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Physiology - GI


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name some long loop reflexes
1) swallowing reflex
2) receptive relaxation reflex (expands stomach in response to food delivery
3) variey of tother felexes that occur in anticipation of a meal...)
Effecets of autonomics on intestinal blood flow
1) para: vasodilatory
2) symp: vasoconstrictive
Autonomic effects on GI motility
1) para: generally excitatory (ACh released stimulates SM contraction. A few exceptions where para fibers release NO).

2) Symp: usually inhibitory, though only minor effects unless strong response (fight or flight). RElease primarily norepi.
Autonomic effects on GI secretion
1) Para: generally excitatory
2) symp: inhibitory (execptp salivary glands)
Which autonomic input is more influential?
what are the 2 intrinsic nerve plexi in the walls of the GI tract?
1) myenteric plexus
2) submucosal plexis
Describe the myenteric plexus
1) between inner and outer muscular layers
2) interfaces with intestinal smooth muscle
3) get info mainly from the submucosal plexus, autonomic input, and mechanorecptors
describe the submucosal plexus
1) lies just beneath the mucosa
2) primarily responsible for interfacing with the mucosa; limited input to SM
3) NEUROCINE regulation; release of signaling molecule from a neuron, but no recognizable synapse and no electric excitation
4) receives info from the mucosa as well (mechano and chemoreceptors). Info is then relayed to myenteric plexus and the CNS
What provides pacemaking in the GI tract
Interstitial cells of Cajal (ICCs)
(muscle like cells that lie along the margins of the muscle layers.
what do ICCs generate?
Driver potenntials
how are driver potenntials passed?
thru gap junctions
what do you call the potentials in the smooth muscle cells
"follower potentials" or "slow wave potentials"
describe the amplitude of the slow wave potentials
just high enough to get the cell in the vicinity of MECHANICAL THRESHHOLD, or where Ca channels begin to open and contrcaition is initiated
What then is the purpose of slow wave potentials?
serve as timing waves, controling the frequency at which actual contractions will/can occur
what happens if the amplitude of slow wave increass?
Contraction is stronger, because there will generally be MORE action potentials at the crest of each slow wave
Where are slow wave potentials most and least frequent?
3/min in the stomach
14/min in the duoodenum, then decrease distally to 7-8/min in the terminal iliem.
what does Ach ddo to slow wave potentials?
Increases amplitudes, producing strong contractions that are in phase wiht pacemaker activity
What does VIP do?
Opposite of Ach. Inhibitory, decreases slow wave amplitudes.
What does Subtance P do
excitatory; released by motor neurons and acts like Ach
Describe the peristaltic reflex model
1) Food bolus causes opening of mechanicallly activated cation channels
2) this stimulates serotonin release from ENEROCHROMAFFIN cells in the epiitheliuum.
3) this activates nearby sensorry receptor cells
4) these cells activate a pooy of interneurons in the submucosal and myenteric plexi
5) Some of these project proximally and cause release of Ach and Substance P from motor neurons, causing constriction behind the bolud
6) others project ahead, causing activation of excitatory neurons for LONGITUDINAL fibers, and inhibitory neurons for circular fibers. This causes dilation and shortening ahead of the bols.
7) bolus propelled forward, cycle starts again.
Is peristalsis short or long loop reflex?
Name a endocrine GI ormone
satiety factor: released from gut, regulates appetite centers in brain
Name an exocrine agent

It is released into and acts WITHIN the lumen of the GI tract
how are hormonesin the CCK/gastrin family soimilar
simialr at carboxy temmini
how are hormones ni the secretin family similar? members?
Similar at the amino termini

Consequences of similar structuures of gastic peptides hormones? Example?
If present in high enough concentrations, one peptide in family will interact wiht receptors for anotherpeptide in the family.

Excample: CCK binds tightest to CCK-A receptor. But it also can bind to the gastrin receptor, which thus is also called the gastrin/CCK-B receptor.

Thus, if you have a hormone secreting tumor, you may exhibit symptomsassociated with actions of other structurally related hormones.
transit time in the esophagus
average of 10 sec
what mediates relaxation of the lower esophageal sphincter
neural release of VIP and NO
how long to empty stomach after a meal?
4-6 hours, since only 1 mL of chyme is expelled through pyloric sphincter with each rhhythmic contraction (3-4/min)
what is "retropulsion"
if food is to big to get through pyloric sphincter, it is expelled backward under pressure, which helps mechanically break it up
transit time through small intestinee
6 hours
transit time in colon
12-36 hours
whhere are oxcyntic glands
in the body of the stomach
What kind of cells make up oxcyntic glands? Functions?
1) surface and neck cells: secrete mucus
2) parietal cells (in midle): cecrete HCl and intrinsic factor
3) Chief cells (lower): secrete pepsinogen
Where are pyloric glands?
Antrum of stomach
compare pyloric gland with oxcyntic glands?
Similar, but no parietal cells (no HCl/Intrinsic factor production) and they DO have GASTRIN producing cells
what is intrinsic factor
Secreted by parietal cells of oxcyntic glands (along with HCl)

Glycoprotein cofactor that complexes with B12 and is essential for B12 absorption in the terminal ilieum
What is the only indispensible component of gastric juice? Without it...
Intrinsic factor

With out it, you lose B12 and get pernicious anemia.
Functions of mucus:
1) protect gastric mucosa from gastric acid and pepsin
2) provide lubrication for the passage of food thru the stomach
What is pepsinogen?
precursor to pepsin
Made by chief cells

Autocatalytically converted by LOW PH.

First protease to come into contact with ingested food. But not necessary for digestion.
what are the gastric endocrine secretions?
1) somatostatin
2) gastrin
3) histamine
what are somatostatin secreting \cells?
D cells
What are gastrin secreting cells?
G cells (in the pyloric glands, mainly)
what is the general fxn of somatostatin?
inhibits acid secretion
What is the general fxn of gastrin and hhistamine?
activate acid secretion
4 phases of digestion
1) interdigestive
2) cephalic
3) gastric
4) intestinal
Events in the interdigestive stage
LOW stomach pH

1) D cells tonically release somatostatin, which inhibits the gastrin/acid proming G cells in the pyloric glands as well as the parietal cells in the oxcyntic glands.
Events of the cephalic stage:
Key event: weak vagal stimulation. This:

1) weakly stimulates HCl release from parietal cells of oxcyntic glands
2) weakly activates G cells in gastric glands to release gastrin
3) (but note: Somatostain is still activated by the acid and is inhibiitng parietal and G cells)
4) BUT: there is STRONG activation of the chief cells to make pepsinogen and intrinsic factor, to prepare for incoming food.
Gastric phase events
Continued vagal stimulation + food buffering

1) digested peptides/AA directly stimulate G cells to release gastrin, which activates parietal cells to releaase HCl
2) Food entry triggers mechano and chemoreceptors that also trigger gastrin secretion AND pepsinogen (chief cell) secretion
3) Vagus continues to activate G cells (via ACh and GRP) and to inhibit D cells making somatostatin.
4) food also buffers acid pH, which decreases somatostatin activity.
5) thus, G cells are minimally inhibited and there is max gastrin release
6) in addition to parietal cell activation, circulating gastrin also activates mast cells, eetc to release HISTAMINE, which FURTHER activates parietal cells to make H+ (along with gastrin and Ach directly)
Early intestinal phase
1) now aa/peptides enntering duodenum also activate G cells in the duodenum, leading to still more gastrin production. this goes into circulation and gets back to stomach, where it further increases histamine release and activates further the parietal cells.

2) NEW: digestion products, when they hit the duodenum, also cause increase in CCK release. This acts to INCREASE TONE on pyloric sphincter (negative feedback loop)
Evenets of the inhibitory astric phase/late intestinal phase.
TERMINATION OF ACID SECRETION: loss of food causes stomach pH to drop below 3

1) the low pH directly inhibits G cell release of gastrin: so less activation of parietal and chief cells to make pepsinogen and HCl
2) low pH also enhances activity of D cells making somatostatin, which inhibits G and parietal cells
3) vagal nerve stimulation ceases: no ACh and GRP to activate G cells and inhibit D cells.

LATE INTESTINAL PHASE: triggered by acid and digestion products

1) Acid causes S cells to release secretin, weakly INHIBITING acid secretion in the stomach
2) digestion products also cause release of ENTEROGASTRONES that strongly inhibit acid secretion in the stomach
3) digestion products still activating I cells that make CCK, which makes pyloric scphincter tone increase; it now also stimulates somatostatin release.

NOTE NOW: CCK and secretin will also have effects on targets other than stomach
what promotes mucus production:
ACh from vagus nerve; mechanical stimulation, Prostoglandins.
What stimulates pepsinogen secretion:
ACh stongly
gastrin, histamine, secretin (???)
What activates gastrin secretion:
free amino acids
what inhibits G cells?
low pH (directly)
somatostatin (D cells)
What stimulates acid secretion:
1) histamine (strong)
2) ACh, gastrin (weaker)
Acid secretion inibitors
1) low pH directly inhibits G cells, also inhibits parietal cells via short reflex
2) low pH causes D cells to make somatostatin, inhibiting parietal cells and G cells
Inhibitors of acid secretion
1) low stomach ph directly inhibits G cells

2) low ph causes D cels to secrete somatostatin, inhibiting parital cells and gastrin release and histamine release

3)Entry of H, fat, digestion products into intestine stimulates release of ENTEROGASTRONES (GIP, secretin, CCK etc) that strongly inhibit acid)
How is HCl formed/released in parietal cells
1) Carbonic anhydrase in cells forms H2CO3 from co2 and h20. H2Co3 dissociates into H+ and HCO3-.

2) H+ secreted on apical side by H/K ATPase antiporter.

3) Cl-enters cell basally by Na/Cl symporter as well as a HCO3-/Cl antiporter. [HCO3 exit causes ALKALINE TIDE in the blood]

4) Cl- exits apically via K/Cl symporter. The K that leaves the cell then drives the H/K ATPase antiporter.

5) SECRETOGUES cause cAMP levels in cell to rise, leading to fusion of organelles with lots of H/K antiporters and INTRINIC FACTOR with the apical membrane. This leads to immmediate intrisic factor release as well as upregulation of the ability of cell to excrete H+.
What hormone has the most potent effect on fusion of H/K - intrinsic factor vesicles with apical membrane?
when does an ulcer form, generaly
when acid and pepsin overcomes the ability of gastric mucosa to protect/repair itself
What is destruction of mucus barrier commonly initiated by?
1) overuse of NSAIDS
2) chronic H. pylori infection
How do H. pylori colonize the stomach?
1) they live INSIDE the mucus lining
2) they make UREASE, which converts urea in the stomach to ammonia which locally buffers the acid.
Describe urease test
Patient given radioactive urea. If they breathe out radioactive CO2, they have urease in the stomach whrich transforms the urea to bicarbonate and ammonia. Biccarbonate eventually becomes CO2.
what is Zollinger-Ellison Syndrome?
High levels of gastric accid, ulcers, overgrowth of gastric mucosa (gastrin is a GF as well for mucosal cells)

Caused when duodenal or pancreatic tumors secrete excess gastrin
Why do you get diarrhea with ZES?
Excessive entry of acid into the duodenum will denature pancreatic enzymes. this leads to malabsorptive fatty diarrhea (steatorrhea)
what is diagnostic of ZES?
Response to injected SECRETIN, which decreases gastrin release from Normal sources and enhances it from tumor sources. So if gastrin goes up with secretin injection, you got a tumor
Antacid/ulcer treatments
1) selective vagotomy: reduces cholinergic innput to G cells, parietal cells, etc.
2) Proglumide: blocks gastrin receptor
3) antrectomy: suurgically remove gastrin secreting cells
4) zantac/tagamet: block histamie receptor
5) omeprazol: inhibits proton pumps in parietal cells. but this leads to excessive gastrin release due to lack of H, which some think may lead long term to tumors due to gastrins mitogenic effects
what is Barret's esophagus
condition due to long term GERD

normal squamus pithelium of esophagus is destroyed and replassed by columnar epithelium. this is associated with increased risk of esophageal cancer
Where are intestinal epithelial cells born?
the crypts
types of epithelial cells in the intestine:
1) paneth cells
2) M cells
3) endocrine cells
4) columnar cells
5) goblet cells
the role of pancreatic juice
Essential for carbohydrate, fat, and protein digestion, as well as being th eSOLE producer of RNAse and DNAse
what is the function of pancreatic bicarbonate?
neutralize HCl from gastric juice as it enters the duodenum.
What are the 3 sources of intestinal bicarbonate?
1) pancreatic
2) bile
3) intestine
What ist eh operating pH of the small intestine lumen
slightly alcaline
interdigestive phase of pancreas secretion
Minimal activity. No vagal stimulation, little secretio of pancreas/liver/gb enzymes
cephalic phase of intestinal digestion
1) sight/smell causes moderat vagal stimulation of pancreas and liver/gb. Vaa stimulation (Ach ) also causes modes CONSTRICTION of the gallbladder and modest RELAXATION of the sphincter of Oddi.

Some pancreatic and hepatic secretions enter the duodenum
Gastric phase of intestinal digestion
1) vagus remains active and continues to stimulate pancreatic enzyme secretion, GB contraction, and relaxation of Oddi.

2) Gastrin released from G cells in the antrum and duo is delivered to GB and pancreas, where it acts WEAKLY on CCK receptors (overlap), further enancing pancreatic secretion and GB constriction.
Late intestinal phase
1) CCK secretion persists, causing contraction of pyloric sphincter, contraction of GB, secretion by acinar cells, relaxation of Oddi

2) chyme in duodenum lowers pH, causing SECRETIN release by S cells. This stimulates strongly ELECTROLYTE SECRETION by pancreatic duct and bile duct cells, which helps to buffer the acid.

3) digestion products stimulate release of ENTEROGASTRONES (including secretin, enteroglucagon, GIP) that inhibit acid productionin the stomach.
what triggers acinar cell secretion
1) vagus release of ACh
2) Gastrin (weakly, probably cross reacting with CCK receptors)
3) CCK
4) secretin potentiates all of these
what are the primariy regulators of pancreatic duct cell secretion? What are they INSENSITIVE to?
1) regulated by secretin and somatostatin
2) insensitive to ACh, gastrin CCK
function of pancreatic duct cells?
secrete HCO3 and water to neutralize acid and was enzyme secretions down the duct.
describe secretory mechanism of water and hco3 in pancreatic duct cell
1) carbonic anhydrase in the cell creates HCO3 and H+
2) H+ secreted out the BASAL membrane in Na/H antiporter
3) HCO3 exchanged apically for Cl-
4) most of that Cl- comes from the cell itself, which happens when SECRETIN activates cAMP accumulation, which leads to opening of CL- selective channels in the apical membrane. Cl- flows out electronegatively. The Cl then comes back in in echange for HCO3
What does somatostatin do to the pancreatic duct cells
opposes secretin, and lowers intracellular camp. Less recruitment of Cl- chhannels to apical membrane, less extracellular cl available to drive CL/HOC3 antiporter, less HOC3 excretion.
So how all does secretin act as "nature's antacid"?
1) Causes pancreatic duct cell secretion of HCO3 in a cAMP dependent manner (whereby CL- channels are opened)

2) acts as a enterogastrone--goes back to the stomach and inhibits acid production by parietal cells.
what are the phagocytic cells in the liver? where are they?
kuppfer cells, in the perisinusoidal space
where are bile salts reabsorbed?
terminal ilieum
how much bile is recycled?
where all is bile salt activly uptaken?
1) terminal ileum
2) hepatocytes
3) what is left goes to the kidney and is uptaken in the renal tubbular epithelial cells.
Where asre bile salts synthesized? from what?
In hepatocytes, from cholesterol
What are the functions of bile salts:
1) emulsify fats
2) form micelles to make products of fat digestion solube
3) facilitate release of enteroniase (?) from the intestinal mucosa
what is the function of bile electrolytes?
neutralize gastric acid, in conjunction with pancreatic electrolytes
So what are the 3 types of molecules in bile?
1) water
2) hydrophobic, insoluble molecules
3) amphipathic molecules
what are the 2 types of gallstones
1) cholesterol stones (75%)--too much cholesteral secreted for the amt of bile salt, and it precipitates

2) pigment stones: hyppersecretion of bilirubin, not enogh conjugation, itprecipitates out.
where does fat digestion begin
how do Fats get into intestinal cells
Micelles are fomred by amphipathic bile salts, plus phospholipid and cholesterol. Fatty acids and monoglycerides dissolve into the hydrophobic center.

Micelle encounters brush border and somehow offloads the fatinto the epithelial cell. Micelle and its bile salts stay in the gut lumen.
what happens to FA once in the enterocyte?
1) FA less than 14 C's exit straight out the BL membrane and enter portal circulation as free FA.

2) Bigger ones (+ chol, etc) enter the SER.

3) they are esterified to make triglyceride or phospholipid.

4) in the GOLGI, the triglycerides are aggregated into droplets and covered with a layer of cholesterop, phospholipid, and apolipoprotein. This = chylcomicron.

5) chylocmicrons secreted via vesicle fusion and diffuse into the LACTEALS.

6) lacteal-->thoracid duct-->blood.

7) lipids then targeted to tissues as a fxn of metabolic state (adipocytes, muscle)
where are the enzymes that catalze the production of monosaccharide end products of carb digestion?
on the brush border, near the carriers that then transport the monosacchs into the epithelium
How are glucose and galactose absorbed?
Secondary active transport (Na dependent)

They share the SGLT1 transporter.

how does fructose get into the gut?
absorbed passively by facilitated diffusion (likely GLUT5).

It is rapidly intracellularly converted to glucose, maintaining the concentration gradient for fructose.
How do glu, gal, and fru exit the epithelium
basolaterally, all by the GLUT2 transporter.

GLUT2 has broad specificity
what causes lactose intolerance?
deficienncy of lactase on the brush border. Lactose stays in gut and draws water in via elevated osmotic presure
What is sucrose-isomaltose malabsorption syndrome?
Caused by simultaneous absence of sucrase and maltase activity, leading to sucrose intolerance.

Symptoms similar to lactose intolerance.

Coordinate incidence of the 2 absent enzymes suggests common genetic or functional control
what is Familial monosaccharide malabsorption syndrome?
Inherited disorder

Probably a SGLT-1 deficiency.

Necessitates carb free diet. Since Glu and Gal can't be absorbed.
does carb digestion occur in the stomach?
what breaks down peptides
1) pancreatic enzymes
2) brush border enzymes...
3) pesin?
how are lare peptides and intact proteins absorbed?
They are not. although they might trigger an immune response if there is enough of it.
how are small (3aa)peptides absorbed?
efficiently, by an apical peptide transport mechanism (unknown). further hydrolysis to AAs occurs in the cell
what other transporters are there?
multiple rush border transporters for AAs. 7 defined so far.
what else is on the brush border?
proteases, which help break down large peptides to smaller absorbable peptides.
what happens to AAs once absorbed?
move out BL side by at least 3 different BL carrier proteins (different from apical uptake proteins). These are more like the ones you find on non epithelial cells.

Once out of cell, they get in circulation and go to liver.
what is cystinuria:
renal and intestinal malabsorption of basic AA and cysteine. probably due to a defective brush border transporter (that also is in the kidney)
what is Hartnup's disease?
renal and intestinal malabsorption of NEUTRAL AA.
What is Lysinuric protein intolerance?
Affects cationic amino acid absorption almost everywhere. probably due to BASOLATERAL tranporter problem.
which of those defects causes more problems?
Basolateral tranporter problems (LPI) is worse. If apical transporters are bad, then you are better off, 1) because the AA tranporters have overlapping specificities, and 2) because the PEPTIDE transporter can always get some of the protein in, getting in some of the transporter-excluded AA.
what does ghrelin injection do?
seems to stimulate appetite..
what can CCK, bombesin, glucagon, insulin, adn somatostatin due wrt apetite
all of them, when injected, can seem to cause appetite suppression..
describe fat genetics
"obese" gene has been isolated. Encodes for Leptin, a protein made by adipose cells and secreted. ob/ob mutants make truncated leptin and are fat. Leptin seems then to be the "THIN" protein.

Proposed path:
1) your CNS makes you hungry
2) you eat
3) you make more fat cells
4) fat cells make leptin
5) leptin turns off your hunger signal.

ALSO: exercise seems to downregulate leptin (decreases adipose mass)

ALSO: when you starve, you stop ovulating. but if you also give leptin, you will still ovulate.

ALSO: in humans, fat people seem to have HIGH leptin levels. So most fatties must be leptin RESISTANT and not necessarily leptin insufficient.
describe the type of transport of glu, gal, and fru
glu and gal are tranported into gut via secondary active transport tied to Na. SGLT-1.

Fru is absorbed passively, via GLUT5.
most of the lethal diarrhea is of what type?
how does Na get from lumen into boy?
1) cotransport (secondary ative) with monosaccharades (SGLT-1) and with some amino acids.

2) in th SMALL INTESTINE villi: 2 pump system. Na-H exchanger, Cl-HCO3 exchanger. NA and CL go in. Hco3 and H go out, forming CO2 and water.

3) ENaC: also located in kidney. Opens spontaneously to let in Na down electrochemicla gradiennt. Amiloride sensitive, aldosterone induced.
which cells do most of the intestinal secretion of ions and fluid?
crypt cells.
function summary of crypt cells:
transfers na, cl, and bicarbonate into the lumen, which drives flow of water into the lumen.
How does nacl/bicarb secretion occur in the gut
1) Na/K antiporter atpase on BL side (like everywhere.

2) Na is recycled back into cell in a Na/K/2Cl- importer on the BL side. this creates high cytoplasamic CL

3) hormones activate a Cl- channel on the apical surface (CFTR channel). Cl- flows out, along with some HCO3-. But there is no counterion, so it creates a negative c
charge iin the lumen.

4) Na+ then comes in paracellularly from the interstitium (after being pumped out by Na/K atpase).

5) increased luminal osmolarity drives water flow.
describe hormonal control of CFTR chloride channel
1) hormone receptors are localized basolaterally and are g-coupled receptors.

2) some are inhibitory, some increase cAMP

3) (cAMP is what leads to opening of CFTR)

4) VIP an d sdcretin bind to stimulatory protein

5) somatostatin acts in opposition and inhibits cAMP.
what things in diet can cause malabsorptive diarrhea?
1) manesium. Not well absorbed.

2) sorbitol

3) olestra
name a disease state/s not already discused that can cause malabsortivve diarrhea
Crohn's disease
ulcerative colitis
celia sprue (gluten alleregy)

causes generalized destruction of mucosa, leading to profound loss of absorptive capacity.
what are the 2 categoies of bacterial rrhea toxins?
heat labile
heat stabile
Describe the heat labile toxins; give example
CHOLERA toxin (all are similar in structure and fxn)

1) binds to apical membrane, selivered to basolateral membrane by transcytosis

2) then it forms pore allowing a subunit to enter cytoplasm

3) subunit IRREVERSIBLY activates stimulatory G protein

4) cAMP dramatically rises, causing mass activation of CFTR Cl- channels

5) mass paracellular transport of Na ensues, followed by water.
give an example of a heat stabile toxin? how wdoes it work
STa toxin, made by pathogenic e. Coli

binds to extracellular domain of a Guanylyl cyclase. This leads to increased intracellular GMP, which activates PKG-II which phosphoylates and activates CTFR.

causes "traveller's diarrhea"

as with choler, best treatment is hehydration with water and electrolytes
describe Verner Morrison syndrome
Non beta islet pancreatic cells make an excess of VIP due to tumor.

VIP is a strong secretory stimulus. Floods circulatory system with VIP, causing watery diarrhea by activating Gs proteins. "Pancreatic cholera."

only cure: tumor removal.

Therapy: give agents that activae the inhibitory side of that g protein (somatosttatin analog--inhibits cAMP, as well as inhibits VIP secretion)
name a non-gi disease involving CFTR

Involves mutation of CFTR such that cl secretion is lost, and lung mucus becomes thick and sticky.

note that CF cooccurs with some pancreatitis and bowel obstruction, indicating CFTR problems elsewhere.

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