion. This is due to the slightly positive interstitium when compared to the gut lumen, allowing the negatively charged chloride ions to be absorbed. (The majority

Chloride is a major determinant of the regulation of water secretion into the small intestine and in intestinal hydration.(Chloride secretion create the osmotic gradient for trans-cellular water secretion into intestinal lumen).

Bicarbonate absorption:
It occurs primarily in the jejunum and requires the formation of carbonic acid in the intestinal lumen from HCO3- and H+.(H which is secreted through counter-transport mechanism along with sodium absorption). Carbonic acid subsequently diffuses back into the enterocyte and is enzymatically cleaved into H+ and HCO3- by the action of carbonic anhydrase.

HCO3- diffuses into the interstitium (via para-cellular route due slight positivity of interstitium) and then into the blood. H+ is re-secreted in exchange for other cations, predominantly Na+ counter-transporter n the duodenIum; HCO3- is secreted in exchange for Cl- absorption ( chloride ions contained within gastric HCL). This efflux of HCO3- provides a mechanism to neutralize gastric acid entering into the duodenum.

Potassium Absorption:
The majority of potassium absorption occurs mainly through passive transport through either:

a) Para-cellular pathway: ( through intercellular pores) b) H+-K+ exchange pathway :facilitated by the intracellular electrochemical gradient that is created predominantly by the basolateral ATPase pump. Intracellular K+ then diffuses across the basolateral membrane via K+ channel or carrier.

Absorption of Minerals:
Mineral: are inorganic elements: accounts for approximately 5% of total adult body mass: 50%; of this mass; calcium 25% 25% The Minerals are either: Macro minerals,(calcium; phosphate, magnesium, sulfur, sodium, chloride, and potassium with daily requirements exceeding 100 mg/d. Micro minerals (trace minerals ;elements) include iron, zinc, copper, manganese, iodine, selenium, fluoride, molybdenum, chromium, and cobalt with daily requirements of less than 15 mg/d. ;phosphate other minerals

Absorption of Minerals:
Many of these minerals are best absorbed in their ionized forms, which is aided by the presence of hydrochloric acid in the gastric lumen. Calcium Absorption:

Calcium is absorbed through both: Active transcellular transport; mainly in the; Passive paracellular diffusion; throughout the length of the small intestine.

Duodenum

AND

When calcium is present intraluminally at low levels, it is transported across the apical membrane of the enterocyte by carrier-mediated Transport. Once calcium is in the cytoplasm, it is bound to calcium-binding proteins(Calbindin) and delivered to the basal membrane. Calcium is then transferred into the interstitium by a Ca2+-ATPase pump. This process is indirectly regulated by parathyroid hormone (PTH). PTH in low-calcium states promotes conversion of vitamin D to its active form, 1,25(OH)2 vitamin D. This activated form of vitamin D causes an increase in the expression of both calcium-binding proteins and Ca2+-ATPase, causing an increase in the absorption of calcium by the small intestine.

When intraluminal calcium is in excess of its capacity to be actively transferred by the apical membrane's carriermediated mechanism, passive para cellular calcium absorption occurs in the distal small intestine.

Abnormal calcium levels (Hypocalcemia) are increasingly seen in surgical patients who have undergone a gastric bypass. calcium citrate is a better formulation for replacement therapy in these patients(more than calcium carbonate, in such patients with low acid exposure)

Iron Absorption:
Absorbable dietary sources of iron are typically either:

Iron-containing proteins (as Heme) :usually from ingested meats Ferrous( Fe2+ ion): usually from vegetables, grains, and fruits.

Vitamin C (ascorbic acid) increases iron absorption by reducing the ferric (Fe3+) ion into the more soluble ferrous state. Absorption of iron occur in the duodenum and proximal jejunum; by: carrier-mediated trans-cellular Transport across the apical membrane of the enterocyte Once in the cytoplasm, the ferrous ion is released by enzymatic cleavage. Ferrous ions may be stored intra cellularly by ferritin or transported into the circulation by transferrin.

The total absorption of iron is dependent on body stores of iron and the rate of erythropoiesis.

The process of iron absorption is regulated:

In the enterocyte: by hypoxia-inducible factor signaling and iron-regulatory proteins Systemically, the central iron-regulatory hormone is hepatic hepcidin. Hepatic hepcidin regulates iron absorption and mobilization from systemic body stores by inhibiting ferroportin, a cellular iron exporter.

Other Minerals and Trace Elements as zinc( Zn2+), copper( Cu2+), manganese( Mn2+); , iodine ';selenium(Se), fluoride, molybdenum, chromium, and cobalt( Co2+),Cupper( Cu2+). A divalent metal transporter has recently been localized to the intestinal brush border, may account for at least a portion of the transcellular absorption of these ions.

VITAMIN ABSORPTION:

Fat-soluble vitamins (A, D, E, and K) are absorbed along with long-chain Triglycerides( incorporated into micelles along with fats in order to pass into the enterocyte. These vitamins are then processed and packaged into chylomicrons so that they can exit into the lymphatic system.) Water-soluble vitamins: are absorbed along the small intestine through a variety of mechanisms:

Vitamin C (ascorbic acid), biotin, and niacin : are actively absorbed by Na+-coupled co-transporter;utilizing specific carrier mechanism Folate, vitamin B1 (thiamine), and vitamin B2 (riboflavin) are absorbed by Na+-independent transporter. vitamin B6 is absorbed by passive diffusion. Vitamin B12 (cobalamin) absorption :

Is dependent on the presence of intrinsic factor, a glycoprotein produced by the gastric parietal cells; occurs primarily in the terminal ileum( Specific receptors in the terminal ileum take up the cobalaminintrinsic factor complex, probably by translocation.)

In the duodenum :one molecule of intrinsic factor binds two molecules of cobalamin to form a complex(B12-intrensic Factor) This complex escape hydrolysis by pancreatic enzymes, allowing it to reach the terminal ileum, and attaches to a specific membrane receptor .

In the terminal ileum; Cobalamin becomes absorbed into enterocytes probably by translocation. In the ileal enterocyte, free vitamin B12 is bound to an ileal pool of transcobalamin II, (B12-binding protein) which transports it into the portal circulation.

Vit,B12 deficiency sorbtion due to:

( usually presents with megaloblastic anemia.):

Due to defective ab-

lack of intrinsic factor:

or atrophic gastritis.

after proximal or total gastrectomy, autoimmunity to gastric parietal cells or intrinsic factor,

Failure of absorbtion of cobalaminintrinsic factor complexes : Ileal Crohn's Disease; terminal ileal resection(Rt.Hemicolectomy).

Bacterial overgrowth : due to bacterial overconsumption of cobalamin.

Endocrine Function Of Small Intestine

The small intestine is the largest endocrine organ in the human body both( with respect to the number of hormone-producing cells and the number of individual hormones produced). There is no specific cell mass that produces these hormones, but rather individual cells scattered along the gastrointestinal tract (Enteroendocrine cells). The secretion of these numerous hormones and neurotransmitters is specific to distinct anatomic zones within the small intestine .In addition to these Peptide Hormones; monoamines, such as histamine and dopamine with hormone-like activities are produced in the intestine.

Now it is clear that "gut hormone" genes are widely expressed throughout the body, not only in entero- endocrine cells, but also in central and peripheral neurons. The products of these genes (The regulatory Peptides) are general intercellular messengers that can act as:

Endocrine mediators: true blood-borne hormones (i.e., discharged into the bloodstream, where an action
is produced at some distant site)

Paracrine,( Autocrine mediators): discharged and act locally

: serve as neurotransmitters.

Neurocrine mediators

Gut Hormones-Receptors Interaction:

These regulatory peptides have complex physiological actions; which can be explained by receptor subtype multiplicity and cell-specific expression patterns for these receptor subtypes.

Gut Hormones: interact with their cell surface receptors to initiate a cascade of signaling events that eventually culminate in their physiologic effects.

Receptors Subtypes:
(A)G proteincoupled receptors: ( they have 7-transmembrane domains and represent the largest group of receptors found in the body.) Agonist (peptide mediator) binding to the receptor is thought to cause a conformational change in the receptor that allows it to interact with the G proteins which are the molecular switches for signal transduction. This will lead to activation of intracellular second messengers: cyclic adenosine monophosphate (c AMP) Ca2+- cyclic guanosine monophosphate (c GMP) Iniositol phosphate. (B)Tyrosine kinase receptors:( which have a single membrane-spanning domain.) They mediate the action of other peptides and growth factors; located in the gastrointestinal mucosa, play a role in cell growth and differentiation :insulin-like growth factor, factor; epidermal growth factor, fibroblast growth factor, platelet-derived growth transforming growth factor- and -,

(C)Ion channellinked receptors: (found most commonly in cells of neuronal transmittion)

They bind specific neurotransmitters; and then undergo a conformational change which allows passage of ions across the cell membrane and results in changes in voltage potential. Excitatory Neurotransmitters: Inhibitory Neurotransmitters: (acetylcholine and serotonin) (-amino-butyric acid, glycine)

Gastrointestinal-Peptide Hormones:-

Gastrin:LOCATION- : Antrum, duodenum(G cells) MAJOR STIMULANTS OF SECRETION : Antral distention, vagal stimulation , peptides; amino acids; gastrinreleasing peptide(bombesin); and hypercalcemia Its release is inhibited by low intraluminal pH, somatostatin, secretin, gastric inhibitory peptide (GIP), vasoactive intestinal polypeptide (VIP), glucagon, and calcitonin. Physiological Actions:-( Gastrin exists in three functional forms (G-34, G-17, G-14). (1)stimulates gastric acid secretion: Gastrin binds to cholecystokinin 2 (CCK2)/gastrin receptors on enterochromaffin-like (ECL) cells, causing a release of histamine, which in turn stimulates the parietal cells in a paracrine fashion to secrete HCL. (2)Stimulate pepsinogen secretion by the chief cells. (3)Stimulate pancreatic enzymes secretion from the pancreatic centroacinar cells. (4)Gastrin increase in the gastric blood flow and Stimulates gastric mucosal growth.

Secretin:LOCATION- :- Duodenum, jejunum(S cells) MAJOR STIMULANTS OF SECRETION :- luminal acidity(low PH); fatty acids, and bile salts.

Physiological Actions:(1) Stimulates release of water and bicarbonate from pancreatic ductal cells (2) Stimulates release of water and bicarbonate from the biliary ductal epithelium and Brunner's glands (The increased pH also provides a negative feedback loop to inhibit further production of secretin.) (3) Inhibits gastric acid secretion and motility and inhibits gastrin release (Secretin produces a paradoxical release of gastrin in patients with gastrinomas.)

Cholecystokinin
LOCATION- : - Duodenum, jejunum(I cells) MAJOR STIMULANTS OF SECRETION Physiological Actions:(1) Stimulates pancreatic enzyme secretion (2) Stimulates contraction and emptying of the gallbladder, increases bile flow, causes relaxation of the sphincter of Oddi (3) Inhibits gastric emptying (4) Trophic effects on the small-intestinal mucosa and pancreas :- amino acids and fatty acids

Gastrin-releasing peptide (mammalian equivalent of bombesin):LOCATION- : - Small bowel MAJOR STIMULANTS OF SECRETION :- Vagal stimulation

Physiological Actions:(1)Universal on switch: Stimulates release of all gastrointestinal hormones (except secretin) (2) Stimulates gastrointestinal secretion and motility (3) Stimulates gastric acid secretion and release of antral gastrin (4) Stimulates growth of intestinal mucosa

Gastric inhibitory polypeptide (GIP):- Glucose-dependent insulin-tropic peptide

LOCATION- :- Duodenum, jejunum(K cells) MAJOR STIMULANTS OF SECRETION :- Glucose, fat, protein and adrenergic stimulation.

Physiological Actions:(1)Inhibits gastric acid and pepsin secretion (2)Stimulates pancreatic insulin release in response to hyperglycemia (Type 2 diabetics are resistant to the effects of GIP.)

Somatostatin:LOCATION- : Pancreatic islets (D cells), antrum, duodenum. MAJOR STIMULANTS OF SECRETION :Pancreas: glucose, amino acids,; cholecystokinin

Gut: fat, protein, acid, other hormones (e.g., gastrin, cholecystokinin) Physiological Actions:Universal off switch: (1) (2) (3) (4) (5) Inhibits release of gastrointestinal hormones Inhibits gastric acid secretion Inhibits small bowel water and electrolyte secretion Inhibits secretion of pancreatic hormones somatostatin decreases splanchnic and portal blood flow.

Vasoactive intestinal Peptide: -(VIP)

LOCATION- : Neurons throughout the gastrointestinal tract MAJOR STIMULANTS OF SECRETION

:- Vagal stimulation

Physiological Actions:-mainly serves as a neurotransmitter

(1)Stimulates pancreatic and intestinal secretion (2)Inhibits gastric acid secretion (3)Potent vasodilator (4) Smooth muscle Relaxant

Motilin:-

LOCATION- : Duodenum, jejunum MAJOR STIMULANTS OF SECRETION:- Release of motilin occurs during the interdigestive and fasting periods. Release may also be related to alkalinization of the duodenum.

Physiological Actions:(1)Stimulates upper GIT motility (2)Motilin's main function is to stimulate the migrating myoelectric complex.(MMC) (Motilin agonists such as erythromycin are used clinically as stimulants of gastrointestinal motility.)

Neurotensin:LOCATION- Small bowel and the colon (N cells) MAJOR STIMULANTS OF SECRETION:- the presence of intraluminal fat. Physiological Actions:
(1) Stimulates pancreatic and biliary bicarbonate secretion (2) Inhibits small bowel motility (3) Stimulates intestinal and colonic mucosal growth.

Peptide YY:-

LOCATION- Distal small bowel, colon MAJOR STIMULANTS OF SECRETION:- Fatty acids, cholecystokinin Physiological Actions:-

(1) Inhibits gastric and pancreatic secretion (2) Inhibits gallbladder contraction: (3) Inhibits intestinal motility and secretion

Enteroglucagon:LOCATION- Small bowel (L cells)

MAJOR STIMULANTS OF SECRETION:- Glucose, fat-

Physiological Actions:Glucagon-like peptide-1: (1) (2) Stimulates insulin release Inhibits pancreatic glucagon release

Glucagon-like peptide 2: (GLP-2) Potent enterotrophic factor (It is currently under clinical evaluation as an intestinotrophic agent in patients suffering from the short bowel syndrome.

Diagnostic and Therapeutic Uses of Gastrointestinal Hormones:GastrinPentagastrin (gastrin analogue)- used to measure maximal gastric acid secretion.

Secretin
The gastrin secretory response to secretin administration forms the basis for the standard test used to
establish the diagnosis of Zollinger-Ellison syndrome. ( Provocative test for gastrinoma)

Cholecystokinin
Biliary imaging of gallbladder contraction. ( evaluations of gallbladder ejection fraction), a parameter that may have use in patients who have symptoms of biliary colic but are not found to have gallstones.

Octreotide, a long-acting analogue of somatostatin Amelioration of symptoms associated with neuroendocrine tumors (e.g., carcinoid syndrome);Diarrhea and Flushing Postgastrectomy dumping syndrome

Enterocutaneous and Pancreatic fistulas, The initial treatment of acute hemorrhage due to esophageal varicees.

IMMUNE FUNCTION:
. The lumen of the gastrointestinal tract is connected to the outside environment and comes in direct contact with many potentially pathogenic microorganisms (Bacteria ;Viruses; and parasites). In the upper small intestine, the bulk of antigen exposure comes from the diet, whereas in the ileum and colon, the additional antigenic load of an abundant and highly complex commensal microflora is prevalent.

The gut-associated immune system represents one of the largest immunologic compartments in the
body.(contains about 70% of the whole body immune cells). To deal with the constant barrage of potential toxins and antigens, the gut associated immune system has evolved into a highly organized and efficient mechanism for antigen processing, humoral immunity, and cellular immunity. The immune system is highly effective at responding selectively to invading pathogens yet on the other hand tolerating a much larger number of harmless food antigens and commensal organisms.

Intestinal Mucosal Barrier

The epithelial cells of the gut mucosa (with total surface area of 400 m2 ). ): have developed features that make the intestinal epithelium an active immunologic as well as anatomic barrier.

These non-classical immune cells express major histocompatibility complex (MHC) class I and II molecules, consistent with their ability to participate in adaptive immune recognition of pathogenic bacteria. Smallintestinal epithelial cells also express Toll-like receptors on their apical surface that enables them to detect bacterial products and to initiate an innate immune response. Anti-gene representing dendritic cells (DCs) also send processes between gut epithelial cells without disturbing tight junction integrity and sample commensal

and pathogenic gut bacteria. The gut epithelial barrier therefore represents a highly flexible structure that limits antigens from entering the systemic circulation.

So the Intestinal Epithelial Cells Act As: Immunological Barrier: (Gut-Associated Lymphoid Tissues) Anatomical Barrier: Healthy Layers of Epithelial Cells with tight junctions in between the cells
that prevent bacterial penetration. Also ;the protective mucous layer covering intestinal epithelial cells form a major barrier to trap pathogens, which are then eliminated when the gut epithelium is shed and replaced by new cells deriving from stem cells in the crypts.

Mechanisms contributing to intestinal Defense Mechanism: 1) Gut-associated lymphoid tissues Most important

2) Single-layer of intestinal epithelial cells; with tight junctions between the cells (covered with
protective mucous layer)

Anatomical Barrier

3) Proteolytic and lipolytic enzymes are produced in high concentrations by extra intestinal cells in
the pancreas and degrade different pathogenic agents at an early phase of digestion.

4) Actively increased peristalsis functions to mechanically get rid of pathogenic agents and potentially dangerous gut content.

The Gut- associated lymphoid tissues(GALT):

1) Aggregated
(lymphoid follicles, Peyer"s patches)

2) Non-aggregated (luminal, intraepithelial, and in lamina propria) immune cells.

1)Non-aggregated lymphoid cells:

Luminal: different cell types present in the intestinal lumen( include neutrophils; lymphocytes, and macrophages). These luminal cells represent an initial effector mechanism in the first front directed toward an antigenic exposure.

Intra-epithelial lymphocytes: (found in- between epithelial cells beneath the tight junctions.) Most of
the intraepithelial lymphocytes are T cells. T cells modulate homeostasis of the gut epithelium through local production of cytokines and have cytolytic effects(. contribute to epithelial cell death through apoptosis) The number of intraepithelial T- lymphocytes can increase dramatically in response to inflammation or infection. After exposure to antigens, these cells reenter the circulation to initiate a systemic immune response.

The lamina propria: diffusely distributed lymphoid tissue, including different types of immune cells (B
lymphocytes and plasma cells, T lymphocytes, macrophages, dendritic cells, eosinophils, and mast cells).

Approximately 60% of the lymphoid cells are T cells: These T lymphocytes are a heterogeneous group of cells and can differentiate into one of several types of effector T cells:

Cytotoxic: effector T cells damage the target cells directly. Helper: are effector T cells that help mediate induction of other T cells or the induction of B cells to produce humoral antibodies.

Approximately 40% of the lymphoid cells in the lamina propria are B cells, which are primarily derived from precursors in Peyer's patches .These B- lymphocytes and their progeny, plasma cells, .are predominantly focused on IgA synthesis and, to a lesser extent, on Ig M, Ig G, and Ig E synthesis.

Mast cells and eosinophils are also present in the lamina propria in small numbers. They exhibit an important role in allergic and hypersensitivity reactions as well as defense against parasites. Parasites including worms are recognized and tagged using monovalent IgE, which is mostly bound to host cell surfaces. Actual parasite killing depends on toxic proteins secreted by eosinophils.

2) Aggregated Lymphoid Tissues: Isolated lymphoid follicles scattered in lamina propria of the small intestine. Peyer's patches; are noncapsulated localized collections of lymphoid follicles that are most prominent and macroscopically visible in the lamina propria of the ileum. Peyer's patches are most prominent in children and gradually disappear with age. These lymphoid follicles are aggregates of B-cell follicles and intervening T-cell areas Overlying Peyer's patches : is a specialized intestinal epithelium containing M cells. These cells possess an apical membrane with microfolds rather than microvilli,( which is characteristic of most intestinal epithelial cells)

M cells are specific cells in the intestinal epithelium over lymphoid follicles allow the selective

uptake of food antigens and microorganisms by endocytosis using trans- epithelial vesicular transport . M cells transfer microbes and other antigens to underlying professional antigen-presenting cells,( such as dendritic cells .and macrophages) Dendritic cells, in addition, may sample luminal antigens diectly through their dendrite-like processes that extend through epithelial tight junctions Antigene-presenting cells (Dendritic cells and macrophages) that receive antigens from M cells ) present them to the gut-associated lymphoid tissue in the Peyer'spatches and scattered lymphoid follicles ; interact with and prime native lymphocytes. These activated lymphocytes exit through the draining lymphatices to enter the mesenteric lymph nodes, where they undergo differentiation. These lymphocytes then migrate into the systemic circulation via the thoracic duct and ultimately accumulate in the intestinal mucosa at effector sites .(During this process they mature into effector lymphocytes with an enriched population of IgA-producing B cells.)

Effector lymphocytes are distributed into distinct compartments:

IgA-producing plasma cells (derived from B cells) and are located in the lamina propria. Cytotoxic(CD8+ )T cells: migrate preferentially to the epithelium(intraepithelial T-lymphocytes beneath
tight junctions) but are also found in the lamina propria. These T-cells have potent cytotoxic activity and modulate homeostasis of gut epithelium

Helper(CD4+ )T cells :are located in the lamina propria. These T cells are central to immune regulation;
mediate induction of other T cells or the induction of B cells into Ig-producing plasma cells.

Immunoglobulin Secretion:
The synthesis and secretion of IgA is one of the major immune protective mechanism of the Gut-associated lymphoid tissue. The intestine contains more than 70% of the IgA-producing cells in the body. IgA is produced by plasma cells in the lamina propria and is secreted into the intestine, where it can bind antigens at the mucosal intestinal surface . IgA exists as a dimer that is linked with two additional molecules: a) The J chainlinking two IgA molecules b) The secretory component trans- membrane immunoglobulin receptor is produced by the intestinal epithelial cell; which transports the IgA complex across the cell and allows release of the complex, into the intestinal lumen. .Also The secretory component may prevent proteolytic degradation of the IgA molecule by intra-cellular lysosomes and luminal bacteria.

Secretory IgA:1) Inhibits the adherence of bacteria; viruses and parasites to epithelial cells and prevents their colonization and multiplication. 2)In addition, secretory IgA neutralizes bacterial toxins and viral activity and blocks the absorption of antigens from the gut. Intestinal IgA ( in sharp contrast with the role of other immunoglobulins) does not activate complement and does not enhance cell-mediated opsonization or destruction of infectious organisms or antigens. Damage of the immunogenic integrity of the intestinal mucosal barrier by different kinds of systemic injury(as in peritonitis, burn, and trauma);will lead to passage of viable bacteria and/or toxins from the intact gastrointestinal tract to the mesenteric lymph node and beyond( has been termed (bacterial translocation)This possibly explaining septic complications and multiple organ failure in these patients. In contrast, over exuberant immune sensitivity or lack of tolerance to dietary antigens or commensal bacteria is believed to contribute to the pathogenesis of chronic inflammatory intestinal disorders such as celiac disease and Crohn's disease.

During the course of a normal day, we ingest a number of bacteria, parasites, and viruses. The large surface area of the small bowel mucosa represents a potential major portal of entry for these pathogens; the small intestine serves as a major immunologic barrier in addition to its important role in digestion and

endocrine function. As a result of constant antigenic exposure, the intestine possesses abundant lymphoid cells (e.g., B and T lymphocytes) and myeloid cells (e.g., macrophages, neutrophils, eosinophils, mast cells). To deal with the constant barrage of potential toxins and antigens, the gut has evolved into a highly organized and efficient mechanism for antigen processing, humoral immunity, and cellular immunity. The gut-associated lymphoid tissue is localized in three areasPeyer patches, lamina propria lymphoid cells, and intraepithelial lymphocytes. Peyer patches are unencapsulated lymphoid nodules that constitute an afferent limb of the gut-associated lymphoid tissue, which recognizes antigens through the specialized sampling mechanism of the microfold (M) cells contained within the follicle-associated epithelium (Fig. 50-11). Antigens that gain access to the Peyer patches activate and prime B and T cells in that site. The M cells cover the lymphoid follicles in the gastrointestinal tract and provide a site for the selective sampling of intraluminal antigens. Activated lymphocytes from intestinal lymphoid follicles then leave the intestinal tract and migrate into afferent lymphatics that drain into mesenteric lymph nodes. Furthermore, these cells migrate into the lamina propria. The B lymphocytes become surface immunoglobulin A (IgA)bearing lymphoblasts, which serve a critically important role in mucosal immunity. B lymphocytes and plasma cells, T lymphocytes, macrophages, dendritic cells, eosinophils, and mast cells are scattered throughout the connective tissue of the lamina propria. Approximately 60% of the lymphoid cells are T cells. These T lymphocytes are a heterogeneous group of cells and can differentiate into one of several types of T effector cells. Cytotoxic T effector cells damage the target cells directly. Helper T cells are effector cells that help mediate induction of other T cells or the induction of B cells to produce humoral antibodies. T suppressor cells perform just the opposite function. Approximately 40% of the

lymphoid cells in the lamina propria are B cells, which are primarily derived from precursors in Peyer patches. These B cells and their progeny, plasma cells, are predominantly focused on IgA synthesis and, to a lesser extent, on IgM, IgG, and IgE synthesis. The intraepithelial lymphocytes are located in the space between the epithelial cells that line the mucosal surface and lie close to the basement membrane. It is thought that most of the intraepithelial lymphocytes are T cells. On activation, the intraepithelial lymphocytes may acquire cytolytic functions that can contribute to epithelial cell death through apoptosis. These cells may be important in the immunosurveillance against abnormal epithelial cells. As noted, one of the major protective immune mechanisms for the intestinal tract is the synthesis and secretion of IgA. The intestine contains more than 70% of the IgA-producing cells in the body. IgA is produced by plasma cells in the lamina propria and is secreted into the intestine, where it can bind antigens at the mucosal surface. The IgA antibody traverses the epithelial cell to the lumen by means of a protein carrier (the secretory component) that not only transports the IgA, but also protects it against the intracellular lysosomes. IgA does not activate complement and does not enhance cell-mediated opsonization or destruction of infectious organisms or antigens, which is in sharp contrast with the role of other immunoglobulins. Secretory IgA inhibits the adherence of bacteria to epithelial cells and prevents their colonization and multiplication. In addition, secretory IgA neutralizes bacterial toxins and viral activity and blocks the absorption of antigens from the gut.

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