1. Physiology Gastrointestinal System
Dr. LL Wang

2. INTRODUCTION Gastrointestinal System includes
GI tract plus the accessory organs.
Digestion of food and absorption of nutrients are accomplished in a long tube connected to the external world at both ends; secretion and motility of “the tube” are major themes in understanding the gut.

3. Functions of Gastrointestinal System
Four processes carried out by the GI tract
Moisten food
Lubrication
Polysaccharide-digesting enzyme
Move food and lubricate
Store, mix, dissolve, digestion;emptyof dissolved food
Secretion of enzyme and bicarbonate
Digest carbohydrates ,fats, proteins and nucleic acids
Elimination in feces
propulsion
defecation
Amylase
Chemoreceptor
React with chemoreceptor, sensation of taste
lysozyme
Functions of Gastrointestinal System .

4. Smooth Muscle of the Gut
(1) General properties
Low excitability
High extensibility
Tonic contraction
Autorhythmicity
High sensitivity to temperature, stretch & chemical stimulation
Distensibility
Musculature
Insensitive to electrical stimuli
Tonic contraction:weak and contiunal contraction,
1)makes pressure in the tublar tract
2) Maintain the shape and location of GI tract
3)basis of other movement

5. (2) Electrophysiological properties
(a) Resting potential:
between -50 and -60 Mv
Ionic basis
Em (selective membrane permeability to K+)
Electrogenic Na+-K+ pump
Like other excitable cells, gastrointestinal smooth muscle cells maintain a electrical potential difference across their membranes.
The resting membrane potential of smooth muscle cells is between -50 and -60 mV.
In contrast to nerves and other types of muscle cells, the membrane potential of smooth muscle cells fluctuates spontaneously. These partial depolarizations are equivalent to fluctuations in membrane potential of 5 to 15 mV.
Fluctuation [ 7flQktju5eiFEn ] n.波动, 起伏
Fluctuate [ 5flQktjueit ] vi.变动, 波动, 涨落, 上下, 动摇
Basal [ 5beisl ] adj.基础的, 基本的, 基部的, 构成基部的

6. (b) Slow wave (basic electrical rhythm,BER)
The spontaneous rhythmic, subthreshold depolarizations of the cell membrane (slow wave) of the gastrointestinal tract
Initiated in the interstitial cells of Cajal (ICC) (pacemaker cell)

7. Intensity: 5~15 mV Frequency: 3~12 cpm Ionic mechanism
Slow wave (basic electrical rhythm)
Intensity: 5~15 mV
Frequency: 3~12 cpm
Ionic mechanism
spontaneous rhythmic changes in Na+-K+ pump activity

8. Frequencies: 3-12 per minute
cpm: cycles per minute
The figure below depicts the varying frequencies throughout the stomach and bowel.
BER varies in resting membrane potential 3-12 cycles per minute depending on area of GI tract: stomach = 3/min, small intestine = 12/min
Jejunum [ dVi5dVu:nEm ] n.[解]空肠
Ileum [ 5iliEm ] n.[解]回肠

9. BER not generated by nervous activity
Mechanisms
BER might be due to spontaneous rhythmic changes in Na+-K+ pump activity
BER not generated by nervous activity
Mechanisms
Its important to remember that slow waves are electrical activity in muscle and are not generated by nervous activity.
origins of fluctuations unknown – may be differential activity of pumps and differential factors gating channels in pacemaker cells

10. always present but do not always cause contraction
Features of slow waves
always present but do not always cause contraction
dictate frequency of contractions
frequency and height modulated by
body temp & metabolic activity
intrinsic & extrinsic nerves
circulating hormones
It’s important to note that slow waves do not produce contractions unless action potentials are triggered EXCEPT in the stomach, where slow wave depolarization can cause contraction without action potentials. So slow waves Always present but do not always cause contractions.
The important feature of the BER is that it regulates the frequency of contractile waves in different parts of the gastrointestinal tract.  
Slow wave frequency and height modulated by
body temp& metabolic activity
intrinsic & extrinsic nerves (increased by Ach,SP; decreased by noradrenaline, NO, VIP)
circulating hormones (CCK, motilin)

11. (c) Spike potentials (action potentials)
only at the peaks of slow waves
Threshold: –40 mV

12. Duration: 10~20 ms Ionic mechanism: Depolarization: Ca2+ influx
Spike potential (Action potential)
Duration: 10~20 ms
Ionic mechanism:
Depolarization: Ca2+ influx
Repolarization: K+ efflux

13. The higher the slow wave potential rises, the greater the frequency of the spike potentials
"spike potentials" - which occur only at the crests of slow waves
It occur when membrane potential rises above –40 mV (a threshold)
The higher the potential rises above threshold, the greater the number of spike potentials
Spike potentials are true action potentials that elicit muscle contraction.
Mechanism: induces movement of Ca2+ into the cell (calcium-sodium channel), and can thereby lead to vigorous muscle contraction.

14. (3) muscle contraction
Ca2+ binds to calmodulin (intracellular protein)  activates myosin light chain kinase  phosphorylates myosin light chain  phosphorylated myosin then (in the presence of ATP) binds to actin
in smooth muscle regulation of contraction occurs by the phosphorylation state of the myosin molecule:
Ca++ binds to calmodulin (intracellular protein)  activates myosin light chain kinase  phosphorylates myosin light chain  phosphorylated myosin then (in the presence of ATP) binds to actin
smooth muscle has little troponin, so contraction occurs by the action of calmodulin on smooth muscle myosin. Calcium binds to calmodulin, which then acts to activate an protein kinase which can act on myosin, myosin kinase. This kinase phosphorylates myosin, resulting in muscle contraction. SMC remain contracted while Ca concentration is high in the cells (>10-6M), and only relaxes when Ca falls (<10-6M).

15. Innervation of the Gut Enteric nervous system Extrinsic nervous system
Control over gastrointestinal function is provided by nervous and endocrine systems.
The innervation of the GI tract is mainly through the autonomic nervous system i.e. it is generally not under conscious control.
The motor innervation of the gut consists of two major parts, the intrinsic or enteric nervous system, and the extrinsic nervous system.
Intrinsic [ in5trinsik ]
Extrinsic [ eks5trinsik ]
Enteric [ en5terik ] adj.肠的

16. Myenteric plexus : control over GI motility
Function
Myenteric plexus : control over GI motility
Submucous plexus: regulate gastrointestinal blood flow and control GI secretion
The principal components of the enteric nervous system are two networks or plexuses of neurons, both of which are embedded in the wall of the digestive tract and extend from esophagus to anus:
The myenteric plexus is located between the longitudinal and circular layers of muscle in the tunica muscularis and, appropriately, exerts control primarily over digestive tract motility.
The submucous plexus, as its name implies, is buried in the submucosa. Its principal role is in sensing the environment within the lumen, regulating gastrointestinal blood flow and controlling GI secretion. ( In regions where these functions are minimal, such as the esophagus, the submucous plexus is sparse and may actually be missing in sections. )
Myenteric
Submucous

17. Local reflex

18. Ach: Stimulatory NE: inhibitory
Neurotransmitters secreted by enteric neurons
Ach: Stimulatory
NE: inhibitory
Others: Substance P, Nitric oxide , Vasoactive intestinal polypeptide (VIP), Opioid peptide, serotonin, histamine, ATP…
The intrinsic nervous system signals through multiple different transmitters, the primary ones being acetylcholine and vasoactive intestinal polypeptide. For example: acetylcholine (Ach), norepinephine (NorEpi) and epinephrine (Epi), nitric oxide (NO), vasointestinal peptide (VIP), ATP, substance P, seratonin, dopamine, cholecystokinin (CCK), somatostatin, effects of many unknown
Ach = excitatory in gut
NorEpi and Epi = inhibitory in gut
NO, VIP, ATP act locally to relax smooth muscle (decrease peristalsis) and increase local blood flow – promotes absorption
Substance P – increases peristalsis
Serotonin [ 7siErE5tEunin ] n.含于血液中的复合胺

19. Gastrointestinal Hormone
The hormones synthesized by a large number of endocrine cells within the gastrointestinal tract
Brain-gut peptides: a number of the classical GI hormones are also synthesized in the brain
There are a bunch of hormones, neuropeptides and neurotransmitters that affect gastrointestinal function.
Interestingly, a number of the classical GI hormones are also synthesized in the brain, and sometimes referred to as "brain-gut peptides". The significance of this pattern of expression is not clear.

20. Physiological functions control of the digestive function
the release of other hormones
trophic action
Trophic [ 5trCfik ] adj.营养的, 有关营养的

21. Five major GI hormones Gastrin Cholecystokinin Secretin
Gastric inhibitory polypeptide (GIP)
motilin
Gastrin - Synthesized in G cells
Cholecystokinin - Synthesized in I cells
Secretin – Synthesized in S cells
Gastrin [ 5^Astrin ] n.[医]胃泌激素
Cholecystokinin [`kClI9sIstE`kaInIn] n.[生化]缩胆囊素,缩胆囊肽, 肠促胰酶肽
Secretin [ si5kri:tin ] n.分泌素
Polypeptide [ 7pCli5peptaid ] n.[生化]多肽

22. DIGESTION IN STOMACH

23. Gastric Secretion Specialized cells in the stomach synthesize and
secrete mucous
fluid, enzyme precursors,
hydrochloric acid,
and hormones.
Note esophageal sphincter correction.
The abundant smooth muscle in the
stomach is responsible for gastric motility.

24. Chief cells synthesize and secrete the protease precursor known as pepsinogen.
Parietal cells synthesize and secrete the hydrochloric acid responsible for the acidic pH in the gastric lumen.

25. (i)Composition and Function
Properties
pH 0.9~1.5
1~2.5 L/day
Major components
Hydrochloric acid
Pepsinogen
Mucus
Intrinsic factor

26. (1) Hydrochloric acid Secreted by the parietal cells Output
Basal: 0~5 mmol/h
Maximal: 20~25 mmol/h

27. Mechanism of HCl secretion
HCl is actively secreted against a huge concentration gradient
H+/K+ ATPase or "proton pump"

28. Four chemical messengers regulate HCl secretion
One inhibitory and
three stimulatory
signals that alter
acid secretion by
parietal cells
in the stomach.
p595

29. Role of HCl
Acid sterilization
Activation of pepsinogen
Promotion of secretin secretion
Assisted effect of iron and calcium absorption

30. (2) Pepsinogen
Secreted by the chief cells as an inactive precursor of pepsin
Activated in the stomach, initially by H+ ions and then by active pepsin, autocatalytic activation
Active pepsin (MW: 35,000)

31. The acidity in the gastric lumen converts the protease precursor pepsinogen to pepsin; subsequent conversions occur quickly as a result of pepsin’s protease activity.

32. Effect of pepsin
Pepsin is an endopeptidase, which attacks peptide bonds in the interior of large protein molecules
Proteins
Proteoses
Peptones
Polypeptides
Pepsin

33. (3) Mucus
Secreted by the epithelial cells all over the mucosa and by the neck mucus cells in the upper portion of the gastric glands and pyloric glands

34. Role Lubrication of the mucosal surface
Protection of the tissue from mechanical damage by food particles
Mucus:
Mucus is secreted by the epithelial cells all over the mucosa of mlumenal surface and by the “neck mucus cells” in the upper portion of the gastric glands & pyloric glands.
It is deposited as a layer ~500 m thick on the surface of the mucosa.
MUCUS is composed chiefly of mucins and inorganic salts suspended in water
a layer ~500 m thick
composed chiefly of mucins

35. Mucus-HCO3- barrier
Epithelial cells and neck mucus cells secrete a bicarbonate-rich mucus that coats and lubricates the gastric surface
Serves an important role in protecting the epithelium from acid and other chemical insults. The mucus layer also traps HCO3- secreted by the mucosal cells and this buffers, or chemically insulates, the mucosa from the acidic stomach contents.

36. (4) Intrinsic factor
A high molecular weight glycoprotein, synthesized and secreted by the parietal cells
The intrinsic factor binds to Vit B12 and facilitates its absorption

38. (5) Secretion of other enzymes
Gastric lipase
Gastric amylase
Gelatinase

39. (ii) Regulation of Gastric Secretion
(1) Basic factors that stimulate gastric secretion
Acetylcholine (+ all secretory cells)
Gastrin (+ parietal cells)
Histamine (+ parietal cells)

40. ‘Short’ reflex pathways
(2) Nervous regulation
‘Short’ reflex pathways
‘Short’ excitatory reflexes: mediated by cholinergic neurons in the plexuses
‘Short’ inhibitory reflexes: mediated by non-adrenergic non-cholinergic (NANC) neurons

41. ‘Long’ autonomic pathways
(2) Nervous regulation
‘Long’ autonomic pathways
‘Long’ excitatory reflexes: parasympathetic
‘Long’ inhibitory pathways: sympathetic

42. 5-hydroxytryptamine (5-HT) Prostaglandin
(3) Humoral regulation
Excitatory
ACh
Histamine
Gastrin
Inhibitory
Somatostatin
Secretin
5-hydroxytryptamine (5-HT)
Prostaglandin

43. (4) Phases of gastric secretion
Cephalic phase
Gastric phase
Intestinal phase

45. (5) Inhibition of gastric secretion
The functional purpose of the inhibition of gastric secretion by intestinal factors is presumably to slow the release of chyme from the stomach when the small intestine is already filled or overactive

46. Gastric Motility Proximal stomach cardia Distal stomach antrum fundus
corpus (body)
Distal stomach
antrum
pylorus
pyloric sphincter

47. Receptive relaxation
Storage function (1.0~1.5 L)
Vago-vagal reflex
Peristalsis
BER in the stomach

48. Waves of smooth muscle contraction mix and propel the
ingested contents of the gastric lumen, but only a small amount of the material enters the small intestine (duodenum) as a result of each wave cycle.

49. Emptying of the stomach
Emptying rate
Fluid > viscous
Small particle > large particle
Isosmotic > hyper- & hypo-osmotic
Carbohydrates > Protein > Fat
Regular meal 4～6 hrs

50. Regulation of stomach emptying
Gastric factors that promote emptying
Gastric food volume
Gastrin
Duodenal factors that inhibit stomach emptying
Enterogastric nervous reflexes
Fat
Cholecystokinin

51. Pancreatic Secretion

52. The exocrine cells in the pancreas play a central role in the production of digestive enzymes; the endocrine functions of the pancreas will be discussed at length in Chapter 16.

53. (I) Pancreatic Secretion
pH 7.8~8.4
~1500 ml/day
Isosmotic
Components:
Pancreatic digestive enzymes: secreted by pancreatic acini
Sodium bicarbonate: secreted by small ductules and larger ducts

54. Were digestive enzymes synthesized in their active form, they would digest the very cells that make them. Hence, inactive precursors (e.g., trypsinogen) become activated (trypsin).

55. Secretion of bicarbonate ions
Secreted by the epithelial cells of the ductules and ducts that lead from acini
Up to 145mmol/L in pancreatic juice (5 times that in the plasma)
Neutralizing acid entering the duodenum from the stomach

57. Secretion of pancreatic digestive enzymes
Carbohydrates -- Pancreatic amylase
Pancreatic lipase (coplipase)
Fat Cholesterol esterase
Phospholipase
Trypsinogen
Proteins Chymotrypsinogen
Procarboxypolypeptidase
Proelastase
-RNAase
-DNAase

58. Starches
Pancreatic amylase
Maltose and
glucose polymers

61. Trypsin Inhibitor
Inhibits the activity of trypsin and thus guards against the possible activation of trypsin and the subsequent autodigestion of the pancreas

62. Acute pancreatitis

63. (II) Regulation of pancreatic secretion
Basic stimuli that cause pancreatic secretion
Ach
Cholecystokinin:
Secreted by I cells
Stimulates the acinar cells to secrete large amounts of enzymes
Secretin:
Released by S cells
Acts primarily on the duct cells to stimulate the secretion of a large volume of solution with a high HCO3- concentration

64. Phases of pancreatic secretion
Cephalic Phase: taste of food- ‘long’ parasympathetic pathways
Gastric Phase: distension of stomach- ‘long’ parasympathetic reflex pathways
Intestinal Phase
The most important regulators are CCK and secretin
Acid, fats, amino acids, peptides and protein are the main stimulus for pancreatic production and secretion

65. Bile Secretion

66. Composition of bile HCO3- Bile salts Lecithin Cholesterol
Bile pigments
Trace metals …
The bile is funneled into the gallbladder and then delivered into the duodenum upon stimulation from CCK.

67. Function of bile Bile salts are facial amphipathic
(1) Bile are critical for digestion and absorption of fats and fat-soluble vitamins
Bile salts are facial amphipathic
There are two fundamentally important functions of bile in all species:
Bile contains bile acids, which are critical for digestion and absorption of fats and fat-soluble vitamins in the small intestine.
Because:
Bile salts are derivatives of cholesterol synthesized in the hepatocyte.
The most abundant of the bile salts in humans are cholate and deoxycholate, They are then conjugated to an amino acid (glycine or taurine) to yield the conjugated form that is actively secreted into cannaliculi.
Bile acids are facial amphipathic, that is, they contain both hydrophobic (lipid soluble) and polar (hydrophilic) faces.

68. "Looking at you with a jaundiced eye"
(2) Eliminate many waste products
Excrete bile pigments or drug metabolites
"Looking at you with a jaundiced eye"
2. Many waste products are eliminated from the body by secretion into bile and elimination in feces.
The liver is well known to metabolize and excrete into bile many compounds and toxins, thus eliminating them (usually) from the body.
One of the most important and clinically relevant examples of waste elimination via bile is that of bilirubin.
is a useless and toxic breakdown product of hemoglobin.
The dead and damaged red blood cells are picked up by phagocytic cells throughout the body (including Kuppfer cells in the liver) and digested.
Within the phagocytic cells, heme is converted through a series of steps into free bilirubin, which is released into plasma where it is carried around bound to albumin, itself a secretory product of the liver.
Free bilirubin is stripped off albumin and absorbed by - you guessed it - hepatocytes. Within hepatocytes, free bilirubin is conjugated to either glucuronic acid or sulfate - it is then called conjugated bilirubin
Conjugated bilirubin is secreted into the bile canaliculus as part of bile and thus delivered to the small intestine.
Bacteria in the intestinal lumen metabolize bilirubin to a series of other compounds which are ultimately eliminated either in feces or, after reabsortion, in urine. The major metabolite of bilirubin in feces is sterobilin, which gives feces their characteristic brown color.
If excessive quantities of either free or conjugated bilirubin accumulate in extracellular fluid, a yellow discoloration of the skin, sclera and mucous membranes is observed - this condition is called icterus or jaundice. Determining whether the excessive bilirubin is free or conjugated can aid in diagnosing the cause of the problem.
Bilirubin (useless and toxic breakdown product of hemoglobin)

69. 90% of gallstones are of cholesterol stones
(3) Prevent the precipitation of cholesterol in the gallbladder and eliminate excess cholesterol
Secretion into bile is a major route for eliminating cholesterol.
Free cholesterol is virtually insoluble in aqueous solutions, but in bile, it is made soluble by bile acids and lipids like lethicin.
In humans, roughly 500 mg of cholesterol are converted to bile acids and eliminated in bile every day. This route for elimination of excess cholesterol is probably important in all animals, but particularly in situations of massive cholesterol ingestion.
Bile Preventing the cholesterol precipitation
Gallstones
Gallstones are concretions that form in the biliary system, usually the gallbladder.
About 90% of gallstones are of cholesterol stones. These stones can be almost pure cholesterol or mixtures of cholesterol and substances such as mucin.
The key event leading to formation and progression of cholesterol stones is precipitation of cholesterol in bile
90% of gallstones are of cholesterol stones

70. (4) Increasing bile synthesis & secretion
Up to 95% of the cholesterol-based bile salts are “recycled” by reabsorption along
the intestine.
Enterohepatic circulation
(5) neutralize the stomach acid

71. Regulation of bile secretion
Substances increasing bile production
Bile salts
Secretin
Cholecystokinin
parasympathetic input
The flow of bile is lowest during fasting, and a majority of that is diverted into the gallbladder for concentration.
When chyme from an ingested meal enters the small intestine, acid and partially digested fats and proteins stimulate secretion of and.

72. Absorption in the gastrointestinal tract

73. (I) Basic principle of absorption
Almost all absorption of nutrients occurs in the small intestine

74. 1. Absorptive surface of small intestinal mucosa
Total area of 250 m2:
Folds: 3-fold
Villi: 10-fold
Microvilli: 20-fold

75. 2. Absorption pathways transcellular route paracellular route
There are two routes for transport across the epithelium of the gut:
Across the plasma membrane of the epithelial cells (transcellular route)
Across tight junctions between epithelial cells (paracellular route)

76. Thank you!