Phases of Digestion and Absorption

1. Cephalic Phase

• Triggers: sight, smell, taste or thought of food
• Neural Pathways:
  • Cortical and limbic centers → dorsal vagal nucleus
  • Vagal efferents release acetylcholine onto enteric neurons and glands
• Secretions:
  • Salivary glands: increased saliva (mucins, α-amylase, lysozyme, lactoferrin)
  • Stomach: parietal cells secrete HCl; chief cells release pepsinogen; G cells secrete gastrin
  • Pancreas: minor increase in pancreatic juice
• Function: primes the mouth, stomach, and pancreas for incoming food

2. Oral Phase

• Mechanical Processing: mastication breaks food into a soft bolus
• Enzymatic Digestion:
  • Salivary (ptyalin) amylase: starch → maltose and dextrins
  • Lingual lipase: secreted by von Ebner’s glands; up to 50% of neonatal lipolysis
• Lubrication & Defense: mucins coat the bolus; immunoglobulins and lysozyme protect against pathogens
• Function: initiates carbohydrate and lipid digestion; prepares bolus for swallowing

3. Gastric Phase

• Triggers & Stimuli:
  • Distension of fundus and antrum
  • Peptides and amino acids in the lumen
  • pH sensors in the antrum (pH > 3 sustains gastrin; pH < 1.5 inhibits it)
• Neural & Hormonal Mediators:
  • Local enteric reflexes and vagovagal pathways
  • Gastrin from G cells
• Secretions:
  • Parietal cells: HCl (denatures proteins, kills microbes); intrinsic factor (vitamin B₁₂ absorption)
  • Chief cells: pepsinogen → pepsin (cleaves hydrophobic/aromatic amino acids; ~20% of protein digestion)
  • Surface mucous cells: mucus and bicarbonate (mucosal protection)
  • Gastric lipase: acid-stable enzyme; ~30% of triglyceride hydrolysis
• Motility Patterns:
  • Receptive relaxation of the fundus
  • Antral peristalsis and retropulsion to grind food and control gastric emptying
• Function: major site of protein digestion and initial fat hydrolysis; regulates chyme delivery to the duodenum

4. Intestinal Phase

• Early Excitation: transient “gastrin-like” boost in acid secretion when chyme first enters the duodenum
• Enterogastric Inhibition: triggered by duodenal acidification, fats, and hyperosmolarity
  • Neural: enteric reflexes reduce vagal outflow and increase pyloric tone
  • Hormonal:
    • Secretin (S cells): increases pancreatic bicarbonate; inhibits gastric HCl secretion
    • CCK (I cells): stimulates pancreatic enzymes and gallbladder contraction; slows gastric emptying
    • GIP/GLP-1: inhibit acid secretion; potentiate insulin release
• Pancreatic & Biliary Secretions:
  • Pancreatic α-amylase; proteases (trypsin, chymotrypsin, elastase); lipase; phospholipase
  • Bile salts emulsify fats and form micelles for lipid absorption
• Brush-Border Enzymes: disaccharidases (maltase, sucrase, lactase); peptidases; nucleotidases
• Motility:
  • Segmentation for mixing chyme
  • Peristalsis for propulsion
  • Migrating Motor Complex during fasting
• Absorption:
  • Carbohydrates: SGLT1 cotransports glucose and galactose; GLUT5 transports fructose
  • Proteins: amino acid transporters; PEPT1 for di- and tripeptides
  • Lipids: micellar diffusion; re-esterification in enterocytes; chylomicron formation and lymphatic transport
  • Electrolytes & Water: paracellular and osmotic uptake
  • Vitamins: fat-soluble via micelles; vitamin B₁₂ with intrinsic factor in the ileum
• Function: final digestion and major nutrient absorption; coordinates feedback to regulate upstream secretions and motility

Summary Table

Digestion and Absorption: Gastric Emptying and Intestinal Processes

Gastric Emptying

Gastric Factors

• Volume of chyme: Emptying rate increases with greater gastric volume.
• Gastric distension: Activates stretch receptors → enhances peristalsis via vagovagal and enteric reflexes.
• Antral contractions: Coordinated peristaltic waves pulverize solids into particles <2 mm; liquids empty in an exponential pattern.

Duodenal Factors

• Particle size: Pylorus retains particles >2 mm until mechanically reduced.
• pH: Acidic chyme (pH <3) in duodenum triggers secretin release and slows emptying.
• Osmolality: Hyperosmolar chyme activates duodenal osmoreceptors → reflex inhibition of gastric motility.
• Nutrient feedback:
  • Fats and fatty acids: Stimulate CCK and peptide YY (PYY) release, delaying emptying.
  • Amino acids and peptides: Drive CCK secretion, reducing antral contractions.
  • Carbohydrates: Glucose-dependent insulinotropic peptide (GIP) contributes to slowing emptying.
• Ileal brake: Unabsorbed nutrients in distal ileum/colon raise PYY, GLP-1, and GLP-2 levels, further inhibiting gastric emptying.

Effects of Chyme in the Duodenum

• Serotonin (5-HT): Released by enterochromaffin cells in response to distension and nutrients; modulates enteric reflexes and hormone secretion.
• Cholecystokinin (CCK): Secreted by I cells in response to fats and peptides; induces gallbladder contraction, pancreatic enzyme release, and slows gastric emptying.
• Secretin: Released by S cells when luminal pH drops below ~4.5; stimulates pancreatic and biliary bicarbonate secretion to neutralize acid.
• Pancreatic exocrine secretion: Coordinated by cephalic (vagal), gastric (gastrin, acid), and intestinal (CCK, secretin) phases; includes aqueous (HCO₃⁻-rich) and enzymatic components.
• Enteropeptidase (enterokinase): Brush-border enzyme on duodenal crypts; converts trypsinogen to trypsin, initiating the activation cascade of pancreatic zymogens.
• Jejunal secretions: Meal ingestion increases isotonic secretion of water and electrolytes (~6–8 L/day) to maintain chyme fluidity.
• Intestinal motility:
  • Postprandial segmentation and peristalsis mix and propel chyme to maximize nutrient contact.
  • Migrating motor complex transitions to a fed pattern, suspending interdigestive housekeeper waves during digestion.

Intestinal Conservation and Recycling

• Acid–base balance: Pancreatic and Brunner’s gland bicarbonate neutralize gastric acid in the duodenum.
• Nitrogen recycling: Endogenous proteins (digestive enzymes, mucins, shed epithelial cells) are hydrolyzed and amino acids reabsorbed.
• Enterohepatic circulation: Approximately 95% of bile acids are actively reabsorbed in the terminal ileum via ASBT and returned to the liver.
• Fluid and electrolyte absorption: The small and large intestines reclaim over 8 L of secreted fluids daily (H2O and Salt); the colon absorbs ~1.4–1.9 L/day.
• Short-chain fatty acids (SCFAs): Colonic bacteria ferment dietary fibers into acetate, propionate, and butyrate, which are absorbed by nonionic diffusion and promote sodium–water absorption.

Fat Digestion and Absorption

A. Overview

• Lipids supply approximately 40% of adult energy requirements.
• Essential fatty acids—linoleic acid (omega-6) and alpha-linolenic acid (omega-3)—must be obtained from the diet.
• The upper two thirds of the jejunum is the primary site of lipid absorption.
• Soluble dietary fiber reduces fat absorption by binding bile acids and disrupting micelle formation.

B. Fat Digestion

• Hydrolysis of triglycerides yields free fatty acids (FFAs), glycerol, and mono-/diglycerides.
• Gastric phase (20%–30% of lipolysis):
  • Gastric lipase and lingual lipase at pH ~4.5 initiate triglyceride hydrolysis.
• Intestinal phase (70%–80% of lipolysis):
  • Pancreatic lipase and colipase at pH >6.5 complete triglyceride breakdown.
  • Bile salts and phospholipids emulsify lipid droplets and form mixed micelles.
• Phospholipid digestion: pancreatic phospholipase A2 hydrolyzes lecithin to lysophosphatidylcholine.
• Cholesterol esters are hydrolyzed by carboxyl ester lipase (pancreatic cholesterol esterase) in the presence of bile salts and calcium.

C. Fat Absorption

• Mixed micelles ferry FFAs, monoglycerides, bile salts, and fat-soluble vitamins across the unstirred water layer to the brush border membrane (BBM).
• Long-chain fatty acids (LCFAs) cross the BBM via fatty acid transport proteins (e.g., CD36, FATP4).
• Inside enterocytes, LCFAs are activated to fatty acyl-CoA by acyl-CoA synthetase and bound by fatty-acid-binding proteins (FABP) to prevent efflux.
• Short-chain and medium-chain fatty acids diffuse directly across the BBM into the portal circulation.

D. Intracellular Processing and Lipoprotein Assembly

• Absorbed FFAs and monoglycerides are transported to the endoplasmic reticulum (ER).
• Triglycerides are resynthesized via:
  • The monoglyceride pathway using monoacylglycerol acyltransferase.
  • The glycerophosphate pathway via α-glycerophosphate acylation.
• Microsomal triglyceride transfer protein (MTP) loads triglycerides, phospholipids, and cholesterol esters onto apolipoprotein B-48; MTP deficiency causes abetalipoproteinemia.
• Chylomicrons are secreted into lymphatics; in fasting state, very low-density lipoproteins (VLDLs) predominate.

E. Disorders of Fat Absorption

• Pancreatic insufficiency (e.g., cystic fibrosis, chronic pancreatitis).
• Cholestatic liver disease and bile salt malabsorption.
• Celiac disease and inflammatory small-bowel disorders.
• Short-bowel syndrome and mucosal resection.
• Abetalipoproteinemia (MTP deficiency) and familial hypobetalipoproteinemia.
• Intestinal lymphangiectasia causing lymphatic protein and fat loss.

Summary Table

Stages of Fat Digestion and Absorption

Carbohydrate Digestion and Absorption

A. Overview of Dietary Carbohydrates

• Carbohydrates supply the primary energy source; ~50% of digestible calories in Western diets derive from starch and simple sugars.
• Polysaccharides:
  • Amylose: linear α-1,4 glucose polymer.
  • Amylopectin: branched α-1,6 and α-1,4 glucose polymer.
  • Glycogen: animal storage form, highly branched α-1,4/α-1,6 polymer.
• Disaccharides & Monosaccharides:
  • Lactose: glucose + galactose (milk).
  • Sucrose: glucose + fructose (table sugar, fruits).
  • Free sugars: fructose and glucose in fruits and vegetables.
• Oligosaccharides & Sugar Alcohols:
  • Sorbitol: sugar alcohol with slow absorption; minimal glycemic effect.
  • FODMAPs: fermentable oligo-, di-, monosaccharides and polyols that can trigger GI symptoms.
• Dietary Fiber & Resistant Starch:
  • Cellulose, hemicellulose, pectin, gums, alginates, lignin: resistant to human enzymes.
  • Resistant starch: classified RS1–RS4; escapes small-intestinal digestion.
  • Soluble fiber: delays gastric emptying and sugar absorption; attenuates postprandial glycemia.
  • Insoluble fiber: increases stool bulk and transit.

B. Intraluminal Digestion

• Oral phase: salivary α-amylase hydrolyzes starch to dextrins and maltose; activity enhanced by chewing and inactivated by gastric acid.
• Gastric phase: minimal carbohydrate digestion; salivary amylase is denatured by low pH.
• Intestinal phase: pancreatic α-amylase breaks starch into maltose, maltotriose, and α-limit dextrins; accounts for majority of polysaccharide hydrolysis.

C. Brush-Border Digestion

• Lactase-phlorizin hydrolase: splits lactose into glucose and galactose.
• Sucrase-isomaltase: cleaves sucrose into glucose and fructose and α-limit dextrins to glucose.
• Maltase-glucoamylase: hydrolyzes maltose and maltotriose into glucose.
• Trehalase: hydrolyzes trehalose into glucose.

D. Absorption

• Glucose & Galactose: active cotransport via SGLT1 on the apical membrane (Na⁺-dependent); Na⁺ gradient maintained by Na⁺/K⁺-ATPase.
• Fructose: facilitated diffusion via GLUT5 on the apical membrane.
• Basolateral exit: GLUT2 transports monosaccharides from enterocyte to portal circulation.
• Short-chain & medium-chain fatty acids: passive diffusion into portal blood (not requiring micelles).
• Colonic fermentation: undigested carbohydrates and fibers are fermented by microbiota to short-chain fatty acids (acetate, propionate, butyrate), which are absorbed by colonocytes and support colonic health.

E. Enterocyte Monosaccharide Transport

• Monosaccharides are transported by saturable carrier systems in the enterocyte brush border membrane (BBM) in the proximal and mid-small intestine.
• Glucose and Galactose:
  • Actively cotransported with Na⁺ via SGLT1.
  • Each molecule of glucose carries two Na⁺ ions and two anions, driving water absorption across the BBM to maintain iso-osmolality.
  • Congenital glucose-galactose malabsorption from SGLT1 mutations causes severe neonatal diarrhea with carbohydrate feeding.
• Fructose:
  • Absorbed via facilitated diffusion by GLUT5 on the apical membrane.
  • Passes minimally metabolized through enterocytes.
  • Exits the basolateral membrane via GLUT2 into the portal circulation.
  • Fanconi-Bickel syndrome: congenital defect in GLUT2 leading to renal Fanconi syndrome, fasting hypoglycemia, hepatomegaly, growth retardation due to glycogen accumulation.
• Approximately 20% of dietary starch escapes small-intestinal digestion and is fermented by colonic bacteria into short-chain fatty acids, providing energy for colonocytes.

Summary Table

Protein Digestion and Absorption

A. Overview

• Protein supplies 10%–15% of calories in Western diets; Recommended Dietary Allowance is 0.8 g/kg/day for adults, higher in growth, illness, and pregnancy.
• Plant proteins have lower digestibility and a lower PDCAAS/DIAAS score than animal proteins due to antinutrients and limiting amino acids.
• High-quality proteins contain all nine essential amino acids in proportions matching human requirements.
• Overall, over 95% of ingested protein is hydrolyzed and absorbed; 3%–5% is lost in stool.

B. Resistant Proteins and Markers of Loss

• Secretory IgA, intrinsic factor, and α₁-antitrypsin resist luminal proteolysis and serve as markers in protein-losing enteropathies.

C. Intraluminal Digestion

• Gastric phase:
  • Chief cells secrete pepsinogen in response to gastrin, histamine, and vagal acetylcholine.
  • Pepsinogen autoactivates to pepsin at pH < 3.5; pepsin cleaves peptide bonds adjacent to aromatic and hydrophobic residues.
• Pancreatic phase:
  • Enteropeptidase on duodenal brush border converts trypsinogen to trypsin.
  • Trypsin activates prochymotrypsin, proelastase, and procarboxypeptidases.
  • Endopeptidases (trypsin, chymotrypsin, elastase) generate oligopeptides; exopeptidases (carboxypeptidase A & B) release single amino acids from C-terminus.
  • Intraluminal digestion yields ~30% free amino acids and ~70% di- and tripeptides.

D. Brush-Border Peptidases

• Aminopeptidase N and dipeptidyl peptidase IV on the enterocyte surface further cleave oligopeptides into free amino acids, dipeptides, and tripeptides.
• Defects in amino acid carriage (Hartnup disease, cystinuria) do not impair overall protein nutrition because peptide uptake remains intact.

E. Absorption of Amino Acids and Peptides

• Peptide transport:
  • PEPT1 (SLC15A1) actively cotransports di- and tripeptides with H⁺; accounts for the majority of nitrogen uptake.
  • Intracellular peptidases hydrolyze peptides to free amino acids.
• Amino acid transport:
  • Neutral amino acids (alanine, serine): B₀AT1 (SLC6A19) cotransported with Na⁺.
  • Cationic amino acids (lysine, arginine): y⁺LAT1 and cationic exchangers.
  • Anionic amino acids (glutamate, aspartate): EAATs cotransported with Na⁺ and H⁺.
  • Secondary active transport is driven by Na⁺/K⁺-ATPase on the basolateral membrane to maintain gradients.

F. Basolateral Exit and Portal Delivery

• Amino acids exit enterocytes via facilitated diffusion carriers (GLUT2-like for neutral, LAT family for branched‐chain and aromatic).
• Peptides may exit intact via H⁺-coupled peptide effluxers but are largely hydrolyzed before release.
• Glutamine is a primary enterocyte fuel, deaminated to glutamate and NH₃, supporting mucosal integrity.
• Over 80% of absorbed nitrogen reaches the portal vein as free amino acids.

G. Summary Table

Neonatal Intestinal Physiology: Digestion, Absorption, and Vitamin Transport

A. Overview of Neonatal Digestion

• Breast milk fat provides over 50% of neonatal caloric needs, 95% as triglycerides.
• Pancreatic lipase activity is low at birth; bile salt–stimulated lipase from human milk and gastric lipase compensate.
• Ileal bile salt transporters (ASBT) are not expressed at full levels until after weaning.
• Protein digestion is immature: pancreatic proteases increase to adult levels only after weaning.
• Enterokinase is present at birth, enabling some activation of trypsinogen.
• Gastric acid and pepsin are secreted at birth and mature by 3–4 months of age.
• Brush-border monosaccharide and amino acid transporters (SGLT1, GLUT5, PEPT1, various amino acid carriers) are expressed prenatally along the crypt–villus axis.
• Human milk contains trypsin and elastase that contribute to intraluminal protein digestion.

B. Lipid Digestion in Neonates

• Milk triglycerides are emulsified into small droplets enveloped in a trilaminar membrane of phospholipids and proteins (albumin, β-lactoglobulin).
• Gastric lipase (pH 4–6 optimum) and milk bile salt–stimulated lipase hydrolyze triglycerides to free fatty acids and diglycerides.
• Pancreatic lipase contribution is minimal until after weaning.
• Digestion products form mixed micelles with bile salts; absorption occurs in the upper jejunum.

C. Carbohydrate Digestion in Neonates

• Lactose is the primary carbohydrate in milk; high lactase activity at birth ensures efficient hydrolysis to glucose and galactose.
• Minimal salivary and pancreatic amylase activity; starch digestion relies on residual salivary amylase, mucosal α-glucosidases, and colonic bacterial fermentation.
• Pancreatic amylase reaches adult levels by weaning; early starch intolerance can occur.

D. Protein Digestion in Neonates

• Gastric pepsin begins protein hydrolysis; activity matures by 3–4 months.
• Pancreatic proteases (trypsin, chymotrypsin, elastase, carboxypeptidases) are present at low levels until weaning.
• Enterokinase activates trypsinogen; breast milk proteases (plasmin) augment proteolysis.
• Infants tolerate up to 3–4 g/kg casein due to efficient peptide absorption and occasional intact macromolecule uptake (e.g., immunoglobulins via endocytosis).

E. Water-Soluble Vitamin Transport Mechanisms

F. Intestinal Conservation and Barrier Maturation

• Pancreatic secretions and bile flow mature post-weaning, enhancing enzymatic digestion and micelle formation.
• Ileal bile acid transporter (ASBT) expression increases after weaning to support enterohepatic circulation.
• Brush-border monosaccharide and amino acid transporters are fully functional at birth, ensuring nutrient uptake despite enzyme immaturity.
• Neonatal mucosal barrier permits selective macromolecule uptake (e.g., maternal antibodies) while gradually adopting adult tight junction properties.