1. Gastrointestinal Physiology Xia Qiang, PhD Department of Physiology Zhejiang University School of Medicine Email: xiaqiang@zju.edu.cn

3. Introduction  Basic processes of digestion and absorption Propulsion and mixing of food in the alimentary tract Secretory functions of the alimentary tract Digestion and absorption in the gastrointestinal tract

5. The four processes carried out by the GI tract: digestion, secretion, absorption, and motility.

6. Many functions in the gut are found in specific locations along its length. Most of the absorption of nutrients occurs in the small intestine, so most of digestion is accomplished there or upstream.

7. Functions of the digestive system  Movement: propels food through the digestive system  Secretion: release of digestive juices in response to a specific stimulus  Digestion: breakdown of food into molecular components small enough to cross the plasma membrane  Absorption: passage of the molecules into the body's interior and their passage throughout the body  Elimination: removal of undigested food and wastes

8. Anatomy: Components of the digestive system

9. Structure of the alimentary canal

11. General properties of gastrointestinal smooth muscle  Low excitability  High distensibility  Tonic contraction  Autorhythmicity  High sensitivity to temperature, stretch and chemical stimulation

12. Electrophysiological properties of gastrointestinal smooth muscle  Resting membrane potential -40~-80 mV Ionic basis  Em (selective membrane permeability to K +, Na +, Cl - and Ca 2+ )  Electrogenic Na + -K + pump

14.  Slow wave (basic electrical rhythm) The spontaneous rhythmic, subthreshold depolarizations of the cell membrane (slow wave) of the gastrointestinal tract that characterizes the underlying electrical activity of the bowel Initiated in the interstitial cells of Cajal (ICC) (pacemaker cell)

15. Santiago Ramon Y Cajal  He and Camillo Golgi received the Nobel Prize in 1906 for introduction of the silver-chromate stain

16. Calcium imaging in ICC-MY from the guinea-pig antrum. A colocalization procedure was used to identify the Rhod-2 signal from ACK2-Alexa 488 labelled ICC-MY. Panel A shows a stack of 30 sequential optical sections made in the Z optical axis of the ACK2-Alexa 488 signal and the Rhod-2 signal; panels B and C show each signal independently. Panel D shows the stack after the colocalization algorithm was used on each confocal slice, showing that most ICC-MY were well labelled with Rhod-2. It was evident from this experiment that some, but not all, ICC-MY were well-labelled with Rhod-2 (see text for more details). The scale bar in panel D is 40 um and it applies to all images

17. Intracellularly recorded electrical activity from a guinea-pig antral ICC-MY identified with ACK2-Alexa 488. Panel A shows a network of ICC-MY labelled with ACK2-Alexa 488 visualized using fluorescence microscopy, and a single ICC- MY impaled with a LY-filled microelectrode. Panel B shows changes in membrane potential recorded intracellularly from an ICC-MY. One slow wave, marked with the horizontal line in Panel B, is shown in Panel C at an expanded time scale. The scale bar is 15 um.

18. Cyclic changes in intracellular calcium in ICC-MY in the murine jejunum. Panel A shows a single confocal image with ACK2-Alexa 488 immunore- activity (green) and Rhod-2 labelling (red) taken from a time series. ICC- MY were distinctly labelled with Rhod-2 as shown in panel B. The average fluorescence intensity delineated by the white circled region was measured from images recorded every second, shown in panel C

19.  Slow wave (basic electrical rhythm) Intensity: 10~15 mV Frequency: 3~12 cpm Ionic mechanism  spontaneous rhythmic changes in Na + -K + pump activity

21. Normal BER frequencies in the gastrointestinal system

22.  Spike potential (Action potential) Duration: 10~20 ms Ionic mechanism:  Depolarization: Ca 2+ influx  Repolarization: K + efflux

24. Neural control of gastrointestinal function  Enteric nervous system (intrinsic)  Autonomic nervous system (extrinsic)

27.  Enteric (Intrinsic) nervous system Myenteric plexus (Auerbach’s plexus) Submucosal plexus (Meissner’s plexus)  Neurotransmitters secreted by enteric neurons Ach, NE, ATP, serotonin, dopamine, cholecystokinin, substance P, vasoactive intestinal polypeptide, somatostatin, leu-enkephalin, met-enkephalin, bombesin, etc.

30. Sympathetic nerve NE Inhibitory (-) Autonomic nervous system Parasympathetic nerve Mainly ACh Stimulatory (+)

31.  Afferent sensory nerve fiber from the gut Sensory fibers with their cell bodies in the ENS terminate in the ENS Sensory fibers with their cell bodies in the ENS send axons upward through the ANS to terminate in the prevertebral sympathetic ganglia Sensory fibers with their cell bodies in the dorsal root ganglia or in the cranial nerve ganglia send axons to multiple area of the spinal cord or brain stem

33.  Gastrointestinal reflexes Three types  Reflexes that are integrated entirely within the enteric nervous system  Reflexes from the gut to the prevertebral sympathetic ganglia and then back to the gastrointestinal tract  Reflexes from the gut to the spinal cord or brain stem and then back to the gastrointestinal tract

34. Gastrointestinal hormones  The hormones synthesized by a large number of endocrine cells within the gastrointestinal tract  Physiological functions Control of the digestive function Control of the release of other hormones Trophic action

35. Gastrointestinal hormones  Four main types Gastrin Secretin Cholecystokinin (CCK) Gastric inhibitory peptide (GIP)

38. Splanchnic circulation

39. Microvasculature of the intestinal villus

40. Digestion in the stomach

41. The swallowing reflex is coordinated by the medulla oblongata, which stimulates the appropriate sequence of contraction and relaxation in the participating skeletal muscle, sphincters, and smooth muscle groups.

42. The coordinated sequence of contraction and relaxation in the upper esophageal sphincter, the esophagus, and the lower esophageal sphincter is necessary to deliver swallowed food to the stomach.

43. The abundant smooth muscle in the stomach is responsible for gastric motility. Specialized cells in the stomach synthesize and secrete mucous fluid, enzyme precursors, hydrochloric acid, and hormones.

46. Gastric juice  Properties pH 0.9~1.5 1.5~2.5 L/day  Major components Hydrochloric acid Pepsinogen Mucus Intrinsic factor

47. Hydrochloric acid  Secreted by the parietal cells  Output Basal: 0~5 mmol/h Maximal: 20~25 mmol/h

49.  Mechanism of HCl secretion Active transport Huge H + gradient (3 million)

50. Acid production by the parietal cells in the stomach depends on the generation of carbonic acid; subsequent movement of hydrogen ions into the gastric lumen results from primary active transport.

51. One inhibitory and three stimulatory signals that alter acid secretion by parietal cells in the stomach.

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

54. Pepsinogen  MW: 42,500  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)

55. 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.

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

57. 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  Role Lubrication of the mucosal surface Protection of the tissue from mechanical damage by food particles

59. Mucus-HCO 3 - barrier

61. Intrinsic factor  A high molecular weight glycoprotein, synthesized and secreted by the parietal cells  The intrinsic factor binds to Vit B 12 and facilitates its absorption

64. Secretion of other enzymes  Gastric lipase  Gastric amylase  Gelatinase

65. Regulation of gastric secretion  Basic factors that stimulate gastric secretion Acetylcholine (+ all secretory cells) Gastrin (+ parietal cells) Histamine (+ parietal cells)

66. Regulation of gastric secretion  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

67. Regulation of gastric secretion  Nervous regulation ‘Long’ autonomic pathways  ‘Long’ excitatory reflexes: parasympathetic  ‘Long’ inhibitory pathways: sympathetic

68. Regulation of gastric secretion  Humoral regulation Excitatory ACh Histamine Gastrin Inhibitory Somatostatin Secretin 5-hydroxytryptamine (5-HT) Prostaglandin

69. Phases of gastric secretion  Cephalic phase  Gastric phase  Intestinal phase

72. 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

73. Inhibition of gastric secretion  Reverse enterogastric reflex: initiated by the presence of food in the small intestine  Secretin secretion: stimulated by the presence of acid, fat, protein breakdown products, hyperosmotic or hypo-osmotic fluids, or any irritating factors in the upper small intestine

74. Delivery of acid and nutrients into the small intestine initiates signaling that slows gastric motility and secretion which allows adequate time for digestion and absorption in the duodenum.

75. Motor function of the stomach Proximal stomach cardia fundus corpus (body) Distal stomach antrum pylorus pyloric sphincter

76. 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.

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

78. Contractions in the empty stomach  Migrating Motor Complex (MMC) Periodic waves of contraction, which move along the gastrointestinal tract from stomach to colon Purpose of this activity: to ‘sweep’ debris out of the digestive tract during the interdigestive period MMCs can lead to hunger contractions, which are associated with discomfort, referred to as ‘hunger pains’

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

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

83. Vomiting

84. End.