physiological functions of the small bowel

7/27/2019 PHYSIOLOGICAL FUNCTIONS OF THE SMALL BOWEL

http://slidepdf.com/reader/full/physiological-functions-of-the-small-bowel 1/25

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 con-tinue 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 charac-

teristic features of absorptive epithelia including epithelial cells with cellular membranes possessing dis-

tinct 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 :- Solutes and Nutrients traverse the cell membranes through specialized mem-

brane transporter proteins,( such as channels, carriers, and pumps). The molecular characterization of trans-

porter proteins is evolving rapidly, with different transporter families, each containing many individual genes

encoding specific transporters, now identified.

Para-cellular transport: -Solutes and Nutrients are transported in-between the cells through the tight junc-

tions. It is apparent that para-cellular permeability is substrate specific, dynamic, and subject to regulation by

specific tight junction proteins.



Carbohydrates:-

Average daily carbohydrate Intake: is 350-400 G; Providing about 50% of caloric supply/day (1,600

kcal (4 kcal/g of carbohydrate).)

Carbohydrates are present in three main digestible forms:

A) Complex starches- (50%) Amylopectin and Amylose: derived from cereals and plants.

Glycogen derived from meat - contributes only a small fraction of dietary carbohydrate.

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 (10%)

. Processed foods contain a variety of sugars including fructose, oligosaccharides, and polysaccharides

Carbohydrate Digestion :

The complex starches ( amylopectin and amylose) are digested with the aid of salivary and pancreatic am-

ylase. Salivary amylase contributes a small amount to this process as it is inactivated by gastric acid, leav-

ing the remainder of this process to be completed by pancreatic amylase. This process yields oligosaccha-

rides (maltose, malt-triose, α-dextrins.) .This digestive process is usually completed before the carbohy-

drate bolus leaves the duodenum.

These small oligosaccharides along with ingested disaccharides, typically sucrose and lactose, are then fur-

ther digested by the brush border enzyme saccharidases in the jejunum; into their component monosac-

charide moieties, such as glucose, fructose and galactose.

The three major monosaccharides that represent the terminal products of carbohydrate digestion are glu-

cose, galactose, and fructose

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 nega-

tively 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 co-transporter

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



The movement of these monosaccharides into the cellular cytoplasm provides an additional osmotic gradi-

ent by which water is absorbed by the enterocytes from the intestinal lumen into ECF.

There is evidence of overexpression of hexose transporters specifically SGLT1, in disease states such as di-

abetes .Several approaches aimed at down-regulation of these transporters are being investigated as a

novel therapy for disease states such as diabetes and obesity.

Under normal circumstances :Carbohydrates Digestion and absorption of monosaccharides occurs in the

duodenum and proximal jejunum.( Although the entire small intestine has the capacity for carbohydrate di-

gestion and absorption)

About 10% of dietary starch (undigested-Resistant Starch) passes unabsorbed into the colon.

Dietary fiber- ( Non-digestible; Non-fermentable complex carbohydrates)=Non-starch complex poly-

saccharides)- 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 se-

rum 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 des-

quamated intestinal epithelial cells is 50 to 60 g of protein per day). Nearly 90&percnt; 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 requirements) as well as the

essential building blocks for production of new proteins.

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 success-

fully 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 ini-

tiated 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.



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 digested and absorbed in the duodenum and upper jejunum

Emulsification:

Emulsification: is the solubilization of water insoluble ingested fats into an emulsion to facilitate further break-

down by water-soluble digestive enzymes.

This is initiated by the mechanical actions of mastication and antral peristalsis causing breakdown of fat

globules into smaller sizes.

Then; emulsification is completed 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

(I)Long-chain Triglycerides; Cholesteroles; Phospholipids; Fat-Soluble Vitamines:-

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 en-

zyme.

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 glycer-

ol);. 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 interacting the prod-

ucts of lipolysis with bile salts .They consist of hydrophobic core of fat (FA;Monoglycerides;Cholesteroles

Phospholipides; fat-sol.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 membrane; in a thin layer of water with an acidic mi-

croenvironment 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 β-monoglycerides are carried by cytosolic fatty ac-

id–binding proteins to the smooth endoplasmic reticulum (SER). In the SER, resynthesize of triglycerides

occurs. These triglycerides and cholesterol esters are further processed in the Golgi apparatus where aphospholipid 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 chylo-

microns are packaged into secretory vesicles; before exiting the Golgi apparatus; then exit through 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 con-

tain a higher cholesterol /triglyceride ratio and provide the major route of entry for dietary cholesterol into the

lymphatic system.

(II)Short-chain and Medium-chain triglycerides:

These are more hydrophilic and are absorbed without undergoing intraluminal hydrolysis, micellular solubiliza-

tion, mucosal re-esterification, and chylomicron formation. Instead, they are directly absorbed by simple diffu-

sion into the enterocyte and then enter the portal venous circulation rather than the lymphatices.

.

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 salt-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, pancreat-

ic, 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 chang-

es in intestinal permeability or rate of flow of the intestinal contents can result in net secretion and diarrhe-

al states.

The villi are mainly absorbing structures, and secretion of water and electrolytes is localized to the crypts.



Water Absorption and Secretion:-

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

In general, after a meal is consumed, (there is addition of large amounts of saliva, gastric juice), and so

hypotonic chyme enters the proximal small intestine; Acid gastric contents are neutralized by the secretion

of bicarbonate, (pancreatic and biliary) ; creating NaCl and water. And as the osmotic pressure of the chyme

is increased further by breakdown of large molecules into smaller ones, still more water secreted into the

lumen. and so decreasing the osmotic pressure of the chyme;( brought into osmotic equilibrium with

blood)

The jejunum is effective at passively absorbing water in a paracellular fashion due to its relatively large

intercellular pores.

As the chyme travels through the length of the small intestine, the intercellular channels become more

tightly arranged and the movement of water becomes dependent on the active trans-cellular transport of

solutes and nutrients .So Water absorption is 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

trans-cellular Cl– secretion.

Mechanisms known to stimulate intestinal secretion of water and electrolytes:-

Intestinal Distention:- Rapid increase in intraluminal pressure stimulates water and chloride secretion into

the lumen(mediated via intra-mural nervous reflex) .This mechanism further contributes to the contraction of

the extracellular fluid volume in intestinal obstruction.

Luminal Secretagogues:-

Bile salts and large-chain fatty acids stimulate intestinal secretion and can, under certain circumstances,

cause Diarrhea.

Bacterial enterotoxin (Vibrio cholera, Escherichia coli, Salmonella, Campylocacter jejani, Yersina entero-

colitica, Clostridium perfringens and C. difficile) cause diarrhea by stimulating intestinal secretion under

pathological conditions

Humoral Agents:-

Acetylcholine, VIP, and serotonin derived from both extrinsic innervation and from the enteric nervous sys-

tem (ENS).Stimulate intestinal secretion.

GI Hormones as- secretin and gastrin; stimulate GI secretion.

The action of these humoral agents is most pronounced in pathological conditions in which they are produced in

abnormally large quantitites, such as carcinoid, VIPoma, or gastrinoma.

.Sodium(Na) Absorption:

Intestinal trans- cellularl 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 electri-



cal 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)/Na-AA cotransporter)

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 in-

flux(Absorption) of NaCl in exchange for H+/HCO3- efflux.

c) Sodium channels : Simple absorption of Na+ ions down the electro-chemichal gradient ( from the sodium-

rich 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 basolat-

eral membrane.

Chloride Absorption:

a) Electroneutral absorption (of NCl) through: counter-transport mechanism.(Na+/ H+ & Cl_/Hco3-counter

transport) (The majority of Cl absorption).

b) Passive diffusion: in a para-cellular fashion; along with active Na absorption. This is due to the slightly posi-

tive interstitium when compared to the gut lumen, allowing the negatively charged chloride ions to be ab-

sorbed.

Chloride secretion 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.

It requires the formation of carbonic acid in the intestinal lumen from HCO 3- 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 absorption of other cations, predominantly Na+ counter-transporter (and

to less extent K+ absorption).

In the duodenum ; HCO3- is secreted in exchange for Cl- absorption ( chloride ions contained within gas-

tric 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+ trans-cellular (counter-transport): K+ absorption is facilitated by the intracellular electrochemical

gradient that is created predominantly by the basolateral ATPase pump (in exchange of H+secretion).

Intracellular K+ then diffuses across the basolateral membrane via K+ channel or carrier.



Absorption of Minerals:

Minerals:- are inorganic elements: accounts for approximately 5% of total adult body mass:

50%; of this mass; calcium

25% phosphate

25% other minerals

The Minerals are either:

Macro minerals ,(calcium; phosphate, magnesium, , sodium, chloride, potassium and sulfur with daily re-

quirements exceeding 100 mg/d.

Micro minerals; (trace minerals ;elements) include: iron, zinc, copper, manganese, iodine, selenium, fluo-

ride, molybdenum, chromium, and cobalt with daily requirements of less than 15 mg/d.

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 trans-cellular transport; mainly in the; Duodenum

AND Passive para-cellular diffusion; throughout the length of the small intestine.

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 conver-

sion 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 cal-

cium by the small intestine.

When intraluminal calcium is in excess of its capacity to be actively transferred by the apical membrane's

carrier-mediated 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 pack-

aged 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 cobalamin–

intrinsic 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 ( usually presents with megaloblastic anemia.): Due to defective absorption due to:

lack of intrinsic factor: after proximal or total gastrectomy, autoimmunity to gastric parietal cells or in-

trinsic factor, or atrophic gastritis.

Failure of absorption of cobalamin–intrinsic factor complexes : Ileal Crohn's Disease; terminal ileal resec-

tion(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 (Entero-

endocrine 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- en-

docrine cells, but also in central and peripheral neurons. The products of these genes (The regulatory Pep-

tides) 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

Neurocrine mediators : serve as neurotransmitters.

Gut Hormones-Receptors Interaction:

These regulatory peptides have complex physiological actions; which can be explained by receptor subtype mul-

tiplicity 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 protein–coupled 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, epidermal growth factor, fibroblast growth factor, platelet-derived growth

factor; transforming growth factor-α and -β,

(C)Ion channel–linked 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: (acetylcholine and serotonin)

Inhibitory Neurotransmitters: (γ-amino-butyric acid, glycine)



Gastrointestinal-Peptide Hormones:-

Gastrin:-

LOCATION- : Antrum, duodenum(G cells)

MAJOR STIMULANTS OF SECRETION : Antral distention, vagal stimulation , peptides; amino acids; gastrin-

releasing peptide(bombesin); and hypercalcemia

Its release is inhibited by low intraluminal pH, somatostatin, secretin, gastric inhibitory peptide (GIP), vasoac-

tive 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 entero-

chromaffin-like (ECL) cells, causing a release of histamine, which in turn stimulates the parietal cells in a para-

crine 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 :- amino acids and fatty acids


(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

Gastrin-releasing peptide (mammalian equivalent of bombesin):-

LOCATION- : - Small bowel

MAJOR STIMULANTS OF SECRETION :- Vagal stimulation




(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.


(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)


Universal “off ” switch:

(1) Inhibits release of gastrointestinal hormones

(2) Inhibits gastric acid secretion

(3) Inhibits small bowel water and electrolyte secretion

(4) Inhibits secretion of pancreatic hormones

(5) 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 peri-

ods. Release may also be related to alkalinization of the duodenum.


(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


(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-


Glucagon-like peptide-1:

(1) Stimulates insulin release

(2) 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:-

-Gastrin

Pentagastrin (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.

-acting analogue of somatostatin-Octreotide, a long

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 variceal Upper GIT Bleeding.

.



IMMUNE FUNCTION:

. The lumen of the gastrointestinal tract is connected to the outside environment and comes in direct con-

tact 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 addi-

tional 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 tox-

ins 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 ef-

fective 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. Small-

intestinal epithelial cells also express Toll-like receptors on their apical surface that enables them to detect bac-

terial 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 lim-

its 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 poten-

tially 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 mac-

rophages). 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 in-

fection. After exposure to antigens, these cells reenter the circulation to initiate a systemic immune re-

sponse.

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 pro-

duce 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 im-

portant role in allergic and hypersensitivity reactions as well as defense against parasites. Parasites includ-

ing 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 non-

capsulated 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 epithe-

lial 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 en-

riched 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 muco-

sal intestinal surface

. IgA exists as a dimer that is linked with two additional molecules:

a) The J chain—linking two IgA molecules

b) The secretory component – transmembrane immunoglobulin receptor is produced by the intestinal epitheli-

al 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 colonizationand 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 gastroin-

testinal 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 areas—Peyer

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 ofintraluminal 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 propriaand 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 insharp 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.

.

.

.



.

physiological functions of the small bowel

Documents