Medical School · Year 2 · Gastrointestinal · includes a quiz and discussion video

Lecture 4: Digestion and Absorption

Unit 2.2: Gastrointestinal System

Learning Objectives

By the end of this lecture, students will be able to:

1. Describe the digestion and absorption of carbohydrates
2. Explain protein digestion and amino acid absorption
3. Describe lipid digestion, micelle formation, and fat absorption
4. Explain vitamin absorption (water-soluble and fat-soluble)
5. Describe mineral and electrolyte absorption
6. Explain water absorption throughout the GI tract

Lecture Content

Overview of Digestion and Absorption

Digestion and absorption transform the complex macromolecules in food into forms the body can use. Digestion refers to the chemical breakdown of food into absorbable units—starches into monosaccharides, proteins into amino acids and small peptides, and fats into fatty acids and monoglycerides. Absorption refers to the transport of these nutrients across the intestinal epithelium into the blood or lymph.

Different nutrients are absorbed at different sites along the gastrointestinal tract. Iron and calcium are absorbed primarily in the duodenum, where the acidic environment from gastric emptying enhances their solubility. Most nutrients—carbohydrates, proteins, fats, and most vitamins—are absorbed in the jejunum, which has the greatest surface area and the highest density of transporters. Bile acids and vitamin B12 are absorbed specifically in the terminal ileum, which has specialized transport mechanisms. The colon absorbs water and electrolytes, concentrating fecal material.

The small intestine achieves its remarkable absorptive capacity through surface area amplification. Three structural features combine multiplicatively. The plicae circulares (circular folds) increase surface area approximately 3-fold. The villi—finger-like projections of mucosa—add another 10-fold increase. The microvilli of the brush border provide approximately 20-fold amplification. Together, these structures increase the absorptive surface by about 600-fold, from roughly 0.5 square meters to nearly 300 square meters—approximately the size of a tennis court.

This enormous surface area provides absorptive capacity far exceeding daily requirements. The intestine can absorb virtually all of the 300-400 grams of carbohydrate, 70-100 grams of protein, and 60-100 grams of fat consumed in a typical Western diet, with absorption efficiency exceeding 95% for each macronutrient under normal conditions.

<image>Panel A: GI tract with absorption sites marked along its length, including the duodenum for iron and calcium, the jejunum as the primary absorption site for most nutrients, the terminal ileum for bile acids and B12, and the colon for water and electrolytes. Panel B: Surface area amplification illustrated in cross-section of small intestine showing plicae circulares providing 3-fold increase, villi providing 10-fold increase, and microvilli brush border providing 20-fold increase for a total 600-fold amplification. Panel C: Surface area comparison showing 0.5 square meters of flat intestine amplified to 300 square meters, depicted alongside a tennis court for scale. Panel D: Absorption efficiency bar chart showing carbohydrate 300-400 g/day at greater than 99% efficiency, protein 70-100 g/day at greater than 95%, and fat 60-100 g/day at greater than 95%.</image>

Carbohydrate Digestion

Dietary carbohydrates come in several forms. Starch (both amylose and amylopectin from grains, potatoes, and legumes) constitutes 50-60% of carbohydrate intake. Sucrose (table sugar, fruits) accounts for 30-40%. Lactose (milk sugar) contributes 5-10%. Smaller amounts of fructose, maltose, and trehalose are also consumed. Dietary fiber (cellulose, hemicellulose) cannot be digested by human enzymes but is fermented by colonic bacteria.

Starch digestion begins in the mouth with salivary α-amylase (ptyalin). This enzyme cleaves internal α-1,4 glycosidic bonds within starch chains but cannot cleave the α-1,6 branch points in amylopectin. Salivary amylase is inactivated by gastric acid, so its contribution to total starch digestion is modest unless food is poorly chewed and swallowed rapidly.

Pancreatic α-amylase continues starch digestion in the duodenum and jejunum. This enzyme is secreted in active form and works at the neutral pH established by pancreatic bicarbonate. Like salivary amylase, it cleaves only α-1,4 bonds. The products of amylase digestion are maltose (two glucose units), maltotriose (three glucose units), and α-limit dextrins (branched oligosaccharides containing α-1,6 bonds that amylase cannot cleave).

Final digestion occurs at the brush border. The enterocyte apical membrane contains disaccharidases that complete carbohydrate breakdown. Maltase and glucoamylase cleave maltose and maltotriose to glucose. Isomaltase (α-dextrinase) cleaves the α-1,6 bonds in α-limit dextrins, releasing glucose. Sucrase cleaves sucrose into glucose and fructose. Lactase cleaves lactose into glucose and galactose. Trehalase cleaves trehalose (found in mushrooms and insects) into two glucose molecules.

The final products of carbohydrate digestion are three monosaccharides: glucose (from starch, sucrose, and lactose), galactose (from lactose), and fructose (from sucrose and free dietary fructose). Only these monosaccharides can be absorbed.

<image>Panel A: Starch molecular structure showing amylose as a linear chain with alpha-1,4 glycosidic bonds and amylopectin as a branched chain with both alpha-1,4 and alpha-1,6 bonds at branch points. Panel B: Digestion pathway from salivary amylase in the mouth through pancreatic amylase in the small intestine, both cleaving only alpha-1,4 bonds, producing maltose, maltotriose, and alpha-limit dextrins. Panel C: Brush border enzymes on the enterocyte surface showing maltase and glucoamylase cleaving maltose and maltotriose to glucose, isomaltase cleaving alpha-1,6 bonds to glucose, sucrase cleaving sucrose to glucose and fructose, and lactase cleaving lactose to glucose and galactose. Panel D: Final monosaccharide products color-coded as glucose in blue, galactose in green, and fructose in yellow, representing the only absorbable carbohydrate forms.</image>

Carbohydrate Absorption

Glucose and galactose absorption depends on the same transporter: SGLT1 (sodium-glucose cotransporter 1) on the enterocyte apical membrane. SGLT1 couples the transport of glucose or galactose to sodium, moving two sodium ions for every sugar molecule. Sodium moves down its concentration gradient (maintained by the basolateral Na⁺/K⁺-ATPase), and this energy drives sugar uptake against its concentration gradient. This is secondary active transport—the sodium gradient, established by primary active transport (the Na⁺/K⁺-ATPase), powers sugar accumulation.

Once inside the enterocyte, glucose and galactose exit across the basolateral membrane via GLUT2, a facilitated diffusion transporter. From the interstitial space, these sugars enter capillaries and travel via the portal vein to the liver.

Fructose uses a different mechanism. GLUT5 on the apical membrane transports fructose by facilitated diffusion, not requiring sodium coupling. This means fructose absorption depends on its concentration gradient and has a lower capacity than glucose absorption. High fructose loads can overwhelm GLUT5 capacity, causing fructose malabsorption with osmotic diarrhea, bloating, and gas. Fructose exits the basolateral membrane via GLUT2.

Clinical conditions illustrate these mechanisms. Lactose intolerance results from reduced lactase activity, which is the ancestral human state; lactase persistence into adulthood evolved in populations with dairy traditions. Undigested lactose reaches the colon, where bacterial fermentation produces gas (bloating, flatulence) and the osmotic effect draws water into the lumen (diarrhea). Glucose-galactose malabsorption is a rare autosomal recessive disorder caused by SGLT1 mutations, presenting in infancy with severe watery diarrhea upon exposure to glucose, galactose, or lactose (which contains galactose). Affected infants can absorb fructose normally.

<image>Panel A: Enterocyte with apical brush border facing the intestinal lumen and basolateral membrane facing the capillary, showing SGLT1 transporter coupling two sodium ions with one glucose or galactose molecule for secondary active transport into the cell. Panel B: GLUT5 transporter on the apical membrane mediating fructose entry by facilitated diffusion along its concentration gradient, with lower capacity than SGLT1, alongside the basolateral Na+/K+-ATPase maintaining the sodium gradient. Panel C: Basolateral GLUT2 transporter releasing all three monosaccharides (glucose, galactose, fructose) into the interstitium for entry into capillaries and transport via the portal vein. Panel D: Clinical correlations showing lactose intolerance with undigested lactose reaching the colon causing bacterial fermentation, gas, and osmotic diarrhea, and glucose-galactose malabsorption from SGLT1 defect with preserved fructose tolerance.</image>

Protein Digestion

Protein digestion begins in the stomach with pepsin. Chief cells in the gastric mucosa secrete pepsinogen, an inactive zymogen. The acidic gastric environment (pH 1-3) triggers autocatalytic cleavage of pepsinogen to active pepsin. Pepsin is an endopeptidase that works optimally at low pH and cleaves proteins preferentially at aromatic amino acid residues (phenylalanine, tyrosine, tryptophan). Although pepsin is not essential for protein digestion (patients without gastric function can still digest proteins), it initiates the process and produces large polypeptides that become substrates for pancreatic proteases.

Pancreatic proteases perform the bulk of protein digestion in the duodenum and jejunum. All are secreted as inactive zymogens and activated in the intestinal lumen. The key initiating event is the action of enterokinase (enteropeptidase), a brush border enzyme that cleaves trypsinogen to produce active trypsin. Trypsin then activates all other pancreatic proteases, including more trypsinogen (autocatalytic amplification), chymotrypsinogen → chymotrypsin, proelastase → elastase, and procarboxypeptidases → carboxypeptidases A and B.

Trypsin, chymotrypsin, and elastase are endopeptidases (cleaving internal peptide bonds) with different specificities: trypsin cleaves after basic amino acids (lysine, arginine), chymotrypsin after aromatic residues, and elastase after small neutral residues. Carboxypeptidases are exopeptidases that remove amino acids from the C-terminus: carboxypeptidase A removes neutral amino acids, carboxypeptidase B removes basic amino acids.

Final digestion occurs at the brush border. Aminopeptidases remove amino acids from the N-terminus. Various dipeptidases and tripeptidases cleave small peptides. The products are free amino acids and small peptides (di- and tripeptides), both of which can be absorbed.

<image>Panel A: Gastric phase showing chief cells secreting pepsinogen, autocatalytic activation to pepsin in the low pH environment, and pepsin cleaving proteins at aromatic amino acid residues to produce large polypeptides. Panel B: Pancreatic phase showing enterokinase on the brush border activating trypsinogen to trypsin, which then activates chymotrypsinogen, proelastase, and procarboxypeptidases in a cascade diagram. Panel C: Enzyme specificities labeled for each protease, including trypsin cleaving after lysine and arginine, chymotrypsin after phenylalanine, tyrosine, and tryptophan, elastase after small neutral residues, and carboxypeptidases removing C-terminal amino acids. Panel D: Brush border phase showing aminopeptidases and dipeptidases on the enterocyte surface completing digestion to free amino acids and di- and tripeptides.</image>

Protein and Amino Acid Absorption

Amino acids are absorbed by multiple sodium-coupled transporters on the enterocyte apical membrane, each with specificity for different amino acid classes. The neutral amino acid transporter handles most amino acids. Basic amino acid transporters handle lysine, arginine, and ornithine. Acidic amino acid transporters handle glutamate and aspartate. The imino acid transporter handles proline and hydroxyproline. Like glucose absorption, these transporters use the sodium gradient maintained by basolateral Na⁺/K⁺-ATPase to drive amino acid uptake.

Remarkably, di- and tripeptides are absorbed more efficiently than free amino acids. The peptide transporter PepT1 on the apical membrane couples peptide uptake to the proton gradient (H⁺ cotransport). This transporter has broad specificity and can transport virtually any di- or tripeptide regardless of amino acid composition. Once inside the enterocyte, intracellular peptidases rapidly hydrolyze these peptides to free amino acids, which then exit across the basolateral membrane via various amino acid transporters (often facilitated diffusion) into the portal circulation.

This explains why protein hydrolysates (partially digested proteins containing peptides) in enteral nutrition formulas may be absorbed better than formulas containing only free amino acids. It also explains how certain drugs designed as dipeptides (like the ACE inhibitors enalapril and lisinopril) are well absorbed.

Intact protein absorption is normally minimal in adults. Tight junctions between enterocytes prevent paracellular passage of large molecules. However, specialized mechanisms exist for specific situations. In neonates, enterocytes can take up intact immunoglobulins (particularly IgA) from breast milk by transcytosis, providing passive immunity. M cells overlying Peyer's patches sample antigens (including intact proteins) for presentation to the immune system. Pathologic breakdown of the epithelial barrier (as in celiac disease or food allergies) can allow inappropriate intact protein absorption, triggering immune responses.

Genetic defects in amino acid transporters cause specific diseases. Hartnup disease results from defective neutral amino acid transport, causing tryptophan malabsorption and niacin deficiency (tryptophan is a niacin precursor). Cystinuria involves defective transport of cystine and basic amino acids in both intestine and kidney, leading to cystine kidney stones.

<image>Panel A: Enterocyte apical surface showing multiple sodium-coupled amino acid transporters labeled by specificity for neutral, basic, acidic, and imino amino acids, each cotransporting one sodium ion with one amino acid. Panel B: PepT1 transporter on the apical membrane mediating proton-coupled uptake of di- and tripeptides, with intracellular peptidases converting absorbed peptides to free amino acids, and an inset demonstrating that peptide absorption is more efficient than free amino acid absorption. Panel C: Basolateral membrane amino acid transporters releasing free amino acids by facilitated diffusion into the portal circulation, with a note on minimal intact protein absorption and exceptions including neonatal IgA uptake and M cell antigen sampling. Panel D: Clinical correlations showing Hartnup disease with defective neutral amino acid transport causing tryptophan malabsorption and niacin deficiency, and cystinuria with defective basic amino acid transport leading to cystine kidney stones.</image>

Lipid Digestion

Dietary lipids present a unique challenge: they are hydrophobic and do not mix with the aqueous intestinal contents. Triglycerides constitute approximately 90% of dietary fat. Phospholipids, cholesterol, and fat-soluble vitamins make up the remainder.

The first step in fat digestion is emulsification—breaking large fat globules into small droplets to increase surface area for enzyme action. Mechanical mixing in the stomach and intestine, combined with the surfactant properties of bile acids and phospholipids, creates a fine emulsion of fat droplets.

Fat digestion begins even before the duodenum. Lingual lipase (secreted by tongue glands) and gastric lipase (secreted by gastric chief cells) work at acidic pH and initiate triglyceride hydrolysis, accounting for 10-30% of total fat digestion. These acid-stable lipases are particularly important in neonates, whose pancreatic function is immature.

Pancreatic lipase performs the bulk of triglyceride digestion in the duodenum. However, pancreatic lipase requires a cofactor: colipase, also secreted by the pancreas. Bile acids coat fat droplets and would exclude lipase from the interface if not for colipase, which anchors lipase to the droplet surface in the presence of bile acids. Pancreatic lipase cleaves fatty acids from the 1 and 3 positions of triglycerides, yielding two free fatty acids and one 2-monoglyceride.

Other lipases complete digestion of other lipid classes. Phospholipase A2, secreted as a proenzyme and activated by trypsin, cleaves phospholipids to yield lysophospholipids and fatty acids. Cholesterol esterase hydrolyzes cholesterol esters to free cholesterol and fatty acids. Remarkably, cholesterol esterase is active against a broad range of lipid substrates.

<image>Panel A: Dietary lipid composition showing triglyceride structure with three fatty acids attached to a glycerol backbone representing 90% of dietary fat, alongside phospholipids and cholesterol. Panel B: Emulsification process with large fat globules broken into small droplets by amphipathic bile acids coating the surface with hydrophilic heads facing water. Panel C: Lipase action showing gastric lipase at low pH accounting for 10-30% of digestion, and pancreatic lipase in the duodenum anchored to bile-coated droplets by colipase, cleaving fatty acids at positions 1 and 3 to yield two free fatty acids and one 2-monoglyceride. Panel D: Additional lipid enzymes including phospholipase A2 cleaving phospholipids to lysophospholipids and fatty acids, and cholesterol esterase cleaving cholesterol esters to free cholesterol and fatty acids.</image>

Lipid Absorption

The products of fat digestion (fatty acids, monoglycerides, cholesterol, lysophospholipids) are incorporated into mixed micelles formed by bile acids. These micelles are tiny aggregates (3-10 nm diameter) with bile acids forming the outer shell (hydrophilic portions facing the water) and lipid digestion products in the interior. Micelles ferry lipids through the unstirred water layer adjacent to the brush border, where they cannot otherwise penetrate due to their hydrophobicity.

At the enterocyte brush border, lipids diffuse out of micelles and cross the apical membrane. Long-chain fatty acids and monoglycerides are sufficiently hydrophobic to diffuse across the lipid bilayer, though fatty acid transport proteins (particularly CD36) facilitate this process. Cholesterol uptake involves a specific transporter, NPC1L1 (Niemann-Pick C1-like 1), which is the target of the cholesterol absorption inhibitor ezetimibe. The bile acids themselves remain in the lumen—they are not absorbed here but continue to the terminal ileum for reclamation.

Inside the enterocyte, absorbed lipids are re-esterified. Fatty acids are activated by CoA attachment and combined with monoglycerides to reform triglycerides in the smooth endoplasmic reticulum. Cholesterol is re-esterified by ACAT (acyl-CoA:cholesterol acyltransferase). These reformed lipids must be packaged for transport because they cannot travel freely in the aqueous blood.

Chylomicrons are the lipid transport vehicles. These large lipoprotein particles have a core of triglycerides and cholesterol esters, surrounded by a shell of phospholipids, free cholesterol, and apolipoproteins. Apolipoprotein B-48 is essential for chylomicron assembly; its absence (abetalipoproteinemia) prevents chylomicron formation and causes severe fat malabsorption. ApoA and ApoC are also incorporated.

Chylomicrons are too large to enter blood capillaries directly. Instead, they exit the enterocyte basolaterally and enter lacteals—specialized lymphatic capillaries in the villus core. Chylomicrons travel via lymphatic vessels to the thoracic duct, which empties into the left subclavian vein. Thus, dietary fat bypasses the portal circulation initially, entering the systemic circulation directly.

<image>Panel A: Mixed micelle structure as a spherical aggregate 3-10 nm in diameter with bile acids on the surface and lipid digestion products in the interior, approaching the brush border through the unstirred water layer. Panel B: Enterocyte apical membrane showing lipid diffusion from micelles with CD36 assisting fatty acid uptake and NPC1L1 transporting cholesterol, while bile acids remain in the lumen for reclamation in the terminal ileum. Panel C: Intracellular processing in the smooth endoplasmic reticulum with re-esterification of fatty acids and monoglycerides to triglycerides and cholesterol re-esterification by ACAT, followed by chylomicron assembly in the Golgi with a core of triglycerides and cholesterol esters and a shell of phospholipids, free cholesterol, ApoB-48, ApoA, and ApoC. Panel D: Chylomicron export by exocytosis from the basolateral membrane, entry into lacteals rather than capillaries due to large size, and lymphatic transport via the thoracic duct to the systemic circulation, bypassing the liver initially.</image>

Fat-Soluble Vitamin Absorption

The fat-soluble vitamins—A, D, E, and K—share the same basic absorption mechanism as dietary fat. They require bile acids for micellar solubilization and are absorbed along with lipid digestion products. Conditions that impair fat absorption (bile acid deficiency, pancreatic insufficiency, mucosal disease) cause deficiency of all fat-soluble vitamins.

Vitamin A comes in two dietary forms. Preformed vitamin A (retinol and its esters) is found in animal products. Provitamin A carotenoids (primarily β-carotene) are found in plants. Retinyl esters are hydrolyzed in the intestinal lumen, and free retinol is absorbed. Inside enterocytes, β-carotene is cleaved to yield retinal, which is reduced to retinol. Retinol is re-esterified and packaged into chylomicrons for transport to the liver, the primary storage site.

Vitamin D absorption is similar. Both vitamin D2 (ergocalciferol, from plant sources) and vitamin D3 (cholecalciferol, from animal sources and skin synthesis) are absorbed in the proximal small intestine, incorporated into micelles, and transported in chylomicrons. The liver then converts these to 25-hydroxyvitamin D (calcidiol), the main circulating form.

Vitamin E encompasses several tocopherols and tocotrienols, with α-tocopherol being the most biologically active. Vitamin E is absorbed passively, transported in chylomicrons, and subsequently distributed to tissues where it serves as the primary membrane-bound antioxidant.

Vitamin K exists as K1 (phylloquinone, from green leafy vegetables) and K2 (menaquinones, produced by intestinal bacteria). Dietary K1 requires bile for absorption, while bacterial K2 may be absorbed in the colon without bile. Vitamin K is essential for carboxylation of clotting factors (II, VII, IX, X) and osteocalcin. Fat malabsorption or antibiotic suppression of gut bacteria can lead to vitamin K deficiency and coagulopathy.

<image>Panel A: General principle of fat-soluble vitamin absorption showing vitamins A, D, E, and K incorporated into micelles with bile acids, absorbed alongside lipids, and packaged into chylomicrons for transport. Panel B: Vitamin A absorption with retinol from animal sources absorbed directly and beta-carotene from plants cleaved to retinol in the enterocyte then re-esterified for chylomicron transport and liver storage, alongside vitamin D showing D2 from plants and D3 from animal sources and skin absorbed via chylomicrons and transported to the liver for 25-hydroxylation. Panel C: Vitamin E as alpha-tocopherol absorbed passively and functioning as a membrane-bound antioxidant, alongside vitamin K showing K1 from vegetables requiring bile for absorption and K2 from intestinal bacteria with possible colonic absorption, functioning in clotting factor carboxylation. Panel D: Consequences of fat malabsorption causing deficiency of all four vitamins, with night blindness from vitamin A deficiency, rickets from vitamin D deficiency, neuropathy from vitamin E deficiency, and coagulopathy from vitamin K deficiency.</image>

Water-Soluble Vitamin Absorption

Water-soluble vitamins generally require specific transport mechanisms, though several can be absorbed by passive diffusion at high concentrations. Unlike fat-soluble vitamins, water-soluble vitamins are not stored significantly, so regular dietary intake is necessary.

The B vitamins use various transport mechanisms. Thiamine (B1) is absorbed by sodium-coupled transporters at low concentrations; passive diffusion contributes at high intakes. Riboflavin (B2) uses carrier-mediated transport with saturable kinetics. Niacin (B3) can be absorbed by both passive diffusion and sodium-coupled transport. Pantothenic acid (B5) uses a sodium-coupled transporter (SMVT). Pyridoxine (B6) crosses by passive diffusion. Biotin (B7) uses the sodium-dependent multivitamin transporter (SMVT, shared with pantothenic acid). Folate (B9) uses the proton-coupled folate transporter (PCFT) in the proximal small intestine.

Vitamin B12 (cobalamin) has the most complex absorption mechanism of any vitamin. B12 in food is bound to proteins, which must first be digested. Gastric acid and pepsin release B12 from food proteins. In the stomach, B12 binds to R-proteins (haptocorrins) secreted by salivary and gastric glands—R-proteins have higher affinity for B12 at acidic pH than does intrinsic factor.

In the duodenum, pancreatic proteases digest R-proteins, releasing B12. Free B12 then binds to intrinsic factor (IF), a glycoprotein secreted by gastric parietal cells. The IF-B12 complex is resistant to proteolysis and travels to the terminal ileum. There, specific receptors (cubilin, along with amnionless) on ileal enterocytes recognize and internalize the IF-B12 complex. B12 is released intracellularly and enters the circulation bound to transcobalamin II.

Any disruption in this pathway causes B12 deficiency. Pernicious anemia results from autoimmune destruction of parietal cells, eliminating both acid (needed to release B12 from food) and intrinsic factor. Gastrectomy or atrophic gastritis has similar effects. Pancreatic insufficiency impairs R-protein digestion. Ileal resection or Crohn's disease affecting the terminal ileum eliminates the absorptive site.

Vitamin C (ascorbic acid) is absorbed via sodium-dependent vitamin C transporters (SVCT1 and SVCT2). At high doses, passive diffusion also contributes, though absorption efficiency decreases.

<image>Panel A: B vitamin transport mechanisms in table format showing thiamine via sodium-coupled transport, riboflavin via carrier-mediated transport, pyridoxine via passive diffusion, biotin via the sodium-dependent multivitamin transporter, and folate via the proton-coupled folate transporter. Panel B: Vitamin B12 absorption pathway through the GI tract, from release of B12 from food proteins by gastric acid and pepsin, to binding with R-proteins in the stomach, to R-protein digestion by pancreatic enzymes in the duodenum freeing B12 to bind intrinsic factor. Panel C: IF-B12 complex traveling to the terminal ileum where cubilin receptors mediate internalization, with B12 entering the blood bound to transcobalamin II, and causes of B12 deficiency annotated at each disruption point including pernicious anemia, gastrectomy, pancreatic insufficiency, and ileal disease or resection. Panel D: Vitamin C absorption via SVCT1 and SVCT2 sodium-dependent transporters shown separately from the B vitamins.</image>

Mineral Absorption

Iron absorption is tightly regulated because humans have no mechanism for iron excretion; body iron is controlled solely through absorption. Most dietary iron is in the ferric (Fe³⁺) form or bound in heme. Non-heme iron absorption occurs primarily in the duodenum and requires reduction to the ferrous (Fe²⁺) form.

At the brush border, duodenal cytochrome b (DcytB) reduces Fe³⁺ to Fe²⁺. The divalent metal transporter 1 (DMT1) then transports Fe²⁺ across the apical membrane. Once inside the enterocyte, iron has two fates. It can be stored bound to ferritin, which sequesters iron and prevents its transfer to the body (this iron is lost when the enterocyte sloughs). Alternatively, iron can cross the basolateral membrane via ferroportin, the only known iron exporter. Hephaestin (a ferroxidase) oxidizes Fe²⁺ back to Fe³⁺ as it exits, and Fe³⁺ binds to transferrin for transport in blood.

Hepcidin, a hormone produced by the liver, is the master regulator of iron homeostasis. Hepcidin binds to ferroportin and induces its internalization and degradation, preventing iron export from enterocytes (and from macrophages that recycle red cell iron). When iron stores are adequate, hepcidin is high and iron absorption is low. When iron stores are depleted, hepcidin falls and ferroportin activity increases, enhancing absorption. Inflammation also increases hepcidin, explaining the anemia of chronic disease.

Calcium absorption occurs by two mechanisms. Transcellular (active) absorption predominates at low calcium intake and is vitamin D-dependent. Vitamin D induces expression of apical calcium channel TRPV6, the intracellular calcium-binding protein calbindin, and the basolateral calcium ATPase (PMCA) and sodium-calcium exchanger (NCX). Paracellular (passive) absorption through tight junctions predominates at high calcium intake and does not require vitamin D.

Other minerals use specific transporters. Magnesium is absorbed via TRPM6 and TRPM7 channels in the intestine. Zinc uses the ZIP4 transporter; mutations cause acrodermatitis enteropathica. Phosphate is absorbed via sodium-phosphate cotransporters. Copper enters via CTR1.

<image>Panel A: Iron absorption in the duodenum showing ferric iron reduced to ferrous iron by DcytB at the brush border, ferrous iron entering via DMT1, and intracellular fate as either storage in ferritin lost when the cell sloughs or export via ferroportin with hephaestin converting iron back to the ferric form for binding to transferrin in blood. Panel B: Hepcidin regulation of iron absorption showing the liver producing hepcidin when iron stores are replete, hepcidin binding ferroportin and causing its degradation, thereby blocking iron export from enterocytes. Panel C: Calcium absorption via the transcellular vitamin D-dependent pathway with TRPV6 apical channel, calbindin shuttling calcium through the cytoplasm, and PMCA and NCX on the basolateral membrane, alongside the paracellular passive pathway through tight junctions predominating at high calcium intake. Panel D: Other mineral transporters including magnesium via TRPM6 and TRPM7, zinc via ZIP4, phosphate via sodium-phosphate cotransporter, and copper via CTR1.</image>

Water and Electrolyte Absorption

The gastrointestinal tract processes enormous volumes of fluid daily. Dietary intake provides about 2 liters. Salivary, gastric, pancreatic, biliary, and intestinal secretions add another 7 liters. Of this 9-liter total, the small intestine absorbs 7-8 liters, the colon absorbs 1-2 liters, and only 100-200 mL appears in feces. The colon has reserve capacity to absorb up to 4-5 liters daily, which is why diarrhea typically occurs only when this capacity is exceeded.

Water absorption is passive, driven by solute absorption. There are no active water transporters. When sodium and other solutes are absorbed, water follows osmotically through aquaporin water channels in cell membranes and through tight junctions (paracellular pathway). The small intestine has relatively leaky tight junctions, allowing efficient bulk water absorption. The colon has tighter junctions, allowing feces to become hypertonic relative to plasma.

Sodium absorption in the small intestine occurs by several mechanisms. Co-transport with glucose (SGLT1) and amino acids couples nutrient and sodium absorption. The sodium-hydrogen exchanger (NHE3) absorbs sodium while secreting hydrogen. These mechanisms allow efficient sodium and water absorption during and after meals.

In the colon, the epithelial sodium channel (ENaC) is the primary absorptive mechanism. This is the same channel present in the renal collecting duct and is aldosterone-regulated. Hyperaldosteronism increases colonic sodium absorption just as it increases renal sodium retention.

Chloride absorption is partially coupled to sodium (through tight junctions maintaining electroneutrality) and partially through chloride-bicarbonate exchangers. In the ileum and colon, coupled NHE3 and Cl⁻/HCO₃⁻ exchange produces net NaCl absorption.

Potassium is secreted in the colon (unlike the small intestine, where it is absorbed). This becomes clinically significant in severe diarrhea, which can cause hypokalemia.

<image>Panel A: Fluid balance overview showing 2 liters of dietary input plus 7 liters of GI secretions totaling 9 liters, with the small intestine absorbing 7-8 liters, the colon absorbing 1-2 liters, and only 100-200 mL appearing in feces, with colonic reserve capacity of 4-5 liters per day noted. Panel B: Small intestine sodium and water absorption showing SGLT1 and amino acid cotransporters bringing sodium with nutrients, NHE3 exchanging sodium for hydrogen, and water following osmotically through aquaporins and leaky tight junctions. Panel C: Colonic absorption showing the aldosterone-regulated epithelial sodium channel ENaC absorbing sodium, chloride following for electroneutrality, tighter junctions concentrating feces, and potassium secretion into the lumen. Panel D: Coupled sodium chloride absorption in the ileum and colon with NHE3 and chloride-bicarbonate exchanger working together, and a clinical note that severe diarrhea causes hypokalemia from colonic potassium secretion.</image>

Summary

• Carbohydrates: Amylase → brush border enzymes → SGLT1/GLUT5/GLUT2
• Proteins: Pepsin → pancreatic proteases → brush border → Na⁺-coupled AA transporters, PepT1
• Lipids: Emulsification → lipase/colipase → micelles → chylomicrons → lymphatics
• Fat-soluble vitamins (ADEK): Require bile and fat; absorbed with lipids
• B12: Requires intrinsic factor; absorbed in terminal ileum
• Iron: Fe²⁺ via DMT1; regulated by hepcidin
• Water: 9 L/day absorbed; follows solute absorption

Key Terms

This content is subject to the MIT License. © 2024–2026 Hibbert School of Medicine.

Read this lecture as Markdown