Intestinal Absorption: Anatomy, Physiology, Pathology & Medicine

1. ANATOMY

Gross Structure

1. Plicae circulares (valvulae conniventes) - circular folds of mucosa and submucosa, most prominent in the jejunum
2. Villi - finger-like projections of the mucosa (~0.5-1.5 mm), covered by columnar absorptive cells (enterocytes) and goblet cells
3. Microvilli (brush border) - dense projections on the apical surface of enterocytes; each cell has ~1,000 microvilli, forming the "brush border"

The Enterocyte (Absorptive Cell)

• Apical (brush border) membrane (BBM) - faces the lumen; site of digestive enzymes (lactase, sucrase, peptidases) and nutrient transporters
• Basolateral membrane (BLM) - faces blood/lymph; site of exit transporters that deliver absorbed nutrients to the portal circulation or lacteals

Crypt-Villus Axis

• Crypt cells (of Lieberkuhn) - secrete fluid and electrolytes; home to stem cells
• Villus cells - absorb fluid and nutrients
• Tight junctions between cells can be "leaky" (jejunum/ileum) allowing paracellular movement, or "tight" (colon) restricting paracellular flow

Segment-Specific Features

2. PHYSIOLOGY

Fluid and Electrolyte Absorption

• Na+-glucose cotransporters (SGLT1)
• Na+-amino acid cotransporters
• Na+-H+ exchange (driven by carbonic anhydrase)
• Na+-K+ ATPase on the basolateral membrane extrudes Na+ into blood, maintaining the inward gradient
• Net result: absorption of NaHCO₃ + sugars + amino acids

Fig. Mechanisms of electrolyte transport in the jejunum - Costanzo Physiology 7th Edition

• Cl⁻-HCO₃⁻ exchange in the apical membrane
• Cl⁻ transporter (instead of HCO₃⁻) in the basolateral membrane
• Net result: NaCl absorption (H+ secreted to lumen; HCO₃⁻ also secreted to lumen via the apical exchanger)

Fig. Mechanisms of electrolyte transport in the ileum - Costanzo Physiology 7th Edition

• Apical Na+ channels (ENaC) and K+ channels
• Na+ absorption is aldosterone-induced
• Aldosterone increases ENaC expression → increased Na+ entry → increased basolateral Na+-K+ ATPase activity → K+ secretion
• In diarrhea, high flow rate increases colonic K+ secretion → fecal K+ loss → hypokalemia

Nutrient-Specific Absorption Mechanisms

Carbohydrates

• Starch digested by salivary and pancreatic amylase to oligosaccharides, then by brush-border disaccharidases (lactase, sucrase-isomaltase, maltase) to monosaccharides
• Glucose & galactose: absorbed by SGLT1 (Na+-dependent cotransporter, apical) → exit via GLUT2 (basolateral)
• Fructose: absorbed via GLUT5 (facilitated diffusion, apical) → exits via GLUT2 (basolateral)

Proteins

• Gastric pepsin + pancreatic proteases (trypsin, chymotrypsin, elastase, carboxypeptidases) → oligopeptides and amino acids
• Brush-border peptidases complete digestion
• Di- and tripeptides absorbed via PepT1 (H+-dependent cotransporter, apical) - actually more efficient than free amino acid transport
• Free amino acids absorbed via specific Na+-dependent amino acid transporters
• Hartnup syndrome = defect in neutral amino acid transporter → tryptophan malabsorption → niacin deficiency

Lipids

• Pancreatic lipase + colipase hydrolyze triglycerides to 2-monoglycerides + fatty acids
• Products emulsify with bile salts and phospholipids to form mixed micelles - the vehicle for lipid transport to the brush border
• At the BBM, fatty acids and monoglycerides diffuse passively into the enterocyte
• Inside the cell, they are re-esterified in the smooth ER to triglycerides, packaged into chylomicrons with apolipoproteins
• Chylomicrons exit via exocytosis at the basolateral membrane → enter lacteals (lymphatics) → thoracic duct → systemic circulation
• Optimal luminal pH for micelle formation: 6-8 (requires pancreatic HCO₃⁻ to neutralize gastric acid)
• Medium-chain fatty acids bypass this system and absorb directly into portal blood

Iron

• Dietary iron is either heme (from meat) or non-heme (Fe³+)
• Fe³+ is reduced to Fe²+ by duodenal cytochrome B (Dcytb) on the brush border
• Fe²+ enters via DMT1 (divalent metal transporter 1) on the apical membrane
• Exported via ferroportin on the basolateral membrane
• Regulated by hepcidin (liver-produced hormone): hepcidin ↑ → ferroportin degradation → iron trapping in enterocytes
• Absorbed primarily in the duodenum and proximal jejunum

Vitamin B12 (Cobalamin)

• Binds intrinsic factor (IF) secreted by gastric parietal cells
• B12-IF complex binds cubilin receptors in the terminal ileum → endocytosis
• B12 deficiency results from: pernicious anemia (lack of IF), terminal ileum resection/disease, or bacterial overgrowth (bacteria consume B12)

Water-Soluble Vitamins

• Most absorbed via specific Na+-dependent transporters or carrier-mediated mechanisms at the brush border
• Key transporters (per Sleisenger & Fordtran's):
  • Vitamin C: SVCT-1 (Na+-dependent) at the apical membrane
  • Thiamine: THTR-1, THTR-2 (Na+-dependent)
  • Riboflavin: RFT-1, RFT-2
  • Folate: PCFT (proton-coupled folate transporter) + RFC (reduced folate carrier)
  • Biotin, pantothenic acid: SMVT (Na+-dependent multivitamin transporter)
  • DHAA (oxidized vitamin C): absorbed via GLUT1, GLUT3, GLUT4 (glucose transporters) - competitively inhibited by glucose

Calcium

• Absorbed by two routes:
  • Transcellular: vitamin D (1,25-dihydroxyvitamin D3) activates calbindin synthesis → facilitates Ca²+ movement through enterocyte → exported by Ca²+-ATPase (PMCA1b) at basolateral membrane
  • Paracellular: passive, concentration-dependent, occurs throughout small intestine
• Primary site: duodenum and proximal jejunum

Intestinal Secretion (Counterpart to Absorption)

• Crypt cells secrete Cl⁻ via apical CFTR channels
• Basolateral NKCC1 cotransporter loads Cl⁻ into the cell
• Cl⁻ secretion drives Na+ (paracellular) and water into the lumen
• Normally balanced by villus absorption
• Secretion activated by cAMP (ACh, VIP, cholera toxin) or cGMP (heat-stable E. coli enterotoxin)
• Cholera: Vibrio cholerae toxin permanently activates adenylyl cyclase → massive cAMP → maximal Cl⁻ secretion → overwhelms absorptive capacity → life-threatening secretory diarrhea

3. PATHOLOGY

Classification of Malabsorption

Celiac Disease (Gluten-Sensitive Enteropathy)

• Triggered by gluten (wheat, rye, barley) in genetically predisposed individuals (HLA-DQ2 in ~90%, HLA-DQ8 in most of the rest)
• Gluten peptides are deamidated by tissue transglutaminase 2 (TG2) → negatively charged peptides bind HLA-DQ2/8 on antigen-presenting cells → activation of gluten-specific CD4+ T cells → IFN-γ, IL-21, IL-2 production
• Gluten-TG2 complexes → anti-TG2 IgA plasma cells (up to 20% of all intestinal plasma cells in active disease)
• CD4+ T cells + IL-15 → expansion of intraepithelial CD8+ cytotoxic T cells expressing NKG2D/NKG2C → attack epithelial cells via interaction with HLA-E and MICA

• Intraepithelial lymphocytosis (CD8+ T cells in the villous epithelium - most sensitive finding)
• Crypt hyperplasia (increased mitotic activity)
• Villous atrophy - loss of absorptive surface → malabsorption
• Loss of brush-border surface area + impaired enterocyte differentiation → reduced terminal digestion and transepithelial transport
• Increased plasma cells, mast cells, and eosinophils in the lamina propria
• Most pronounced in the second duodenum and proximal jejunum (highest gluten exposure)

• Classic: diarrhea, steatorrhea, weight loss, abdominal distention, failure to thrive (children)
• Non-classic: iron deficiency anemia, osteoporosis, infertility, neurologic symptoms (ataxia, neuropathy), dermatitis herpetiformis
• Silent: positive serology + villous atrophy without symptoms

Bacterial Overgrowth Syndrome

• Normally, motility and gastric acid limit bacteria in the upper small bowel
• Any condition causing local stasis allows a "colonic" flora (coliforms, Bacteroides, Clostridium) to colonize the small intestine
• Anaerobic bacteria deconjugate bile salts → unconjugated bile salts absorbed passively (high pKa) → bile salt concentration falls below critical micellar concentration → fat and fat-soluble vitamin malabsorption
• Bacteria also: consume vitamin B12, release proteases that degrade brush-border disaccharidases → carbohydrate malabsorption
• Bacteria synthesize folate → serum folate normal or high (distinguishes from tropical sprue, where both B12 and folate are low)

• Rifaximin 400 mg orally three times daily
• Alternatives: tetracycline, doxycycline, ciprofloxacin, amoxicillin-clavulanic acid, metronidazole
• Prokinetics for dysmotility: prucalopride, metoclopramide, erythromycin
• Octreotide (50 µg SC daily) for scleroderma-related overgrowth

Crohn's Disease and Malabsorption

• Diarrhea/malabsorption mechanisms include: (1) bacterial overgrowth from obstruction or fistulization, (2) bile acid malabsorption from terminal ileal disease/resection, (3) intestinal inflammation → decreased water and electrolyte absorption, and (4) protein-losing enteropathy
• Bile salt diarrhea (cholerheic diarrhea): unconjugated bile salts reach the colon → secretory diarrhea; treated with cholestyramine

Pancreatic Exocrine Insufficiency

• Lack of lipase, protease, and amylase → impaired intraluminal digestion
• Common causes: chronic pancreatitis, cystic fibrosis, pancreatic cancer
• Treatment: pancreatic enzyme replacement therapy (PERT)

Lactase Deficiency

• Most common cause of selective carbohydrate malabsorption worldwide (primary lactase non-persistence in adults)
• Unabsorbed lactose → osmotic diarrhea + fermentation by colonic bacteria → gas, bloating, cramping
• Diagnosis: hydrogen breath test after lactose load

4. CLINICAL MEDICINE

Approach to Malabsorption

1. History: prior surgery, alcohol use, travel, family history, medications (orlistat causes malabsorption by design)
2. Fecal fat test: positive → malabsorption confirmed
3. Imaging: CT/MR enterography for mucosal disease, lymphoma, strictures; abdominal X-ray for pancreatic calcification
4. Endoscopy + biopsy: upper endoscopy with duodenal biopsies for celiac disease; colonoscopy to terminal ileum for IBD
5. Serology: anti-TG2 IgA (celiac), total IgA level
6. Breath tests: H2 and methane breath tests for lactose/fructose malabsorption or bacterial overgrowth
7. Small intestinal aspirate culture: gold standard for bacterial overgrowth (>10³ CFU/mL)

Key Drug-Related Malabsorption

Oral Rehydration Therapy (ORT) - Clinical Application of Physiology

Parenteral and Enteral Nutrition

• When intestinal absorption is severely compromised (short bowel syndrome, severe Crohn's, radiation enteritis), enteral or parenteral nutrition is required
• Short bowel syndrome: managed with intestinal rehabilitation, teduglutide (GLP-2 analogue that promotes intestinal adaptation), and parenteral nutrition for irreversible cases

• Costanzo Physiology 7th Edition - Intestinal Absorption, Electrolyte Transport
• Sleisenger and Fordtran's Gastrointestinal and Liver Disease - Intestinal Absorption, Bacterial Overgrowth, Water-Soluble Vitamins
• Robbins, Cotran & Kumar Pathologic Basis of Disease - Celiac Disease (Pathogenesis, Morphology)
• Goldman-Cecil Medicine - Malabsorptive Syndromes, Bacterial Overgrowth
• Harrison's Principles of Internal Medicine 22E (2025) - Crohn's Disease