GI System (Wayne--Week 1, 2) Flashcards
Mouth
Chewing and some amylase begin digestion
Swallowing
Esophagus
Propels food to stomach
Secretes mucus
Stomach
Stores, mixes, dissolves, continues digestion of food
Regulates gastric emptying
Kills some microbes
Secretes: HCl, pepsinogen, intrinsic factor, mucus
pH 2 or below after eating food??
Small intestine
Digestion and absorption, mixing luminal contents, propel contents toward large intestine
Secretes: CCK, ??, water, salt, mucus
Large intestine
Store and concentrate undigested material
Absorb salt and water
Mix and propel contents
Defecation
Secretes: mucus
Salivary glands
Parotid (CN IX), submandibular (CN VII), sublingual (CN VII)
Secrete hypotonic solution to moisten food
Secrete mucus to lubricate food
Secrete amylase to digest polysaccharides
Xerostomia = dry mouth; sialorrhea = excessive salivation
Pancreas
Secretes many enzymes into small intestine to digest carbohydrates, proteins, fats, nucleic acid
Secretes bicarbonate to neutralize HCl entering small intestine from stomach
(Exocrine pancreas)
Liver
Secretes bile into gallbladder
Secretes bicarbonate to neutralize HCl entering small intestine from stomach
Detoxifies and allows organic waste products and materials to be eliminated in feces
Gallbladder
Stores and concentrates bile between meals (releases bile into small intestine in response to fatty meal)
Regulation of GI functions
1) Neural regulation (extrinsic and enteric nervous systems)
2) Hormone and paracrine regulation
Hormones of GI system
Gastrin
CCK
Secretin
GIP
Motilin
Ghrelin
Paracrine factors of GI system
Somatostatin
Histamine
Cholecystokinin (CCK)
Secreted by I cells of small intestine
Stimulated by chyme coming into small intestine from stomach containing fat/triglycerides (most important) and proteins
Inhibits gastric emptying
Stimulates small intestine motility
Stimulates pancreas to secrete enzymes
Stimulates gallbladder contraction and relaxation of Sphincter of Oddi
Negative feedback because as fat is digested, there is less of it in the small intestine to stimulate CCK secretion
Ghrelin
Secreted by P/D1 cells in the stomach (and some in small intestine)
Stimulated by fasting (ie between meals or overnight)
Stimulates HCl secretion from parietal cells, gastric emptying, motility
Stimulates appetite center in hypothalamus
Stimulates growth hormone secretion from pituitary
Histamine
Paracrine factor
Stimulated by gastrin
Secreted from ECL cells in body of stomach
Stimulates parietal cell HCl secretion (directly and by potentiating actions of gastrin and ACh)
Cephalic phase
Happens before any food reaches stomach (seeing, smelling, tasting, chewing, emotions)
by stimulation of receptors in the head
Parasympathetic efferent pathway activated (vagus efferent)–> enteric nerves activated (ACh) –> G cells secrete gastrin and parietal cells secrete HCl –> HCl and stomach motility prepare stomach in advance for food
Gastric phase
Happens when food enters the stomach
AAs and peptides stimulate: G cells to secrete gastrin (which stimulates parietal cells to secrete HCl and activates stomach motility)
Stomach distention stimulates: (1) Vagus nerve to stimulate enteric nervous system (ACh) and (2) mechnoreceptors to stimulate enteric nerves, which both stimulate parietal cells to secrete HCl and G cells to secrete gastrin
Note: caffeine directly stimulates parietal cells to secrete HCl
Intestinal phase
Happens when food bolus enters small intestine
Distention of small intestine, acidity, hyperosmolarity, fat/AAs stimulate extrinsic and enteric neural reflexes and cause secretion of secretin, CCK, GIP
Note: different response from cephalic phase and gastric phase!
Secretion of saliva
Stimulated by food in mouth, act of chewing, smell/thought of food (CN VII = submandibular and sublingual, CN IX = parotid, use ACh; sympathetic T1-T3 use NE)
Inhibited by dehydration, fear, sleep
Rate of secretion increased with larger bites of food or acidic foods
Both sympathetic and parasympathetic stimulate secretion (and there is no hormonal regulation)
Swallowing
Afferent from pharynx activate swallowing center in brainstem, then efferent from swallowing center stimulate pharyngeal muscles to contract proximal to distal–peristaltic contractions
1) Food into pharynx by tongue
2) Soft palate elevates
3) Epiglottis covers glottis and UES relaxes
4) Food enters esophagus, UES closes, glottis opens and breathing resumes
Anatomical and functional divisions of stomach
Anatomical: fundus is top, body is middle, antrum is bottom
Functional: top is orad (relaxes to accommodate food), bottom is caudad (peristalsis)
What is the only essential function of the stomach?
Only necessary function is secretion of intrinsic factor
Basal electric rhythm (slow waves)
Rhythmic fluctuations in membrane potential in caudad region of stomach that occur 3 times per minute (always)
Interstitial cells of Cajal (ICC) are what drive this pacemaker rhythm
If magnitude of plateau is low (sympathetic activation hyperpolarizes Vm) then lower frequency of AP firing during plateau and weaker contractions of caudad stomach
If magnitude of plateau is high (parasympathetic activation, gastrin and motilin all depolarize Vm) then higher frequency of AP firing during plateau and stronger contractions of caudad stomach
HCl in the stomach
Converts pepsinogen to pepsin
Kills ingested microbes
Causes high acidity which inhibits gastric emptying if chyme entering small intestine is very acidic
Mechanism of HCl secretion by parietal cells
Inside parietal cell, CO2 and H2O converted to H+ and HCO3- –> H+ active transport out into lumen via H/K ATPase –> Cl- enters (via active transport, against electrochemical gradient) into cell as HCO3- leaves –> Cl- channels on luminal side let Cl out also
More H/K ATPase means more H+ pumped out
Note: Don’t get buildup of H+ in cell when you block pumps because just don’t have driving force for reaction to create H+ anymore
What stimulates HCl secretion from parietal cells, and how?
Cephalic and gastric phases cause release of gastrin (from G cells) and ACh (from enteric nerves) –> gastrin acts directly on parietal cells and stimulates histamine secretion –> gastrin, histamine and ACh increase number of H/K ATPase inserted nto luminal membrane of parietal cells –> increased HCl secretion
1) Vagus/enteric nerves to parietal cells directly
2) Gastrin onto parietal cells directly
3) Gastrin to ECL cells to histamine to parietal cells
4) ACh onto parietal cells directly
Pepsin secretion
Pepsinogen is secreted from chief cells of stomach –> HCl (secreted from parietal cells) turns pepsinogen into pepsin –> pepsin also turns pepsinogen into pepsin (positive feedback) –> pepsin cleaves protein into peptides
How is vitamin B12 absorbed?
Different from other water soluble vitamins because it is not absorbed by diffusion or mediated transport
Vitamin B12 (VB) is bound to food –> pepsin optimizes release of VB, but is not necessary –> intrinsic factor (IF) forms a complex with VB in duodenum –> IF-VB complex binds receptor in ileum and is endocytosed into epithelial cells
Note: VB (aka cobalamin) necessary for RBC maturation, get pernicious anemia without VB
Causes of vomiting
Distention of stomach or small intestine (eat too much too fast)
Chemoreceptors in intestine wall and brain
Increased pressure in skull
Rotation of head (motion sickness)
Pain
Emotion
Tactile sensation at back of throat
Steps in vomiting
1) Autonomic discharge causes salivation, sweating, increased HR, skin pallor, nausea
2) Retching (deep breath, closure of glottis, elevation of soft palate, abdominal muscles contract, LES and body of stomach relax, stomach contents enter esophagus but UES closed so stomach contents do not go into mouth)
3) Vomiting (further increase in abdominal muscle contractions, large increase in intrathoracic pressure, stomach contents forced through UES and out mouth; can also have reverse peristalsis in upper small intestine so intestinal contents forced into stomach
What determines rate of gastric emptying into duodenum?
Quality of chyme:
1) High acidity –> enteric neural reflex –> contraction of pyloric sphincter
2) High fat content –> CCK secretion –> contraction of pyloric sphincter
3) Hyperosmotic chyme –> contraction of pyloric sphincter
Why is it important to slow gastric emptying?
1) Limit amount of acid in duodenum
2) Fatty/hyperosmotic chyme has enough time to be optimally digested
Sementation contractions in small intestine
Shortly after eating meal, when chyme enters small intestine
Rhythmic contractions that mix up luminal contents by dividing it up (NOT peristalsis)
Higher frequency of contractions at more proximal end and slower at distal end of small intestine
Peristaltic contractions in small intestine
Shortly after eating meal, when chyme enters small intestine
Wave of contractions that push bolus of chyme along (relaxation in front of bolus)
Migrating myoelectric complex (MMC) in small intestine
Happens during fasting, 1x every 90 minutes
Periods of brief intense contractions once every 90 minutes during otherwise period of quiescence
Sweeps undigested luminal contents from stomach through small intestine, and maintains low bacterial count in upper intestine
Note: if no MMC, then bacterial buildup in upper intestine and would get uncomfortable gas in places it shouldn’t be
What stimulates small intestine motility?
Motilin secreted during fasting stimulates MMC
CCK secreted during eating (fat) stimulates segmentation and peristalsis
Gastrin from stomach stimulates segmentation and peristalsis
Insulin from endocrine pancreas stimulates segmentation and peristalsis
Serotonin from EC cells after eating stimulates motility
What inhibits small intestine motility?
Epinephrine (due to stress –> sympathetic –> adrenal medulla) inhibits motility
To divert energy away from intestine and toward heart/lungs/etc that need it; if chronic stress, can get indigestion
How does the exocrine pancreas secrete HCO3-?
CO2 diffuses from blood into pancreatic duct cell –> H+ is pumped back into blood across serosal membrane via Na/H exchanger (due to Na gradient) –> HCO3-/Cl exchanged across luminal membrane to get HCO3- secreted into lumen
Open Cl- channels let Cl- out into lumen, which is key!
How is pancreatic HCO3- secretion hormonally controlled?
Secretin
Acid from stomach –> stimulates small intestine to secrete secretin (from S cells of duodenum) into bloodstream –> stimulates pancreas to secrete HCO3- (by increasing expression of Cl- channels and increasing open probability of Cl- channels) –> neutralization of intestinal acid
Negative feedback
How does the pancreas secrete enzymes into duodenum?
Enzymes secreted as zymogens to ensure that the pancreas doesn’t digest itself
Trypsinogen converted to trypsin by membrane bound enterokinase on intestinal epithelial cells
Trypsin converts other zymogens into active enzymes
Active pancreatic enzymes that digest proteins into peptides
Trypsin
Chymotrypsin
Elastase
Carboxypeptidase
Active pancreatic enzymes that digest emulsified fats into free fatty acids and monoglycerides
Lipase
Cholesterol ester hydrolase
Phospholipase A2
Active pancreatic enzymes that digest starch into disaccharides (converted to monosaccharides later by intestinal brush border enzymes)
Amylase
Active pancreatic enzymes that digest DNA and RNA into free nucleotides
Deoxyribonuclease
Ribonuclease
How is zymogen secretion by the pancreas hormonally controlled?
CCK
Intestinal fatty acids, AAs –> CCK secretion in small intestine –> increased secretion of zymogens
Negative feedback
What is bile for?
Solubilizes fat in small intestine (required for lipid absorption)
Bile composition
Bile salts (functionally most impt)
Phospholipids
Cholesterol
Bile pigments
Inorganic ions (Na, K, Ca, Cl, HCO3)
Bile salts (synthesis, secretion, recycling)
Synthesized in liver (only 5% needs to be synthesized)
Secreted from liver –> common bile duct –> gallbldder –> duodenum
95% of bile salts recycled (reabsorbed in ileum, returned to liver via enterohepatic circulation)
What stimulates bile release from gallbladder to duodenum?
CCK
Fatty acid in duodenum –> secretion of CCK –> gallbladder contraction, relaxation of Sphincter of Oddi
Between meals, is bile still secreted?
Bile is not secreted into the duodenum between meals because the Sphincter of Oddi is closed
However, bile is secreted from the liver into the gallbladder to be stored
How and when does chyme move from small to large intestine?
After a meal, there is reflex contraction of ileum –> ileocecal sphincter relaxes –> chyme enters cecum and distends cecum –> distention of cecum activates neural reflex that causes ilealcecal sphincter to contract (prevents fecal material from moving backward)
Why would it be bad for chyme to move backward from large to small intestine?
Lots of bacteria in large intestine, and don’t want that getting into small intestine
(If bacteria in small intestine, it would metabolize/ferment all the nutrients that we need to absorb!)
Segmentation contractions in large intestine
1x every 30 min to slowly propel fecal material through large intestine (takes 18-24 hours to go all the way through)
Note: segmentation contractions in large intestine do (slowly) move material, but segmentation contractions in small intestine do not move material, just mix
Mass movement contractions in the large intestine
Happens when you eat a meal (gastrocolic reflex)
Spreads rapidly across transverse segment of large intestine toward rectum
(makes you feel like you hav to go?)
Internal vs. external anal sphincter
Internal: smooth muscle; autonomic control
External: skeletal muscle; voluntary control
Defecation reflex
Mass movement of fecal material into rectum –> distention of rectum –> mechanoreceptor-mediated reflex –> contraction of rectum and relaxation of internal anal sphincter –> voluntary relaxation of external anal sphincter –> defecation
How does the small intestine have such a large surface area?
Villi
Microvilli-glycocalyx complex (brush border)
Carbohydrate digestion
Amylase in mouth, then intestine –> disaccharides
Enzymes on brush border: glucoamylase, sucrase, isomaltase, trehalase, lactase
End products are monosaccharides: glucose, galactose, fructose
How are monosaccharides absorbed?
Glucose: SGLT1 (Na/glucose cotransport into cell) –> GLUT2 (into blood)
Galactose: SGLT1 (Na/glucose cotransport into cell) –> GLUT2 (into blood)
Fructose: GLUT5 (facilitated diffusion down gradient) –> GLUT2 (into blood)
What is our body’s limit for glucose absorption?
22lbs of monosaccharides in 24 hours! HUUUGE!
We never reach our limit
Na+ is the limiting factor and we always have enough luminal Na+
Lactase deficiency
Cannot digest lactose –> lactose remains in gut –> osmotic diarrhea, gas (abdominal distention and pain), fermentation of lactose by bacteria in gut (so breathe out more hydrogen)
Most people (other than from Northern Europe) lose activity or amount of lactase bound to brush border (glycocalyx)
Cure: avoid dairy or take lactase pills so you can digest lactose
How are proteins digested and absorbed?
Digestion in stomach by pepsin (not necessary) and in small intestine by trypsin, chymotrypsin, elastase, carboxypeptidase –> large peptides, di/tri-peptides, free AAs –> large peptides further digested by peptidases into di/tri-peptides and free AAs –> secondary active transport to get di/tri-peptides and free AAs into cell –> some di/tri-peptides further digested by cytoplasmic peptidases –> di/tri-peptides and free AAs into blood by facilitated diffusion
Some proteins/large peptides are endocytosed/exocytosed to get into blood (mostly in infants)
Cystic Fibrosis effect on GI
Problem with Cl channel in pancreatic duct cells –> pancreatic insufficiency so can’t secrete pancreatic “juice” –> deficit in trypsin –> insufficient activation of zymogens –> deficit in protein, fat, carbohydrate digestion/absorption
Fat digestion
In small intestine, bile salts and phospholipids emulsify large fat globules into smaller pieces and prevent reaggregation –> lipase splits triglyceride into fatty acids and monoglyceride –> loosely held micelles are aggregates of fatty acids and monoglycerides (micelles easily break down though) –> fatty acid and monoglyceride enter epithelial cells by diffusion –> once inside cell, re-form triglyceride in smooth ER, enclosed in membrane –> exocytosed, combine with phospholipids, cholesterol, fat-soluble vitamins to form chylomicrons –> chylomicrons enter lacteals, go into lymphatic system to thoracic duct to veins –> circulating chylomicrons are source of triglycerides for fuel for cells of body
What are the deficits you get from insufficient lipase?
1) Deficit in fat digestion
2) Steatorrhea (fatty stool)
3) Malabsorption of fat soluble vitamins (need process of fat absorption to absorb these
Note: you get lipase insufficiency if you have chronic pancreatitis
Two barriers to pathogen invasion via the GI tract
1) Non-immune mechanisms
2) Intestinal immune system
Non-immune mechanisms of GI protection
1) Acidic stomach
2) Digestive enzymes, bile acids, antimicrobial peptides (??)
3) Mucus in GI lumen
4) Peristaltic contractions
5) Commensal bacteria in colon
Immune mechanisms of GI protection
Both innate and adaptive immunity in the gut
GALT: Peyer’s patches, tonsils/adenoids, salivary glands, appendix; intraepithelial lymphocytes in intestinal epithelium; lymphoid cells (mononuclear cells) in lamina propria
Peyer’s Patches
Afferent (sense invaders) component of GI immune system
Located in small intestine, highest density in terminal ileum
>/= 5 lymphoid follicles of T and B cells
Above Peyer’s patch is follicle associated epithelium with M cells (APC!) and dendritic cells (APC, obvi!)
M cells present to underlying follicles!
Intestinal epithelium
Made up of epithelial cells and intraepithelial lymphocytes (IELs)
Regular epithelial cells are APCs!
IELs between lumen and lamina propria (soooo, in epithelium..?), and are CD8+ T cells (secrete cytokines); first line of defense against pathogens
Lamina propria
Contains T cells, B cells, plasma cells (secrete IgA), macrophages, mast cells, eosinophils, neutrophils
What does IgA secreted by plasma cells of the lamina propria do?
Luminal IgA binds microbial/food antigens, viruses, and prevents intestinal absorption
Intracellular IgA in vesicles binds antigens and transports them to apical surface to be expelled from the cell into the lumen where there is luminal IgA waiting for them
Does NOT activate inflammation
How do infants have immunity?
IgA not produced until 5-6 months of age, and before this, baby gets IgA from mother’s milk
Mother ingests something with pathogen –> Peyer’s patch sends out lymphoid cells to lead immune response –> lymphoid cells get to all mucosal tissues including mammary glands and mount immune response, including IgA secretion –> secrete IgA into breast milk –> baby ingests IgA and has protection against that same antigen
Does the GI immune system protect other immune systems and vice versa?
Yes, GALT is connected to other MALTs
GALT –> lymphoid cell –> lymph vessel –> regional lymph nodes –> peripheral blood –> mucosal tissues’ MALT (nasal passages, airways, urogenital tract, mammary glantds)
Innate immune system of GI tract
Pattern recognition receptors on IELs, macrophages and DCs
Remember, GI tract in a constant state of low level inflammation because constantly innundated with foreign molecules (food, microbes)
Oral tolerance
Absence of peripheral immune response in presence of antigen-activated mucosal immune response and production of IgA
Oral tolerance to food antigens and commensal bacteria
Dependent on type of antigen, frequency, dose, and host factors (genetics, age)
Potential therapeutic use to treat auto-immune diseases
Oral tolerance mechanism not understood
Food allergy
Breakdown of normal mechanism of oral tolerance
Ingest food you see as foreign –> antigen binds to IgE on surface of mast cells in lamina propria, sensitization –> more antigen transported across epithelium into lamina propria –> next time food eaten, binding to IgE on mast cells causes secretion of chemicals that increase intestinal Cl- secretion and alter motility –> diarrhea
Allergic response to food triggers visceral hypersensitization (esp colorectal distention, which causes pain in colorectal compartment), so if distend colorectal compartment with balloon, they’re in a ton of pain compared to controls
Syetemic response to allergen –> anaphylaxis
Food sensitivity
Get abdominal pain and diarrhea, but this is not an allergy
Only way to know diff between food allergy and food sensitivity is to do immune test
Mechanism not understood
Intestinal “commensal” bacteria
400 different species in intestine
Highest concentration in colon, lowest in stomach
GI tract sterile at birth, but at 1 month, fully colonized intestines
Acquired from what we eat and drink
What are the benefits of commensal bacteria in the large intestine?
1) Important for development of mucosal immune system and mucosal epithelium proliferation and differentiation
2) Aid in metabolism of endogenous (bilirubin –> urobilogen; bile acids) and exogenous (dietary fiber, carbs, peptides) substances
3) Inhibit colonization of intestinal mucosa by pathogenic microbes by outcompeting for food
Antibiotics can cause diarrhea in humans, but what treatment can reduce this?
Probiotics (good bacteria found in yogurt)
Somatostatin
Secreted from D cells in antrum of stomach (paracrine) and pancreas and enteric nervous system interneurons (neurocrine)
Low pH in stomach stimulates secretion
Paracrine functions: inhibits G cells from secreting gastrin; inhibits parietal cells from secreting HCl; inhibits pepsinogen secretion; inhibits gastric emptying; inhibits histamine secretion from ECL cells (?)
Neurocrine: inhibits small intestine motility; inhibits zymogen secretion from pancreas; inhibits contraction of gall bladder
Released at highest rate during interdigestive phase (between meals)
ANTI-GROWTH HORMONE (inhibits digestion/absorption and these are needed for growth! Also directly causes GH not to be released…)
What is special about the ileum?
Where intrinsic factor/B12 are absorbed into bloodstream
Where bile salts are reabsorbed into bloodstream (to be recycled)
Also has highest density of peyer’s patches
Why does aspirin give you ulcers?
Aspirin is a COX2 inhibitor which means you won’t be able to produce prostaglandins
Prostaglandins are needed to decrease acid secretion by parietal cells
Prostaglandins are needed to increase mucus production by mucous cells
What are examples of parasympathetic postganglionic nerves that do NOT release ACh?
Para post neurons release NO and VIP to relax LES (smooth muscle)
Para post neurons release NO to relax blood vessels of corpus cavernosum (for erection)
Para post neurons release GRP onto G cells in the stomach to release gastrin
Note: these are called non-adrenergic non-cholinergic (NANC)
Glucose-dependent Insulinotropic Peptide/Gastric Inhibitory Peptide (GIP)
Hormone that is secreted by K cells in duodenum and jejunum of small intestine
Stimulated by protein, fat, carbohydrates (FOOD) in the duodenum and jejunum
Inhibits parietal cell HCl secretion
Stimulates insulin secretion
Acetylcholine as GI neurocrine
Secreted by sympathetic and parasympathetic preganglionic fibers and parasympathetic postganglionic fibers
Stimulates contraction of smooth muscle in wall of digestive tube
Inhibits contraction of digestive sphincters
Stimulates salivary gland acinar cell secretion
Stimulates parietal cell secretion of HCl in body of stomach
Stimulates ECL cells in body of stomach to secrete histamine
Stimulates pancreatic acinar cell secretion of zymogens and pancreatic ductal cell secretion of bicarbonate
NE as GI neurocrine
Secreted by sympathetic postganglionic fibers and small amount from adrenal medulla
Inhibits contraction of smooth muscle wall in intestine, resulting in wall relaxation and decreased motility
Stimulates contraction of digestive sphincters
Stimulates salivary gland acinar cell secretion
5HT as GI neurocrine
Secreted by enteric nervous system interneurons and EC cells in GI mucosa, and from brain
Stimulates intestinal wall motility
Activates vagal afferents (vomiting)
Vasoactive intestinal peptide (VIP) as GI neurocrine
Secreted by enteric nervous system interneurons
Inhibits contraction of smooth muscle in wall of small intestine, resulting in relaxation of wall and decreased motility
Inhibits smooth muscle contraction in splanchnic blood vessels, resulting in vasodilation
Stimulates intestinal Cl- and water secretion
Enkephalins as GI neurocrine
Secreted by enteric nervous system interneurons; brain
Stimulates contraction of LES, pyloric sphincter, ileocecal sphincter
Inhibits peristalsis in small intestine
Inhibits intestinal secretion
Contributes to contraction of Sphincter of Oddi and gallbladder
Note: enkephalins are a family of opioids (constipation)
Nitric oxide (NO) as GI neurocrine
Secreted by enteric nervous system interneurons
LES relaxation
Inhibits contraction of smooth muscle in wall of small intestine, resulting in relaxation of wall and decreased motility
Inhibits smooth muscle contraction in splanchnic blood vessels, resulting in vasodilation
