What are the four main functions of the GI tract?
Where does the bulk of absorption occur?
T or F. Practically the entire GI tract is colonized by bacteria
T. 99% in the large intestine and rectum, and none usually in the stomach due to the acidic nature
The epithelium is polarized both functional and structural with the basal membrane being attached to the BM and the apical membrane being formed into many microvilli (aka brush border)
What are the main cells of the epithelium?
the absorptive, endocrine, goblet, and M cells
Describe the anatomy of GI epithelium
it is folded heavily into finger-like villi with intermittent, depression-like crypts which house the stem-cells of the epithelium. The epithelium sloughs and is renewed about every 3-4 days
How does blood flow to the GI change after a meal?
increases up to 8x
NOTE: This effect can be so pronounced as to decrease peripheral BP after/during a meal/heavy stomach activity
What mediates the increase in GI blood flow during/after a meal?
secretion of mucosal vasodilators, such as CCK, VIP, gastrin, and secretin
Kallidin is secreted and activiates bradykinin, a potent vasodilator
And the reduced O2 concentration to the heavy metabolic activity might result in increased blood flow
How might villi respond to chronic levels of low oxygen?
Because there is a continuous arterial-to-venous blood shunt that occurs along the vertical path of the villi that even under normal circumstances shunts 80% of oxygenated blood into venous circulation without perfusing the villi, a. hypoxia would exacerbate this shunt and lead to villi necrosis
How is the GI blood flow regulated?
Parasympathetic increased blood flow and sympathetic decreases
Describe the parasympathetic innervation of the GI
this mostly consists of the efferent and affarent fibers of the vagus and pelvic nerves from the brain and sacral regions of the spinal cord.
Describe the sympathetic innervation of the GI
Neurons in the spinal cord synapse in the celiac, SM, and IM ganglia, which then use another set of ANS fibers to synapse into the GI organs
Where is the myenteric plexus located?
between the circular and longitudinal layers of smooth muscle in the muscularis externa
The enteric system can allow the GI to function even in the absence of central neural input
What neurotransmitters function in the extrnsic nervous system of the GI? Intrinsic?
Extrinsic- Ach and NE
Intrinsic- Substance P and VIP
What are the main functions of substance P and VIP?
Substance P is activating to the GI smooth muscle, and VIP is inhibitory
What are the main types of neurotransmitter systems in the GI?
Endocrine (e.g. gastrin)
Paracrine (e.g. histamine)
What are the 5 major GI hormones?
What are the candidate (i.e. the physiologic function is not completely established yet) GI hormones?
What are the main criteria for GI hormones?
-stimulation and activity seen in different parts of the GI
-Effective in the absence of nerves (ie not neurocrine)
-Can be isolated from the site of stimulation
-Substance and structure confirmed
What are the major groups of GI hormones?
-based on structure homology
gastrin-family (gastrin, CCK)
secretin family (secretin, VIP, GIP, and Glucagon)
Describe the structure of Gastrin
It is a 17 AA peptide that is aminated at the C-terminal and cyclized at the N-terminal, which both make the peptide VERY stable (cant be broken down by carboxypeptides, aminopeptidases, etc.)
NOTE: Gastrin is originally synthesized as a 34-AA pro-gastrin structure in the G-cells in the stomach, which produce a protease to produce a glycine-exteded gastrin, which does NOT act on CCK-2 receptors (may have other receptors). Amination of the C-terminal removes the glycine to produce active G-17
What is the minimum sequence required for biologic activity of Gastrin?
Trp-Met-Asp-Phe (NH2) at the C-terminal.
What is the main function of gastrin?
to stimulate perietal cells to secrete gastric acid via binding to the gastrin/CCK-2 receptors (not CCK-1 receptors)
What is the difference between Gastrin 1 and 2?
Gastrin 1 is not sulfated at the 12-AA tyrosine, while Gastrin 2 is, which has a MUCH higher affinity for the gastrin receptor and thus is much more active
What is the half-life of G17?
NOTE: There is also a G-34 produced by G cells in the duodenum that is not the same as the pro-gastrin produced in the stomach and has a half-life of about 38 minutes. We dont know its function yet
Notice that since the 5-AA on the C-terminal are identical to gastrin, it can also stimulate acid secretion
Notice here the tyrosine moves to the 7AA from the C-terminal and is ALWAYS sulfated unlike gastrin
What receptor does CCK work through?
CCK-1 only when sulfated and CCK-2 when desulfated
NOTE: sulfated gastrin II cannot bind to CCK-1 receptors, so it seems that having the tyrosine on the 7AA position is important for acting through CCK-1
T or F. If the 7-AA tyrosine from the C-terminal is desulfated, it cannot work on the CCK-1 receptors
T. When this happens, it can bind to CCK-2 receptors and act like gastrin to stimulate acid secretion
One of the main functions of CCK is gallbladder contraction via CCK-1 receptor binding
T or F. For the hormones of the secretin family, i.e. secretin, VIP, GIP, and glucagon, there is no minimum sequence needed for activity, but instead the ENTIRE sequence is needed
The apical membrane may have receptors that stimulate release of hormones into the circulation
Blue is where these hormones are made normally and the black is where they can be made under pathological conditions
What are the criteria for physiologic roles of GI hormones?
-responds to endogenous normal stimuli
-active dose (D50) matches endogenous concentration
-Response to continuous administration, not just bolus
What are the main functions of gastrin? What stimulates it to be released?
acid secretion and mucosal growth
It is stimulated to be released from protein, stomach distension, and nerve input after/during a meal because protein digestion requires acid and proteases (acid inhibits its release)
What are the main functions of CCK? What stimulates it to be released?
pancreatic HCO3- and enzyme secretion
gallbladder contraction (to stimulate more HCO3- release from bile)
inhibited gastric emptying
Stimulators: protein, fat, and acid (some) because fat digestion and absorption requires lipases and bile salts
What are the main functions of Secretin?
-pancreatic HCO3- secretion
Bile HCO3- secretion
What stimulates secretin release?
acid and fat (some)
What are the main functions of GIP?
stimulates insulin release from oral glucose
inhibits acid secretion
What are the main functions of Motilin?
stimulates gstric and intestinal motility
What are the main neurocrines of the GI?
-Bombesin or GRP
What is the site of release of VIP?
mucosa and smooth muscle of GI tract
What are the actions of VIP?
relaxes sphincters and gut circular muscle
stimulates intestinal and pancreatic secretions
relax vascular smooth muscle to increase blood supply to the intestine
What is the function of Bombesin/GRP?
This is released from gastric mucosa neve endings that stimulates gastrin release from G cells in the stomach antrum
Where are Emkephalins released?
mucosa and smooth muscle of GI tract
What are the functions of Enkephalins?
stimulate smooth muscle contraction and inhibit intestinal secretions
What are the main paracrine molecules?
somatostain and histamine
What are the actions of somatostatin?
inhibits gastrin release and basically all other hormone release (glucagon, insulin, growth hormone, etc.)
Where is somatostatin released from?
GI mucosa and pancreatic D cells
What are some releasers of somatostatin?
NOTE: Vagus nerve inhibits release
What are the main functions of histamine in the GI?
stimulates acid secretion (gastrin can directly act on parietal cells to some extent but mainly promote acid release by stimulating histamine)
Where is histamine released in the GI?
oxyntic gland mucosa ECL-cell
What are the main releasers of histamine in the GI?
gastrin and Ach
What are the main releasers of GIP?
protein, fat, and carbs
What are the main releasers of Motilin?
nerve primarily, and
some fat and acid
What is Zollinger-Ellison Syndrome?
A syndrome marked by a gastrinoma, a gastrin-secreting tumor that can occur in the pancreas, although it is most commonly found in the duodenum
Where do most gastrinomas occur?
More than 80% of gastrinomas arise within the triangle defined as the confluence of the cystic and common bile duct superiorly, the second and third portions of the duodenum inferiorly, and the neck and body of the pancreas medially.
Those occurring in the pancreas have a greater potential for malignancy
What is the clinical triad of Zollinger-Ellison syndrome?
Duodenal ulcers, diarrhea, and steatorrhea
What causes the diarrhea seen in ZES?
The acidic content of the small intestine causes the release of secretin, which is responsible for the diarrhea, in part, caused by the outpouring of water and bicarbonate from the pancreas and small intestine.
Excessive HCl acid production also causes hyperperistalsis
What causes of steatorrhea seen in ZES?
the high amounts of acid cause inactivation of pancreatic lipase causing decreased absorption of fat, leading to increased fat in feces
What is Werner-Morrison Syndrome?
Aka VIPoma, this is a rare endocrine tumor, usually (about 90%) originating from non-β islet cell of the pancreas, that produce vasoactive intestinal peptide (VIP). It may be associated with multiple endocrine neoplasia type 1.
How does a VIPoma present?
The massive amounts of VIP in turn cause profound and chronic watery diarrhea and resultant dehydration, hypokalemia, achlorhydria (hence WDHA-syndrome, or pancreatic cholera syndrome), metabolic acidosis, vasodilation (flushing and hypotension), hypercalcemia and hyperglycemia.