GI Physiology (2024) PDF

의료인공지능 융합인재양성 사업 Digestive system - 소화기계 생리 - Dept of Physiology Ajou University School of Medicine Digestion The breakdown of large insoluble food molecules into small water-soluble food molecules so that they can be absorb...

의료인공지능 융합인재양성 사업 Digestive system - 소화기계 생리 - Dept of Physiology Ajou University School of Medicine Digestion The breakdown of large insoluble food molecules into small water-soluble food molecules so that they can be absorbed into the watery blood plasma  Mechanical digestion  Chemical digestion  Regulation The four major processes  Motility  Secretion  Digestion  Absorption  Functional Anatomy and General Principles of Regulation Components of Digestive System (소화기관의 구성) Alimentary Canal (소화관) - about 8-9 m long tube of muscle - consisted of mouth (구강), pharynx (인두), esophagus (식도), stomach (위), small intestine (소장) and large intestine (대장) Auxillary Organs (부속 소화기관; gland 샘) - salivary gland (침샘), liver (간), gall bladder (담낭), pancreas (췌장) Structure and Function of the GI Tract (위장관계의 구조와 기능) Sphincters for one-directional motility Structure of the Gastrointestinal Tract myenteric (Auerbach's) submucosal plexus (Meissner's) plexus mucosa (점막), submucosa (점막하층), muscularis (근육층) and serosa (adventitia, 장막)  Structure of the GI Tract (소화관의 기본구조) 1) Mucosa (점막) - Function: tissue protection, secretion (mucus, enzyme), absorption Epithelial layer (상피층) Lamina propria (고유점막층: 결합조직) Muscularis mucosae (점막근판) 2) Submucosa (점막하층) - gland (분비샘), blood vessel, lymphatic duct, neurons, connective tissue Gland in submucosa (점막하샘) Submucosal (Meissner's) plexus (점막하신경총) 3) Muscularis (근육층) - segmentation, peristalsis Circular muscle (환상근, 윤주근) Longitudinal muscle (종주근) Myenteric (Auerbach's) plexus (근층간신경총) 4) Serosa (adventitia, 장막) - outer epithelium/connective tissue: secretes serous fluid (lubricant) Gastrointestinal Circulation (소화기계 혈액순환) ▪ Blood supply (혈류의 공급)  Splanchnic circulation (내장순환): Celiac artery (복강동맥), superior mesenteric artery (상창자간막동맥), inferior mesenteric artery (하창자간막동맥)  Portal veins (간문맥) Regulation of GI System (소화계의 조절) THREE MECHANISMS OF COMMUNICATION - Regulation: Motility and Secretion MEDIATE RESPONSES IN THE GI TRACT  Neural Regulation  Endocrine Regulation  Paracrine Regulation ▪ Intrinsic regulation - Intrinsic nervous system, GI hormones, paracrine, myogenic regulation (근원성 조절) ▪ Extrinsic regulation - Nervous system (autonomic NS), hormone  Neural Regulation (신경성 조절) 1. Enteric Nervous System (Intrinsic Nervous system, 내인성 신경계) : intramural plexuses (장내 신경총) ▪ Submucosal plexus (점막하 신경총, Meissner’s plexus) ▪ Myenteric plexus (근육층 신경총, Auerbach’s plexus) 2. Extrinsic Nervous system (외인성신경계) ▪ Sympathetic nerves (교감신경) ▪ Parasympathetic nerves (부교감신경) 3. Reflex Control 1. Intrinsic nervous system (내인성 신경계) = Intramural plexus (장벽내신경총) = Enteric nervous system (1) intramural plexus (장벽내신경총) - myenteric and submucosal nerve plexuses - contain sensory-, motor-, interneurons - short reflex regulation - coordinate activity in the absence of extrinsic innervation (2) neurotransmitters - ACh, NE, adenosine triphosphate, serotonin, dopamine, CCK, SP, VIP etc. (3) Myenteric plexus (Auerbach’s plexus) - mostly excitatory and inhibitory motor neurons - sensory (1/3) and interneurons (4) Submucosal plexus (Meissner’s plexus) - regulate glandular, endocrine and epithelial secretion - stimulatory secretomotor neurons (ACh, VIP) - sensory neurons: stimulated by serotonin (released from enterochromaffin cells in mucosa) 2. Extrinsic nervous system: Autonomic Nervous System ▪ Sympathetic nerves (교감신경) - prevertebral ganglia (척추앞 신경절): Celiac ganglion (복강 신경절), superior mesenteric ganglion (위장간막 신경절), inferior mesenteric ganglion (아래장간막 신경절) ▪ Parasympathetic nerves (부교감신경) - vagus (미주신경) - pelvic (골반신경) NE Cholinergic  Extrinsic nervous system Activation of GI function Inhibition of GI function GI function - Vasodilation - Motility - Secretion Sympathetic/parasympathetic nerves connect myenteric plexus/submucosal plexus to regulate motility and secretion of GI tract Sympathetic/parasympathetic nerves can stimulate or inhibit Preganglionic fibers GI function independently of enteric nerves Direct Intrinsic nervous system innervation 3. Reflex Control  Afferent fiber (구심신경) : sensory receptors in the mucosa and in the muscular externa - chemoreceptors - mechanoreceptors  Efferent fiber (원심신경) ▪ Short (local or intrinsic) and long (central) reflex arc Short reflex: a process from a receptor to an effectors through intrinsic nerve plexus Long reflex: a process from a receptor to an effectors through afferent fiber, central nervous system, autonomic nerves and intrinsic nerve plexus  Hormonal Regulation (호르몬에 의한 조절) - Enteroendocrine cell (EEC, 장관 내분비세포) 1. Hormones of GI origin (1) gastrin (produced at stomach, duodenal endocrine cell) : stimulates gastric motility, secretion (HCl) (2) cholecystokinin (CCK): stimulates pancreatic secretion (3) secretin: stimulates pancreatic secretion (4) gastric inhibitory peptide (GIP): inhibits gastric motility (5) motilin: stimulates gastric motility 2. Paracrine Mediators (1) histamine (released from cells in the wall of the duodenum) : physiological agonist for HCl secretion (2) inflammatory mediators (adenosine, NO, prostaglandins, leukotrienes, cytokines, etc) and antibodies : released by cells of the extensive gastrointestinal immune system  Regulation of Digestive System by Hormones (호르몬에 의한 소화 조절) 호르몬 분비부위 자극제 억제제 작용 Gastrin 유문부 위벽 팽창 자극, 위장내 낮은 위산 및 pepsinogen 분비 촉진 (G세포) 부교감신경, 아미 pH (1.5), 위점막 성장 촉진 노산, 펩타이드 Somatostatin 위의 연동운동 촉진 Cholecystokinin 소장 점막 십이지장내 지방 위 내용물 배출 억제 (CCK) 산, 아미노산, 펩 담낭수축 타이드 Oddi 괄약근 이완 – 담즙 장내배출 촉진 췌액 (소화액) 분비 촉진 Secretin 소장 점막 소장내 산성 (pH) Somatostatin 췌액 (NaHCO3) 분비 촉진 – 중화 효과 CCK 효과 증진 gastrin 분비 억제 - 위산분비 억제 Gastric Inhibitory 공장 (K세포) 포도당, 지방 위산분비 억제 Peptide (GIP) 위의 연동 운동 억제 인슐린 분비 촉진 Somatostatin D세포(소화관, CCK 부교감신경 gastrin, secretin, insulin, glucagon 분비억제 췌장) Motilin M세포 (십이 십이지장의 알칼 운동촉진 (위배출증가) 지장 및 공장) 리성 위 펩신 분비 자극 식도괄약근 이완 담낭수축  Gastrointestinal Motility (위장관 운동) Motility pattern (위장관 운동의 형태) - Contraction and relaxation of smooth muscle (circular/longitudinal muscle) · contraction of circular muscle (윤주근 수축): narrowing digestive tube · contraction of longitudinal muscle (종주근 수축): shortening digestive tube  Propulsion: propulsive peristalsis (추진성 연동운동)  Mixing: non-propulsive peristalsis (비추진성 연동운동); segmentation movement (분절운동), pendular movement (시계추운동)  Tonic contraction (강직성 수축) Segmentation and mixing Digestion in Mouth and Esophagus Mouth/Pharynx/Esophagus (구강/인두/식도) Mouth connected to the lip at the front and pharynx at the back teeth and tongue: chewing, mixing and swallowing saliva (침샘): amylase secretion Pharynx (인두) (연구개) a passageway leading from the oral (비강) and nasal cavity in the head to (비인두) the esophagus and larynx nasopharynx (비인두), oropharynx (구인두) (경구개) (구인두) hypopharynx (하인두) (혀) a passageway for foods (하인두) prevent food getting to the trachea and nose (후두개) (후두) Esophagus (식도) (기관) (식도) tubular digestive organ connecting pharynx to the cardia of stomach: about 25 cm length upper 1/3: striated muscle, lower 2/3: smooth muscle UES (상부식도괄약근): prevent regurgitation when swallowing LES (하부식도괄약근): prevent regurgitation from stomach to esophagus Digestion in mouth/Deglutition (구강내 소화/연하) 1) Mastication, chewing (저작 咀嚼) lubricate, mix with salivary amylase, and subdivide the food carried out voluntarily, but more frequently a reflex behavior chewing center: medulla (연수) 2) Saliva (침) makes food easier to swallow stimulates taste bulb (미뢰) to feel taste contains amylase: hydrolyze starch to maltose and glucose center for secretion: medulla (연수) parasympathetic stimulation: secretion↑ 3) Swallowing, deglutition (삼킴, 연하 嚥下) transfer broken foods to stomach through mouth, pharynx and esophagus voluntary initiation, thereafter, almost entirely under reflex control (반사조절) swallowing center: medulla (연수), lower pons (교뇌) 2) 침 (Saliva) A. 침샘 (Salivary gland)  Acinar cell (선방세포): serous cell (장액세포: amylase, water secretion), mucous cell (점액세 포: mucin (점액) secretion)  Duct cell (도관세포): Na+ reabsorption, K+/HCO3- secretion Name Location Duct opening Cell type % Parotid below and on side of cheek serous ~25 (귀밑샘, 이하선) in front of ear Stensen's duct Submaxillary posterior floor of mouth floor of mouth serous & ~70 (턱밑샘, 악하선) Wharton's duct mucous Sublingual anterior floor floor of mouth mostly mucous ~5 (혀밑샘, 설하선) of mouth under tongue in the mucosa throughout mouth mucous Buccal negligible covering the palate, buccal (볼샘, 협선) area, lips and tongue B. Function of saliva (침의 기능) 1) moistening and lubrication of the mouth and food 2) oral hygiene  wash away bacteria  destroy factor: thiocyanate ion (SCN-), proteolytic enzyme  antibody 3) maintenance of calcium phosphate in the matrix of the teeth : by secreting Ca3(PO4)2 , pH buffering 4) breakdown carbohydrates and fats 5) facilitation of taste 6) protection of mucosal surface in the mouth lack of functional salivary gland - xerostomia (구강건조증, dry mouth; in Sjögren syndrome, antihistamines) dental caries, infection of buccal mucosa (inflammation) C. Secretion of saliva - two-stage model 1st stage: mucus, amylase, NaCl secretion at acinar cells 2nd stage: NaCl absorption, K+, HCO3- secretion in duct cells isotonic isotonic  Acinar cell: serous cell, mucous cell hypotonic D. Regulation of salivary secretion - primarily controlled by neural input - parasympathetic innervation is important Parasympathetic stimulation major, stronger, more lasting secrete a large volume of watery fluid (amylase, electrolytes) visual and olfactory stimuli Acetylcholine: Muscarinic receptor - IP3/Ca2+; promotion of secretion Sympathetic stimulation slight increase in serous and mucous secretion (highly viscous) Norepinephrine - 𝛼 receptor: IP3/Ca2+; promotion of electrolyte secretion - β receptor: cAMP; amylase secretion 3) Swallowing, Deglutition (삼킴, 연하 嚥下) 1. Oral phase (구강상) transfer food from mouth to pharynx voluntary initiation, reflex control (경구개) the tongue moves bolus upward (touching hard palate) (연구개) and then backward into the mouth lowering soft palate (epiglottis(후두개) is open (후두개) → breathable) (기도) 2. Pharyngeal phase (인두상) (식도) phase of food contact to pharynx involuntary (center: medulla); less than 1 second respiration is reflexly inhibited → contraction of palatopharyngeal muscles; Pharynx (인두) soft palate goes up closing nasopharyngeal cavity → epiglottis covers the opening of the larynx Larynx (후두) constrictor muscle of hypopharynx: contract; upper esophageal sphincter: relax → peristaltic wave 3. Esophageal phase (식도상) begins at the entry of bolus of food to esophagus stimulated via vagal reflex (미주신경반사) by swallowing center (medulla) → UES (상부식도괄약근) constriction to prevent regurgitation: LES (하부식도괄약근) opening → peristaltic movement → after food enters the stomach, LES contracts (prevent regurgitation) Esophagus Components Pharyngoesophageal sphincter (Upper esophageal sphincter: UES, 상부식도괄약근) Gastroesophageal sphincter (Lower esophageal sphincter: LES, 하부식도괄약근) Esophageal musculature - upper 1/3: striated muscle; lower 2/3: smooth muscle Function transfer bolus of food from pharynx to stomach (peristaltic movement) prevent air from entering at the upper end of the esophagus keep corrosive gastric contents from refluxing back into the esophagus Regulation of Esophageal phase deglutition (swallowing) center: reflex Acetylcholine: contract sphincter (basal tone) Gastrin: LES constriction (prevent regurgitation of gastric acid) Vagovagal reflex (미주신경반사) : sensory neurons in LES; respond to acid closure of LES and relaxation of stomach  Disorders of swallowing (연하이상)  Gastro-Esophageal Reflux Disorder (GERD, 위식도역류장애) - incompetence of LES (LES is unable to maintain its normal tone) - regurgitation (위산역류) → reflux esophagitis (역류성식도염) - commonly referred to as heartburn (속쓰림) or indigestion (소화불량) - treatment: H2 receptor antagonist [cimetidine(Tagamet® ), ranitidine(Zantac® )]  Achalasia (식도이완불능증) - neuromuscular disorder (신경근 이상) - degeneration of ganglial cells in myenteric plexus (신경총의 퇴화) - dysfunction of LES relaxation (하부식도괄약근 기능이상)  Esophageal spasm (식도경련) - long lasting strong constriction of LES after swallowing (instead of peristalsis) → causing pain Digestion in Stomach Stomach Structure a pocket-shaped digestive organ located in the upper left abdomen (size: 1.2~1.4 L) functional anatomy - 3 functional parts: Cardia (분문부), Corpus (fundus and body, 기저부, 위체부), Antrum (유문부) - proximal part (LES ad corpus; 상부) and distal part (antrum and pylorus; 하부) pylorus (유문)/cardia (분문): rich in circular muscle (sphincter: LES, pyloric sphincter) Layer of Stomach (위벽의 구조) Mucosa (점막) Mucous cell (점막세포): mucus Submucosa (점막하): gland, blood vessel, Parietal cell (벽세포): gastric acid lymphatic duct, nerve plexus Chief cell (주세포): pepsinogen Smooth muscle layer (oblique muscle/circular Enteroendocrine cell: gastrin muscle/longitudinal muscle) Serosa (장막) Basal electrical rhythm (BER)  Slow waves of the stomach - originating in a pacemaker within the longitudinal muscle layer - responsible for the rhythm and frequency of gastric contraction (frequency: 3/min; velocity: 1 cm/sec) → provide peristaltic wave Gastric motility Function 1. a reservoir for food to be ingested 2. break food into smaller particles and mix food with gastric secretions 3. empty gastric contents into the duodenum at a controlled rate Gastric motility receptive relaxation (수락이완): a reflex in which the gastric fundus and body dilates when food passes down the pharynx and the esophagus (deglutition) segmentation and peristalsis (분절 및 연동): mixing and moving of food - BER (basal electrical rhythm) from pacemaker → peristaltic movement (insufficient without stimulation of nervous system or hormones) - peristaltic wave induces constriction of LES (하부식도 괄약근) Gastric emptying peristaltic movement of antrum (mixing and emptying) a small amount of chyme (유미즙) moves to the duodenum → emptying time: 3 - 4 hrs function of pyloric sphincter (유문괄약근): (1) controls gastric emptying (2) prevents regurgitation of duodenal contents Mixing and Trituration by Gastric Contraction JETLIKE RETROPULSION THROUGH THE ORIFICE OF THE ANTRAL CONTRACTION TRITURATES SOLID PARTICLES Regulation of gastric emptying (위배출 조절) - regulated by signals from stomach and duodenum  mechanical and chemical stimuli (ex. gastric distension and digested protein)  hormonal and neural mechanism 1) Gastric factors: promote emptying  Increased food volume: stretching elicits local myenteric reflexes  Gastrin: mild to moderate stimulatory effect 2) Duodenal factors: inhibit emptying  Acidity (pH less than about 3.5)  High osmotic pressure  High fat content (triglyceride, phospholipid, fatty acid)  Peptides, amino acids  Neural mechanism  parasympathetic impulse: gastric factors  enterogastric inhibitory reflex: duodenal factors  Hormonal regulation  stimulator: gastrin  inhibitor: CCK, secretin, VIP (vasoactive intestinal peptide), GIP (gastric inhibitory polypeptide), enterogastrone, systemic catecholamines Regulation of gastric emptying Gastric Secretion Gastric Gland - about 35 millions of gastric gland (위샘) in gastric mucosa a. cardiac glandular region: mucus-secreting cells b. oxyntic glandular region: parietal, chief cells, ECL (enterochromaffin-like) cells, D cells (somatostatin secreting), surface mucous cell, mucous neck cells c. pyloric glandular region: mucus-secreting cells, G cells, D cells a b c Type of cell secretory product Mucous mucins, Na+, K+, Ca++, Cl- & HCO3- Parietal H+, Cl-, Na+, K+ & intrinsic factor Chief pepsinogen Components of gastric secretion - inorganic and organic components 1) Gastric acid (Hydrochloric acid) secreted by parietal cell (벽세포) strong acid (pH = 1): bacteriocidal action convert pepsinogen (inactive form) to pepsin (active); maintain optimal pH for pepsin action H+ generation from blood CO2; exchange of HCO3- and Cl- by anion exchanger → acid (HCl) secretion by H+/K+ ATPase and Cl- facilitated transport - Omeprazol: H+/K+ ATPase inhibitor (gastric ulcer treatment) stimulant for acid secretion: parasympathetic neuron (ACh), gastrin, histamine; Cimetidine (Tagamet®): H2 antagonist Alkali tide 2 3 1 5 4 2) Pepsin 'a group of proteases’ secreted as zymogen (pepsinogen) by chief cell (주세포) converted to pepsin by gastric acid: catalytic site is open by acid → converted to active pepsin by autocatalytic action responsible for 15% of total protein degradation optimal pH: pH 1.0-3.0 parasympathetic (vagus nerve) stimulation → secretion↑ 3) Intrinsic factor glycoprotein, MW 55K secreted by parietal cell (벽세포) required for vitamin B12 absorption: - intrinsic factor-B12 complex → resistance to digestion → bind the complex at terminal ileum - deficiency leads to pernicious anemia 4) Mucin (점액) Mucin: glycoprotein; mucin tetramer forms a sticky gel secreted by surface epithelial cell and mucous neck cell - mucous neck cells: clear mucus (soluble mucus) - surface epithelial cells: visible mucus, cloudy mucus  secretion is stimulated by mechanical stimulation  HCO3- secretion (surface epithelial cell) → maintain alkalinity of mucus layer protect gastric mucosal cells from gastric acid and pepsin maintenance of the protective mucus layer requires continuous synthesis of new mucins (due to degradation by pepsin) Functions of gastric secretion 1) protein digestion 2) protections against bacteria (by a low pH) 3) absorption of Vitamin B12 4) formation of gastric mucosal barrier (unstirred layer) - gel on the luminal surface of mucosa - prevent the bicarbonate-rich secretion of the surface epithelial cells from rapidly mixing with the contents of the gastric lumen - slightly alkaline pH - slow diffusion of H+ and pepsin to the surface, HCO3- into the lumen - H+, HCO3- diffusion takes 1 min for 1 mm thick mucus layer Gastric mucosal barrier Regulation of Gastric secretion 1) Secretion of Gastric juice - 1-3 liters/day of isotonic solution (~ 1-2 ml/min) - at rest: 15-20 ml/hr (HCO3- rich) - at stimulated: more than 150 ml/hr (HCl rich, 0.1 M) 2) Secretion regulators (1) Stimulators Stimulant Stimulant Source Source Acetylcholine (ACh) Stimulant Enteric neurons pepsinogen↑, acid↑, mucus↑ Source Gastrin G cells in gastric antrum acid↑, pepsinogen↑ (weak) Histamine ECL cells in gastric corpus acid↑, pepsinogen↑ (indirect) Secretin S cells in Duodenum pepsinogen↑ (acid secretion↓)  potency of acid secretion: acetylcholine > gastrin  duration of acid secretion: gastrin > acetylcholine  stimulation of pepsinogen secretion - acid in contact with the gastric mucosa: local cholinergic reflex - secretin, released by duodenal mucosa in response to acid GRP: Gastrin Releasing Peptide, neuropeptide ECL: enterochormaffin like cells A: acetylcholine G: gastrin H: histamine (2) Inhibitors  Somatostatin, PGs, EGF, TGFa  Secretin: inhibit acid secretion (but stimulate pepsinogen secretion) 3) Three phases of gastric secretion Cephalic phase (뇌상): 30~50% Gastric phase (위상): 40~50% Intestinal phase (장상): 5% Phases of Gastric Secretion Diseases associated with abnormal gastric secretion  Peptic ulcer (소화성궤양): high acid and peptic content; irritation, infection, poor blood supply, poor secretion of mucus - Gastric ulcer (위궤양): abnormal gastric mucosal barrier, aspirin, stress, bacterial infection (H. pylori) - Duodenal ulcer (십이지장궤양): strongly hereditary (psychogenetic factors, stress, etc.); diminished inhibition of acid by secretin  Hypochlorhydria (저산증): destruction of parietal cell (autoimmune disease); pepsin and acid secretion↓  Pernicious anemia (악성빈혈): with achlorhydria, intrinsic factor↓  Helicobacter pylori - increase in sensitivity to antibiotics by decreasing acidity : stop using acid blocker  H. pylori flourish  ulcer recurrence Digestion in Small Intestine Structure of Small Intestine about 6.0 m long tube from pylorus to large intestine. Filling up most of abdominal cavity Duodenum (십이지장): 25cm long tube from pylorus, diameter 5cm, located behind the peritoneum; common bile duct (총담관) and pancreatic duct (췌관) are merged to duodenum (bile/pancreatic juice excretion) Jejunum/Ileum: begins at left upper abdomen and links to the cecum at lower right abdomen, unclear boundary (40% jejunum, 60% ileum) - jejunum (공장): larger diameter, thick wall, rich in blood vessel absorb most of nutrients - ileum (회장): absorb vitamin B12 and bile juice Mesentery (장간막): double fold of peritoneum, (십이지장) attached to the posterior abdominal wall. (공장) blood vessels, neurons, lymphatic duct (상행결장) → nourishing the wall of the small intestine (결장) (장간막) (충수돌기) (회장) Ampulla of Vater and Sphincter of Oddi Ampulla of Vater: the spot where the pancreatic and bile ducts release their secretions into the intestines Sphincter of Oddi: controls excretion of bile/pancreatic juice Structures of Small-/Large-intestine Structure of Villi (소장 융모의 구조) Enlarged surface area: 600 times larger than ordinary cylinder - plicae circulares, circular folds (윤상 (돌림) 주름) - villi (장융모) - microvilli (미세융모; intestinal epithelial cells, 장상피세포): absorb nutrients capillary: transport water soluble nutrients lacteal (유즙관): transport fats Intestinal motility (장운동) Function of intestinal motility  mix chymes with digestive secretion  contact with absorptive surface  propel chymes toward colon Types of small intestinal movement  Segmentation contractions (분절 수축): mixing; strong at the upper intestine, weakened as go down, stimulated by parasympathetic neurons  Peristalsis (연동운동): moving; fast at the upper intestine, slow at the lower intestine. - reverse peristalsis (역연동운동): effective mixing of chymes with bile/pancreatic juice in the vicinity of the duodenum  MMC (이주성 운동복합체) Electric Physiology of Intestinal Smooth Muscle (1) Regular slow waves (서파의 규칙적 발생) - maximum in the duodenum (11 ~ 13/ min), decline along the length of the small bowl - independent of extrinsic innervation - pacemaker: found in the longitudinal muscle near the entry of the bile duct - induces segmentation (분절운동) and short-range peristaltic movements (2) Extrinsic neural circuits (외인성 신경회로의 작용) - modulate contractile activity - essential for long-range intestinal reflex Control of intestinal movement (소장운동의 조절) 1) Intestinal reflex (장반사) (1) intestino-intestinal reflex(장-장 반사): when one part of the intestine gets overdistension, the other part relaxes (2) gastroileal reflex (위-회장 반사): when gastric movement or secretion is increased, ileal motility (peristaltic movement) increases and, chyme moving through ileocecal sphincter increases (3) ileogastric reflex (enterogastric reflex, 장-위반사): when ileal distension increases, gastric emptying decreases by neural reflex and increase of peptide YY. (signals from colon and small intestine inhibit gastric motility and secretion) (4) ano-intestinal-inhibitory reflex: when anal distension increases, intestine relaxes * law of intestine (peristalsis): contraction of intestine above the bolus and relaxation of intestine below the bolus 2) Hormonal control (호르몬 조절) (1) stimulation: gastrin, CCK, 5-HT, motilin, insulin, opioids (2) inhibition: catecholamines, secretin, glucagon, NO, VIP  Peristalsis – Law of Intestine (Intrinsic reflexes) Oral Direction of propulsion Aboral  Migrating Myoelectric (Motor) Complex, “MMC” (이주성운동복합체) - occurs during fasting - to clear undigested food particles, slow peristaltic waves sweeping whole of GI tract - pattern of repeated contraction approximately every 90 min  Phase I: almost have no contractions, 40-60 min  Phase II: have few contractions, 30-45 min  Phase III: have continuous contractions, 5-10 min * Importance of MMC 1. Sweep the contents of the small intestine towards the colon  housekeeper of the small intestine 2. Inhibit the migration of colonic bacteria into the terminal ileum Intestinal secretion (소장 및 부속기관의 분비) 1. Small intestinal secretion A. Mucin (점액: 당단백질) - protect duodenal mucosa from low pH, proteolytic enzymes - lubricant effect (aid the movement of chyme) Brunner's gland in duodenal bulb and Goblet cell in the crypts stimulated by a. direct tactile effect and chemical irritation of the chyme b. parasympathetic stimulation c. hormones (CCK, gastrin, secretin) inhibited by sympathetic stimulation B. Intestinal juices (장액) - 2-3 L/day, similar ionic composition to plasma, pH = 6.5 to 7.5 stimulated by distension and mechanical stimulation a. parasympathetic neuron b. hormones (CCK, gastrin, secretin and gastric inhibitory peptide) inhibited by catecholamine (sympathetic nerve) Function: alkalization of chyme, maintenance of the chyme fluidity C. Enzyme 1) Enteropeptidase 2) Alkaline phosphatase 2. Pancreatic secretion A. Structure of Pancreas exocrine- and endocrine-function a gray, triangular organ lying laterally behind the stomach head is embedded in the duodenum and the tail faces the spleen divided into lobules (소엽): lobules are composed of acini (선방, 샘포) acinus (선방): composed of acinar cell (선방세포: secrete pancreatic juice containing digestive enzymes, Na+, Cl-) and duct cell (secrete electrolytes and HCO3–) pancreatic duct: conduit for pancreatic juice. Merged to bile duct (ampulla of Vater), and linked to duodenum (at Oddi’s Sphincter, 간췌장괄약근) B. Composition of Pancreatic juice - Aqueous components, enzymes 1) Aqueous components - major ionic components: Na+, K+, HCO3-, Cl- (Na+ and K+ : similar to plasma) - stimulated by secretin ionic transport a) acinar cell (선방세포) - slightly hypertonic - supply organic constituents b) duct cell (도관세포) - isotonic - HCO3- secretion: by Cl- exchange - faster the flow rate, higher HCO3- conc. functions of HCO3- secretion a) neutralizing the acid discharged into the small intestine b) maintaining optimal pH for digestive enzymes 2) Enzyme components - zymogen secretion - stimulated by CCK  Enzymes a) alpha-amylase b) proteases (inactive zymogen form) c) lipid digesting-enzymes glycerol ester hydrolase, cholesterol ester hydrolase, PLA2 d) deoxyribonuclease, ribonuclease  Nonenzyme proteins a) trypsin inhibitor b) colipase c) albumin d) globulin(Ig A) e) monitor peptide * release of zymogen granules and granule-free pathway C. Regulation of secretion 1) Aqueous components - stimulated by secretin  S cell: pH sensor in the duodenum and upper jejunum; releases secretin in response to acid in the lumen of the duodenum and upper jejunum (pH 4.5 or below)  secretin: HCl > fat > peptide; CCK: peptide > fat > HCl > amino acids - cholecystokinin: potentiate the effect of secretin 2) Enzyme components - stimulated by CCK(cholecystokinin) - CCK secretion: mucosal cell (I cell) of the duodenum and jejunum 〮 stimulators: certain amino acids, some peptides, long chain fatty acids (peptide > fat > HCl > AA); releasing factors (CCK-RP, monitor peptide) 〮 vagus nerve (미주신경); acetylcholine, GRP(gastrin releasing peptide) CCK-RP: CCK releasing peptide (from paracrine cell) GRP: gastrin releasing peptide Monitor peptide: pancreatic juice (from acinus cell) Release of CCK from duodenal I cells 3) Three phases of pancreatic secretion (1) Cephalic phase: ~20% of total secretion after meal - same nervous signals as cephalic phase of gastric secretion - vagal impulses: ACh release - secrete moderate amounts of enzymes - low volume of pancreatic juice with a high protein content (2) Gastric phase: 5~10% of total secretion - secrete small amounts of enzymes (3) Intestinal phase - response to chyme’s entering the small intestine - secrete large amount of pancreatic juice - acid in the duodenum and upper jejunum → (secretin): high volume, poor enzyme (rich in HCO3-) - peptide, amino acid, fatty acid → (CCK): enzyme-rich pancreatic juice ∙ hormone action ∙ vagovagal reflex (미주신경반사) by CCK → enhances in acinus secretion and release of ACh, GRP and VIP via activation of pancreatic enteric neurons 3. Liver A. Structure of Liver largest organ in the body; located in the upper right part of the abdominal cavity below the diaphragm; composed of two lobes (right- and left lobe) hepatic portal vein (문맥), hepatic artery (간동맥) and bile duct (담관) enter or exit from the lower side: get blood supply from portal vein and hepatic artery hepatic veins gather and enter inferior vena cava (하대정맥) from the back of the liver consists of about 500 thousands of liver lobule (간소엽, structural unit of hepatic tissue in hexagonal column) Inferior vena cava Aorta B. Function of liver 인슐린 및 글루카곤에 반응해서 글리코겐이나 포도당 Glycogen 합성, 분해 합성, 분해 대사기능 Albumin, globulin, fibrinogen등 혈장인자 및 응고인자 혈장단백질의 합성 metabolism 합성 지질대사 중성지방, 인지질, 콜레스테롤 합성 호르몬대사 성호르몬, vasopressin등 불활성화 해독, 배설기능 해독기능 암모니아-요소, 알코올-알데히드 detoxication 배설기능 해독물질을 소변 또는 담즙으로 배설 담즙생산 지방의 유화작용 담즙산, 인지질, 콜레스테롤, 담즙색소로부터 담즙생성 bile production 저장기능 철, 비타민의 저장 철, 또는 지용성 비타민 저장 storage 혈장의 저장 다량의 혈액 저장 (순환혈액량 조절) 혈구생성, 제거 혈액정화 적혈구제거 (Kupffer cell) erythropoiesis, RBC removal 적혈구 생성 태아기 적혈구 생성장소 C. Hepatic bile (담즙) generated in the liver; bitter tasted, dark green/brown colored fluid. composed of 85% water, 10% bile acids, 3% mucus/pigment, 1% fat, 0.7% salts bile acids (담즙산): taurocholic acid and glycocholic acid; ~ 65% of dry weight of bile emulsification (지방의 유화): aids fat digestion in the small intestine concentrated and stored in the gallbladder (담낭): after food intake, amino acids/fats stimulate CCK secretion → contract gallbladder and release bile juice “water-soluble” “lipid-soluble”  simple diffusion “more water-soluble” “bile salt of Na+” 4. Gallbladder (담낭)  Functions: bile concentration, storage and emptying 1) Concentration and storage of bile - GB capacity: 15 - 60 ml (20 fold concentrated) - absorbing Na+, Cl- and HCO3- via Na+,K+-ATPase action → osmotic pressure↑ → absorption of water → bile juice is concentrated 2) Emptying of the gallbladder (bile release) - begins within 30 minutes after meal; GB contracts and Oddi’s sphincter relaxes - during cephalic and gastric phase: mediated by cholinergics (parasympathetic neuron) - during intestinal phase: mediated by CCK (the highest rate) Concentration of Bile during storage Neurohormonal control of biliary secretion Digestion and Absorption of Carbohydrates 1. Carbohydrate Digestion - carbohydrates in the diets: starches, sucrose, lactose, glycogen, alcohol, lactic acid, pyruvic acid, pectin, dextrin, cellulose  digestion in the mouth (mastication & a-amylase) - ptyalin: 20 - 40 % of CHO starch → maltose, a-dextrin  digestion in the stomach - salivary amylase: blocked by gastric acid (pH 4.0 inactive)  digestion in the small intestine  pancreatic amylase: 50-80% of CHO starch, oligosaccharides  intestinal epithelial enzymes: highest in upper jejunum ; lactase, sucrase, a-dextrinase (isomaltase) in brush border * sucrase-isomaltase complex Monosaccharide Polysaccharide  Amylose: a-1,4 glycosidic linkage Amylopectin: a-1,6 glycosidic linkage branch Cellulose: b-1,4 linkage Isomaltase (dextrinase)  Brush Border Enzymes and Carriers Dextrin: low-molecular-weight carbohydrates produced by the hydrolysis of starch or glycogen. Mixtures of polymers of D-glucose units linked by α-(1→4) or α-(1→6) glycosidic bonds 2. Absorption of Carbohydrates In Brush border - Glucose, Galactose: Na+-dependent secondary active transport, SGLT1 - Fructose: facilitated transport, Glut5 In Basolateral membrane: Glut2 Active transport: Sodium/Glucose cotransporter = SGLT Facilitated transport: Glucose transporter = Glut 3. Carbohydrate Malabsorption Syndromes 1) Lactose malabsorption syndrome (유당불내성) ▪ deficiency of lactase in brush border ▪ lactose intolerance (more than 50% of the adult): severe in Asian & African ▪ intestinal distension, borborygmy, diarrhea * Congenital lactose intolerance ▪ infants, lack of lactase severe diarrhea, dehydration and electrolyte imbalance ▪ special formula: sucrose or fructose instead of lactose 2) Sucrose-isomaltase deficiency (설탕불내성) ▪ autosomal, recessive, inherited disorder ▪ intolerance to sucrose (10% of Greenland Eskimos, 0.2% of North American) ▪ synthesis is inhibited or destroyed by antibodies 3) Glucose-galactose malabsorption syndrome (포도당-갈락토스 불내성) ▪ rare inhereditary disorder ▪ missense mutation in SGLT1 abnormal absorption of glucose and galactose ▪ ingestion of glucose, galactose or starch lead to severe diarrhea (brush border saccharidase is normal normal digestion) ▪ fructose is well tolerated Digestion and Absorption of Fats 1. Digestion of fats 1) First step  Emulsification of fat - firstly by gastric mixing, and enhanced by bile acids in the small bowl  Without bile salt: no absorption of cholesterol, only 60 % of triglyceride is absorbed.  With bile salt: 97% of triglyceride/cholesterol can be absorbed. 2) Second step  Digestion by lipases - Lingual lipase - Gastric lipase - Pancreatic lipase  Glycerol ester hydrolase (simply pancreatic lipase)  Cholesterol esterase  Phospholipase A2 2. Absorption of fats 1) Transport across the mucosal membrane - mostly passive transport (diffusion); in some extent, carrier-mediated 2) Intracellular processing - in sER  reformed into chylomicrons (small lipid droplets about 1nm diameter) - b-lipoprotein synthesized in enterocyte covers the surface of chylomicron - chylomicrons enter the lymphatic duct via exocytosis; without b-lipoprotein, exocytosis will not occur (Abetalipoproteinemia)  chylomicrons fat 87 % cholesterol ester 2 % free cholesterol 1.5 % apolipoprotein B 1.7% phospholipid 6 -8 % * apoprotein A1, B, C, D, E 3) Lymphatic transport of chylomicron - exocytosis and diffuse into lacteal → lymphatic vessel → enter the blood stream at left subclavian vein (좌쇄골하정맥) Lacteal (유미관) is a lymphatic capillary that absorbs dietary fats in the villi of the small intestine. 3. Malabsorption of lipid (지방 흡수부전) 1) complete absence of bile acid 2) lack of pancreatic lipase : extremely low level of pancreatic juice in infant with cystic fibrosis (낭포성섬유종; defective Cl- channel)  steatorrhea (지방변증)  malnutrition 3) tropical sprue, gluten enteropathy: density of microvilli↓, surface of GI-epithelium flatten CFTR: cystic fibrosis transmembrane-conductance regulator Digestion and Absorption of Proteins 1. Digestion of proteins 1) Sources of intestinal protein - endogenous proteins: 150 ~ 400 g/day; secreted protein (mostly proteolytic enzymes), desquamated cells, leakage of plasma proteins into GI lumen - exogenous proteins (diet intake): 50 ~ 100 g/day 2) Digestion - in the stomach: 10 ~ 15% (pepsin) - in the small intestine: mostly (50% in duodenum), pancreatic proteases (trypsin, chymotrypsin, elastase), intestinal peptidase (aminopeptidase, dipeptidase) 3) Absorption (1) intact protein and large peptides - trigger an immunological response - receptor-mediated endocytosis (2) small peptides - the rate of transport of dipeptide, tripeptide: usually exceed the rates of individual amino acids. - secondary active transport (3) transport of free amino acids * 4 transport system for free amino acid system  acidic amino acid (glutamic acid, asparagine)  neutral amino acid (valine, phenylalanine, alanine)  basic amino acid (arginine, cysteine, lysine, ornithine)  imino acid (proline, hydroxyproline) - sodium cotransport, facilitated transport “More abundant than brush border” Absorption of water and minerals 1. Water absorption - 2 L of water is ingested each day, 7 L/day in GI secretion - small intestine: absorb about 7 L/day; mainly jejunum and ileum - colon: relatively small, about 1.9L /day  Osmosis - water absorption: mainly by osmosis due to nutrient absorption - paracellular and transcellular transport - absorption vs secretion  2. Absorption of Ions: Na+, Cl-, K+, HCO3- Jejunum Ileum 3. Mechanisms of salt and water absorption by the intestine 1) Structural considerations  tight junctions - leakest in the duodenum, a bit tighter in the jejunum, still tighter in the ileum, and tightest in the colon  transcellular vs paracellular transport  villous vs crypt cells 2) Ion transport by intestinal epithelial cells  Transporters, exchangers, channels, electric charge 3) Control of intestinal electrolyte absorption (1) the autonomic nervous system  sympathetic: increase the absorption of Na+, Cl-, and water  parasympathetic: decrease the net rate of ion and water (2) adrenal hormones  aldosterone: Na+, Cl-,  glucocorticoid: Na+, K+ -ATPase↑ → stimulates intestinal water absorption (3) opioid peptides (enkephaline), somatostatin: strongly stimulate salt and water absorption Villous versus Crypt cells Intestinal Absorption and Secretion: Relevance to Diarrhea Relevance: pathogens that damage absorptive villus epithelium induce malabsorptive diahhrea: PEDv, Coccidiosis, TGEv, Rotavirus Relevance: bacterial toxins and inflammatory stimuli elicit massive Cl-, HCO3-, and water secretion from the crypt: e.g. E. coli, S. typhimurium, etc  PEDV: Porcine Epidemic Diarrhea virus  TGEV: Transmissible Gastroenteritis Coronavirus Functional disorders of intestine 1. Diarrhea - enterotoxin produced by Escherichia coli, Shigella dysenteriae, and Vibrio cholerae  cholera toxin - acts on the apical membrane of mucosa mainly in the jejunum but also in the ileum, stimulating adenyl cyclase activity * increase in the intracellular concentration of cAMP * secretion of Cl- rich intestinal juice 2. Malabsorption of nutrients  regional enteritis (Crohn’s disease)  tropical sprue  celiac sprue  gluten-sensitive enteropathy  idiopathic steatorrhea Digestion in Colon Structure and Function of the Large Intestine 1. Structure of the large intestine connected to the small intestine. about 6.25 cm diameter, about 1.5 m length from cecum to rectum exit consist of cecum (맹장), colon (결장) and rectum (직장) Cecum (맹장): a short pocket shaped appendix on left posterior wall under ileocecal valve (회맹판) Colon (결장): major part of large intestine; ascending-, transverse-, descending- , sigmoid-colon Rectum (직장): located in the pelvis, connected to the anus Taeniae coli (결장띠) 2. Function of the large intestine 1) General function - absorption of water and electrolytes (proximal half of the colon) - absorption of vitamins (ex. B’s, K) produced by bacteria - storage of fecal matter; distal half - defecation (배변): emptying of the rectum 2) Part-specific function Cecum (맹장, 막창자) - connection between ileum and colon: Ileocecal valve (회맹판): prevent reflux from cecum to ileum; control the emptying - immune action, protect digestive bacteria Ascending colon (상행결장) - a site where chyme is transmitted from the ileum - not the primary site of storage, mixing and removal of water Transverse colon (횡행결장) - specialized for the storage and dehydration of feces IC sphincter - normally closed. : primary site for the removal of water and electrolytes ① prevent the repulsion ② control the emptying - feces are retained for about 24 hrs Descending colon (하행결장) - a conduit between the transverse and sigmoid colon - storage/movement/discharge of feces 3. Movements of the colon Segmental propulsion (분절이동) - proximal colon: 5 cm/hr (fasting), 10 cm/hr after eating - require 8~15 hrs to move chyme from IC valve (회맹판) to the transverse colon: very slow compared with small intestine Haustration (팽기수축) - segmentation movement in the colon: gentle non-propulsive peristalsis - contracts forming a 2.5cm segment. Unstimulated parts are inflated like pockets (haustrations, 팽기) → repeated peristalsis: mixing - chyme is retained in proximal colon; enhancing absorption of water and salt - occurs regularly and large parts contract at once Mass movement (집단연동운동; peristaltic rush) - empties a large portion of proximal colon in an aboral direction at once (from cecum to S-colon or rectum) - usually occurs for 15 min within 1 hr after breakfast → peristaltic rush (급성연동) - 1~3 times/day - duodenocolic reflex, gastrocolic reflex - simultaneous strong contraction of circular and longitudinal muscle Haustra 4. Control of colonic movement  Electric characteristics of colonic muscle - Longitudinal muscle: myenteric potential oscillation → generate action potential, inducing muscle contraction - Circular muscle: despite rhythm-generating cells exist, they do not usually fire action potential → ACh from enteric motor neuron enhances contractions 1) Neural control direct control by intramural plexuses (내재신경) and modulation by extrinsic innervation (mostly autonomic nerves) parasympathetic neuron: enhance peristalsis - vagus nerve (미주신경): proximal colon (cecum, ascending and transverse colon) - pelvic nerve (골반신경): distal colon (descending and, S-colon, rectum, anal canal) sympathetic neuron: inhibit peristalsis - superior mesenteric ganglion (상장간막 신경절): proximal part - inferior mesenteric ganglion (하장간막 신경절): distal part - hypogastric plexus (하복신경총): distal part of colon, rectum, anal canal (항문관) 2) Reflex Gastro-colic reflex, duodeno-colic reflex, colonocolic reflex 3) Hormonal control Gastrin: enhances motility NE Cholinergic 5. Large intestinal secretion * No villi in the mucous membrane, goblet cells (술잔세포) secrete mucin A. Mucin - smaller in volume, but richer in mucus than small intestine - secreted by Goblet cells of the colonic mucosa - stimulated by · direct tactile effect of fecal material · parasympathetic stimulation (cholinergic pathway) - inhibited by sympathetic stimulation B. Intestinal juice - isotonic solution, 60 ml/day - high concentration of K+ and HCO3- (in exchange for Cl-): alkaline (compared with the small intestinal juice) - stimulated by: · distention of the intestine, chemical irritation of the mucosa · parasympathetic stimulation - decreased by sympathetic stimulation - function · neutralizing acidic products of fecal fermentation caused by bacteria in the lumen of the large intestine 6. Absorption in the large intestine  absorption of water, electrolytes, short chain fatty acid  absorption of secondary bile acids (produced by bacterial action in the colon)  composition of the feces  ¾ water  ¼ solid: 30% dead bacteria, 10-20% fat, 10-20% inorganic, 2-3% protein, 30% undigested  color: stercobilin, urobilin  odor: bacterial flora, foods (indole, scatole, mercaptans, hydrogen sulfide)  Water movement (absorption) by osmotic pressure difference: Movement of Na+ (Na+/H+ exchanger, HCO3-/Cl- exchanger, and Na+/K+ATPase in intestinal epithelial cells): 6. Defecation (배변) involves voluntary & reflex activity Intrinsic reflex (myoenteric plexus) & extrinsic reflex (parasympathetic reflex) 1) Defecation Process (배변과정) entering feces into the rectum → rectal distention → stretch receptor → afferent pelvic splanchnic nerve (골반내장신경 구심로) transmit signal to defecation center (spinal cord neurons, 배변중추) → signal transmitted from defecation center to the pelvic nerve (골반신경: efferent, parasympathetic): spinal reflex → contraction of S-colon and rectum, relaxation of internal anal sphincter External anal sphincter: before voluntary relaxation, normally constricted → defecation inhibition (impulses from cerebrum → excitation of pudendal nerve (음부신경) → constriction of external anal sphincter) Defecation: impulses from cerebral cortex (voluntary) inhibit pudendal nerve → relaxes external anal sphincter → discharge feces