GI System

digestive system

• function: deliver nutrients to appropriate sites in the body

• from food, humans must get basic organic molecules to…

  • make ATP

  • build tissues

  • serve as cofactors and coenzymes

digestion

mechanically and enzymatically breaking down polymers (carbohydrates, fats, proteins) into monomer building blocks via hydrolysis reactions

absorption

taking monomers into the bloodstream to be used by cells

“disassembly line”

inside GI lumen, complex nutrients → simple nutrients → absorption into circulation (while preventing uptake of undesirables) → picked up by body cells for use

gastrointestinal tract

• non-sterile environment

• organs:

  • oral cavity

  • pharynx

  • esophagus

  • stomach

  • small intestine

  • large intestine

  • rectum

  • anus

accessory organs

• teeth

• tongue

• salivary glands

• liver

• gallbladder

• pancreas

sphincters

• muscular rings

• create functional divisions

• restrict content flow which optimizes digestion/absorption

• upper esophageal sphincter

• lower esophageal sphincter

• pyloric sphincter

• ileocecal valve

• inner anal sphincter

• outer anal sphincter

motility

movement of food through GI tract

ingestion

eating food

mastication

chewing and mixing with saliva

deglutination

swallowing

peristalsis

rhythmic wave-like contractions of GI smooth muscle to move food through GI tract (primarily propulsive)

segmentation

alternating forward and backward movements in different segments to churn and mix food and move forward (primarily mixing)

exocrine

• secreted through ducts into the lumen of GI tract

• aids digestion

• ex: water, HCl, HCO₃^-, enzymes, bile

endocrine

• hormones secreted into blood, circulate to effect cells of digestive system

• regulates digestion

• ex: gastrin, secretin

paracrine

• affects nearby cells

• hormones and other transmitters

• regulates digestion

• ex: histamine, acetylcholine (both regulate HCl production in stomach)

immune barrier

• epithelium (physical)

  • tight junctions prevent swallowed pathogens from entering body

• connective tissue immune cells (cellular)

  • promote immune responses

• secretions (physical and chemical)

  • contain antimicrobial agents

  • mucus barrier between ingested microbes and cells of the lumen

• gut microflora/microbiota

mucosa

• inner secretory and absorptive layer

• may be folded to increase surface area

submucosa

• very vascular to pick up nutrients

• has some glands and nerve plexuses

muscularis propria

• smooth muscle

• responsible for peristalsis and segmentation

• myenteric plexus for control by ANS

serosa

outer binding and protective layer

parasympathetic division

• “rest and digest”

• extrinsic regulation

• vagus nerve stimulates esophagus, stomach, small intestine, pancreas, gallbladder, and first part of large intestine

• spinal nerves stimulate lower large intestine

sympathetic division

• “fight or flight”

• extrinsic regulation

• inhibits peristalsis and secretion

• stimulates contraction of sphincters

hormones

• secreted from brain or digestive organs

• endocrine secretions

enteric nervous system

• intrinsic regulation

• intrinsic sensory neurons in gut wall

digestion: mouth

• mechanical breakdown (mastication → voluntary muscles)

• secretion → saliva (mucus, antimicrobial agents, salivary amylase)

digestion: esophagus

• peristalsis

• voluntary muscles → upper esophagus

• involuntary muscles → lower esophagus controlled by swallowing center (brain stem)

digestion: stomach

• stores and churns food, mix with gastric secretions

• moves chyme (semifluid, partially digested) to small intestine

• kills bacteria (acid)

• lining has folds (gastric rugae) → increases surface area

• mucosa layer → gastric pits lead to gastric glands that contain specialized secretory cells

surface mucous cells (mucous neck cells)

mucus and bicarbonate protects stomach from acid

parietal cells

secrete HCl and intrinsic factor (required for B12 absorption)

chief cells

secrete pepsinogen (pro-enzyme/zymogen)

ECL cells

secrete histamine and serotonin

HCl secretion

1. getting H⁺ and Cl^- in parietal cell

   • CO₂ + H₂O → H₂CO₃ → H⁺ + HCO₃^-

   • chloride shift → exchange of Cl^- and HCO₃^- across basal membrane by chloride-bicarbonate transporter (active transport)

2. HCl secretion to lumen

   • apical membrane

   • active transport → H⁺/K⁺-ATPase → enzyme and proton pump (PPI target)

   • facilitated diffusion → Cl^-/K⁺ co-transporter

histamine

• activates H₂ receptors on parietal cells

• primary signal → stimulates insertion of proton pump (H⁺/K⁺-ATPase) into parietal apical membrane

• drug target → H₂ blocker or histamine receptor antagonist

gastrin

stimulates release of histamine and has weak direct stimulus for H⁺/K⁺-ATPase

acetylcholine (ACh)

activates M₃ receptors for stimulation of H⁺/K⁺-ATPase insertion (weak)

HCl

• lowers pH to 2

• kills bacteria

• denatures dietary proteins

• optimal pH for pepsin activation and activity

pepsin

• pepsinogen → zymogen made by chief cells

• HCl converts to active pepsin

• starts protein digestion

stomach protection

• HCl and pepsin can damage stomach lining

• protected by…

  • adherent mucus layer with bicarbonate

  • tight junctions

  • constant replacement of epithelial cells

  • prostaglandins (mucosa) protect/repair epithelial cells

gastroesophageal reflux disease (GERD)

• chronic reflux of gastric contents into esophagus

• caused by dysfunctional…

  • lower esophageal sphincter

  • esophageal peristalsis

  • gastric motility

• treatment:

  • pharmacologic → target acid secretion

    • proton pump inhibitors (ex: omeprazole)

    • H₂ blockers (ex: famotidine)

    • antacids

  • non-pharmacologic → anatomical position, small meals, dietary changes

peptic ulcer disease (PUD)

• erosion of stomach mucosa by HCl

• causes:

  • Helicobacter pylori → bacterium reduces mucosal barriers to HCl

  • NSAIDs → reduce prostaglandin production which are protective in mucosal integrity and repair

• treatments: PPIs, H₂ blockers, antibiotics for H. pylori

emesis

vomiting

nausea

imminent need to vomit

retching

labored movement of abdominal and thoracic muscles before vomiting

vomiting

forceful expulsion of gastric contents (retro-peristalsis)

vomiting: process

• abdominal, diaphragm, and stomach muscle contract

• lower esophageal sphincter opens, esophageal dilation

• triggers: inputs to vomiting center → efferent impulses to salivation center

• receptors in each region are druggable targets

digestion: small intestine

• three segments → duodenum, jejunum, ileum

• very large surface area (most digestion and absorption happens here)

  • mucosa and submucosa folded into plica circulares

  • mucosa further folded into villi

  • epithelial apical membranes folded into microvilli

• function:

  • completes digestion of carbohydrates, proteins, and fats

  • absorption of most nutrients

    • duodenum, jejunum → sugars, lipids, amino acids, Ca²⁺, iron

    • ileum → bile salts, vitamin B12, water, electrolytes

villi

• nutrient absorption → lumen → blood capillaries (monosaccharides, amino acids) or lymphatic vessels (fats)

• intestinal crypts → secrete antibacterial molecules (ex: lysozyme, defensin) which affect microbiota

• intestinal stem cells → replace epithelium, new cells migrate from crypts to villi tip every 4-5 days

brush border enzymes

• attached to apical membrane of microvilli → active site exposed to lumen

• enterokinase (enteropeptidase) converts trypsinogen (pancreatic juice) into trypsin

  • trypsin activates many other pancreatic enzymes in small intestine

  • ensures protection of pancreas

intestinal motility

• segmentation

  • main form of motility of small intestine

  • mixes chyme thoroughly

  • more frequent at proximal end, helps to move chyme

• peristalsis

  • much weaker in small intestine

regulation of contraction

• enteric nervous system → GI nervous system → division of ANS

• PNS → increases pacemaker activity (increased GI motility and secretion)

large intestine

• structure:

  • 7 sections

  • haustra → pouches formed on outer surface

    • weakened haustra walls form outpouching → diverticulum (inflammation = diverticulitis)

• function:

  • produces vitamin K and vitamin B via microflora

  • absorption → water (2 L/day), electrolytes, vitamin K, some vitamin B

    • aldosterone (from adrenal gland) stimulates additional salt and water absorption in large intestine

  • stores feces

intestinal microbiota

• several hundred to a thousand different bacteria species (10 times more than human cells)

• initial colonization of bacteria from mother

benefits of microbes

• make vitamin K and B

• outcompete harmful bacteria

• bacteria fermentation produces short-chain fatty acids → used for energy by intestinal epithelial cells

• immune system interactions with healthy microbiota prevent inflammation

• disruptive effects of antibiotics

digestion: large intestine

• presence of material in rectum increases rectal pressure

• internal anal sphincter relaxes → urge to defecate

• voluntary muscle control of external anal sphincter provides control

• excretion aided by abdominal and pelvic skeletal muscle contraction (increases intra-abdominal pressure)

  • valsalva maneuver

valsalva maneuver

• forcefully attempted exhalation against closed airway

• achieved by holding one’s breath and trying to exhale forcefully simultaneously

inflammatory bowel disease (IBD)

• ulcerative colitis (UC) → mucosal inflammatory condition, affects only colon and rectum

• Crohn’s disease (CD) → transmural inflammation (deeper layer into wall), affects any part of GI tract

• exact cause unknown, multiple factors thought to contribute

  • infections may trigger disease

  • genetic predisposition

  • environmental factors

  • immune components

• goal: control dysregulated cytokine production and immune response

irritable bowel syndrome (IBS)

• cause: not well understood, not characterized by tissue changes

• common

• lower abdominal pain

• bloating

• diarrhea/constipation

• treatment focused on symptom relief

diarrhea

• increased frequency, excessive fluid in fecal discharge

• disruption of water and electrolyte balance

• causes: various pathogens, often symptom (not disease)

constipation

• difficult or infrequent passage of feces

• causes:

  • primary → idiopathic, difficult evacuation most common

  • secondary → drugs (ex: opioid), lifestyle (ex: diet, water intake), diseases

liver

• beneath diaphragm (more to right)

• regenerative abilities (hepatocyte mitosis)

• functional unit → lobe (central vein in middle)

• bile ducts → hepatocytes secrete bile → bile canaliculi → bile ducts → hepatic ducts

hepatic portal system

• products absorbed in intestines do not directly enter general circulation

• delivered to liver via hepatic portal vein and liver filters and detoxifies blood (first pass effect)

• GI capillaries → hepatic portal vein → hepatic sinusoids → central vein → hepatic vein → circulation (returns to heart via inferior vena cava)

liver: structure

• 1-2 hepatocytes thick, touching sinusoids

• sinusoids have gaps between endothelial cells → very permeable, allows passage of blood proteins, fat, and cholesterol

  • filtration and detoxification by hepatocytes

  • secretion of glucose and ketone bodies during fasting

Kupffer cells

• specialized liver macrophages (immune cells) living in sinusoids

• remove microbes

enterohepatic circulation

• liver secretes bile and other substances into bile ducts to clear them from blood

• analogous to renal clearance

• some molecules travel a repeated circuit (ex: bile salts → small intestine → hepatic portal vein → liver → bile duct → gallbladder → small intestine)

• most molecules eventually excreted in feces

bile

• function: digestion, kills microbes, bilirubin processing

• composed of…

  • bile salts → fat digestion, kills microbes

  • bilirubin → bile pigment (yellowish-green)

  • phospholipids (lecithin)

  • cholesterol

  • inorganic ions

bilirubin

• produced in spleen, liver, and bone marrow from breakdown of red blood cells (hemoglobin → heme → bilirubin)

• not water-soluble, transported by albumin in blood

• liver takes up bilirubin from blood and conjugates it with glucuronic acid

urobilinogen

• free bilirubin taken up by liver → glucoronic acid conjugate (water-soluble) → secreted in bile → intestine → metabolized by bacteria → urobilinogen

• pathways:

  • major: oxidized → feces

  • minor: oxidized → absorbed → hepatic portal vein → circulation → filtered by kidneys → urine

bile salts

• digestion and absorption of fats in small intestine

• made from bile acids derived from cholesterol

• nonpolar and polar ends

• aggregate

  • polar groups toward water

  • nonpolar groups inward toward fat

  • emulsify large fat globules into small droplets → greater surface area for fat digestion by lipase

  • form micelles to facilitate absorption of fatty acids, fat-soluble vitamins, etc.

detoxification of blood

• how hormones, drugs, and other substances are removed by liver

  1. excreted by bile into small intestine → eliminated in feces

  2. phagocytized by Kupffer cells in sinusoids

  3. metabolized by hepatocytes

     • ammonia → urea → returned to blood → urine

     • porphyrins → bilirubin

     • purines (nucleotides) → uric acid

     • some drugs metabolized, then secreted into bile

glycogenesis

glucose → glycogen

glycogenolysis

glycogen → glucose

lipogenesis

glucose → triglycerides

gluconeogenesis

amino acids → glucose

ketogenesis

free fatty acids → ketone bodies

plasma proteins

• albumin (colloid osmotic pressure, transport of/in blood)

• globulins (transport lipid-soluble substances, blood clotting)

• clotting factors (blood clotting)

• angiotensinogen (regulates blood pressure and fluid balance)

cirrhosis

• progressive fibrosis distorts structure of liver

• fibrotic scar tissue reduces regeneration, filtration, and metabolism

• reduced function and altered blood flow

• types:

  • alcohol cirrhosis → chronic alcohol, fatty liver → alcoholic hepatitis → cirrhosis

  • viral cirrhosis → most common is hepatitis C, least common is hepatitis B

portal hypertension

• complication of decompensated cirrhosis

• increased blood pressure in hepatic portal vein

• responsible for development of ascites (fluid in abdomen) and bleeding from esophagogastric varices

loss of liver function

• jaundice (bilirubin)

• coagulation disorders

• hypoalbuminemia (decreased albumin)

• hepatic encephalopathy

• causes: chronic alcoholic and viral hepatitis

drug-induced liver disease

• a number of drugs may induce liver injury

• most common cause of acute liver failure (fast onset and progression)

• types:

  • direct hepatotoxicity → common, predictable, dose-dependent (high doses of acetaminophen, aspirin, chemotherapy drugs, etc.)

  • idiosyncratic hepatotoxicity → rare, unpredictable, not dose-dependent

gallbladder

• sac-like storage organ attached to liver

• stores and concentrates bile from liver

• liver → bile ducts → hepatic duct → cystic duct → gallbladder → cystic duct → common bile duct → duodenum

• gallbladder removal → bile flows directly from liver into small intestine (difficulty digesting high-fat meals)

pancreas

• has both endocrine and exocrine functions

  • endocrine → islets of Langerhans cells make insulin, glucagon, and somatostatin

  • exocrine → acinar cells make pancreatic juice, secreted by pancreatic duct

pancreatic juice

• made up of bicarbonate (de-acidifies chyme) and ~20 digestive enzymes

• enzymes for all three classes of macromolecules

bicarbonate formation

• pancreatic duct cells → CO₂ + H₂O → H₂CO₃ → H⁺ + HCO₃^-

  • H⁺ → blood

  • HCO₃^- → pancreatic juice

chloride shift

• exchange of HCO₃^- and Cl^- across luminal membrane by chloride-bicarbonate transporter

• HCO₃^- neutralizes acidic chyme from stomach (required for enzyme function)

cystic fibrosis

• trouble secreting bicarbonate

• can lead to destruction of pancreas

• defective chloride channel → reduced bicarbonate secretion → thicker pancreatic secretion → block pancreatic ducts → drop in digestive enzymes in small intestine

pancreatic enzymes

• most are inactive (zymogens) until they reach the small intestine (prevents auto-digestion of pancreas)

• enterokinase → small intestine brush border

  • converts trypsinogen to trypsin

  • trypsin digests proteins and also activates many other enzymes

acute pancreatitis

• causes: obstruction by gallstones, medications

• results in premature activation of trypsinogen into trypsin → activation of other enzymes → auto-digestion

  • cytokine release by acinar cells directly causes injury → enhances inflammatory response

• most patients can recover completely

chronic pancreatitis

• cause: chronic heavy alcohol consumption

• long-standing pancreatic inflammation

• irreversible destruction of pancreatic tissue

• fibrin deposition → loss of exocrine and endocrine functions

regulation of bile secretion

• chyme enters duodenum and produces two hormones

  • secretin

    • stimulates pancreatic juice/bile secretion

    • responsive to low pH (stops when pH is high)

  • cholecystokinin (CCK)

    • stimulates pancreatic juice/bile secretion

    • responsive to partially digested proteins and fats in chyme

• liver is continuous in bile production but secretion is stimulated by food in duodenum

carbohydrate digestion

• most carbohydrates ingested as polysaccharides (starches) or disaccharides (maltose, sucrose, lactose)

• starts in mouth (salivary amylase) → polysaccharides → shorter chains

• stops in stomach (too acidic)

• continues in small intestine (pancreatic amylase) → short chains → disaccharides

• brush border enzymes finish disaccharides → monosaccharides (glucose)

carbohydrate absorption

• monosaccharides absorbed across small intestine epithelium

• apical → secondary active transport with Na⁺

• basal → facilitated diffusion → capillary blood of villi → hepatic portal vein

protein digestion

• begins in stomach (HCl, pepsin) → proteins → short-chain polypeptides

• finishes in duodenum/jejunum → various pancreatic and brush border enzymes

  • polypeptides → amino acids, dipeptides, tripeptides

protein absorption

• apical:

  • free amino acids → secondary active transport with Na⁺

  • dipeptides, tripeptides → secondary active transport with H⁺ gradient, then hydrolyzed into free amino acids in epithelial cells

• basal:

  • facilitated diffusion → capillary blood of villi → hepatic portal vein

fat digestion

• begins and ends in duodenum

• emulsification of fat droplets by bile salts

• hydrolysis of triglycerides in emulsified fat droplets into fatty acids and monoglycerides

• dissolving of fatty acids and monoglycerides into micelles to produced “mixed micelles”

fat absorption

1. fatty acids and monoglycerides in mixed micelles move to brush border

2. leave micelles and diffuse into epithelial cells of villi

3. resynthesized into triglycerides and phospholipids and packaged with proteins into chylomicrons

4. lympathic vessels

5. enter blood at thoracic duct

chylomicrons

carry and deliver dietary cholesterol and triglycerides to body and liver (exogenous source)

endogenous source

• liver is main producer, processor, and packager of cholesterol and triglycerides

• export:

  • liver-produced cholesterol and triglycerides packaged into VLDL (high triglycerides) → deliver triglycerides from liver to body

  • when triglycerides removed from VLDL → LDL

  • LDL delivers cholesterol to body including blood vessels (contributes to atherosclerosis)

• import:

  • HDL → low cholesterol and triglycerides

  • pick up cholesterol from body including blood vessels and return back to liver (can utilize to make bile salts → protects against atherosclerosis)