Nutrient absorption: monosaccharides, amino acids, lipid micelles, and the enterohepatic circulation

Intuition Beginner

After digestion breaks food into small molecules, those molecules must cross the intestinal wall and enter the body. This is absorption. The small intestine, with its villi and microvilli providing roughly 250 square metres of surface area, is the primary site where absorption occurs.

Sugars (monosaccharides such as glucose) and amino acids cross the intestinal epithelium and enter capillaries inside each villus. These capillaries drain into the hepatic portal vein, which carries all absorbed sugars and amino acids directly to the liver before they reach the rest of the body. The liver then decides how much glucose to release into general circulation, how much to store as glycogen, and how to process the incoming amino acids.

Fats follow a different route. After lipase digests triglycerides into fatty acids and monoglycerides, these products diffuse into intestinal cells. Inside the cells, they are reassembled into triglycerides and packaged into protein-coated particles called chylomicrons. Chylomicrons are too large to enter blood capillaries, so they are released into lacteals -- lymphatic vessels inside each villus. The lymphatic system carries them to the thoracic duct, which empties into the bloodstream near the left subclavian vein. Fats therefore bypass the liver on first pass.

Bile acids, which emulsify fats in the duodenum, are not wasted after they do their job. Approximately 95% of bile acids are reabsorbed in the terminal ileum and returned to the liver via the blood, where they are secreted back into bile. This recycling loop is the enterohepatic circulation. The total bile acid pool (about 3-4 grams) cycles 6-10 times per day, with only about 0.5 grams lost in faeces and replaced by new synthesis from cholesterol.

Visual Beginner

Nutrient	Digestion product	Absorption route	Destination
Carbohydrates	Glucose, galactose, fructose	Blood capillary -> hepatic portal vein -> liver	Liver, then systemic circulation
Proteins	Amino acids, small peptides	Blood capillary -> hepatic portal vein -> liver	Liver, then systemic circulation
Triglycerides	Fatty acids, monoglycerides	Reassembled into chylomicrons -> lacteal -> lymphatic system -> thoracic duct -> blood	Systemic circulation (bypasses liver initially)
Iron	Fe2+	Blood capillary -> hepatic portal vein -> liver	Bone marrow (erythropoiesis), liver storage
Calcium	Ca2+	Blood capillary -> hepatic portal vein	Bone, muscle, nerve function
Fat-soluble vitamins (A, D, E, K)	Incorporated into micelles	Lacteal (with chylomicrons)	Systemic circulation
Water-soluble vitamins (B, C)	Specific transporters	Blood capillary -> hepatic portal vein	Systemic circulation
Bile acids	Reabsorbed in terminal ileum	Hepatic portal vein -> liver -> resecreted into bile	Enterohepatic circulation (recycled)

Worked example Beginner

Trace the absorption of a glucose molecule from the intestinal lumen to the liver.

Step 1. Apical uptake. Glucose crosses the apical (luminal) membrane of the enterocyte via SGLT1 (sodium-glucose linked transporter 1). This transporter carries 2 sodium ions and 1 glucose molecule into the cell together. The sodium gradient that powers this transport is maintained by the Na+/K+ ATPase on the basolateral membrane, which constantly pumps sodium out of the cell using ATP.

Step 2. Basolateral exit. Inside the enterocyte, glucose concentration is now higher than in the extracellular fluid. Glucose exits the cell across the basolateral membrane via GLUT2, a facilitated diffusion transporter that moves glucose down its concentration gradient into the interstitial fluid.

Step 3. Capillary uptake. Glucose diffuses through the interstitial fluid into the blood capillary inside the villus.

Step 4. Portal circulation. Capillaries in the villi drain into venules, which merge into the hepatic portal vein. This vein carries all nutrient-rich blood from the intestines directly to the liver.

Step 5. Hepatic regulation. The liver extracts a portion of the incoming glucose. It may store glucose as glycogen (glycogenesis), release it to systemic circulation, or convert it to fat (de novo lipogenesis) if glycogen stores are full. The liver thus acts as a metabolic gatekeeper, regulating how much glucose reaches the rest of the body.

Check your understanding Beginner

Formal definition Intermediate+

Carbohydrate absorption

Three monosaccharides are absorbed by the small intestine: glucose, galactose, and fructose. Each uses a distinct transport mechanism.

SGLT1 (SLC5A1) on the apical membrane is the primary route for glucose and galactose. SGLT1 is a sodium-dependent co-transporter that moves 2 Na+ and 1 hexose molecule into the enterocyte per cycle. The driving force is the sodium electrochemical gradient maintained by the basolateral Na+/K+ ATPase (3 Na+ out, 2 K+ in, consuming 1 ATP per cycle). Because SGLT1 concentrates glucose inside the cell above its luminal concentration, this is secondary active transport: the ATP is consumed indirectly by the Na+/K+ ATPase, not by SGLT1 itself.

GLUT5 (SLC2A5) on the apical membrane mediates fructose uptake by facilitated diffusion. Fructose moves down its concentration gradient without coupling to sodium. The fructose-specific transporter is necessary because SGLT1 does not recognise fructose.

GLUT2 (SLC2A2) on the basolateral membrane serves as the exit pathway for all three monosaccharides. GLUT2 is a facilitated diffusion transporter that releases glucose, galactose, and fructose from the enterocyte into the interstitial fluid, from which they enter capillaries.

At high luminal glucose concentrations (after a carbohydrate-rich meal), GLUT2 is also transiently inserted into the apical membrane, providing a high-capacity facilitated diffusion pathway that supplements SGLT1. This apical GLUT2 insertion is regulated by sweetness receptors (T1R2/T1R3) and by the intracellular signalling cascade involving PKC beta II.

Amino acid and peptide absorption

Dietary proteins are hydrolysed to free amino acids and small peptides (di- and tripeptides) by pancreatic proteases and brush-border peptidases. Absorption occurs through two parallel pathways.

Free amino acid transporters. Multiple Na+-dependent co-transporters on the apical membrane handle different amino acid classes:

Transporter system	Substrate specificity	Mechanism
System B0 (SLC6A19 / B0AT1)	Neutral amino acids (Phe, Leu, Val, etc.)	Na+ co-transport
System b0,+ (SLC7A9 / b0,+AT, rBAT)	Cationic + neutral amino acids (Lys, Arg, Cys)	Na+-independent exchanger
System XAG- (SLC1A1 / EAAC1)	Anionic amino acids (Glu, Asp)	Na+ and H+ co-transport, K+ counter-transport
System IMINO (SLC6A20)	Imino acids (Pro, OH-Pro)	Na+ and Cl- co-transport
System ASC (SLC1A5)	Small neutral amino acids (Ala, Ser, Cys)	Na+ co-transport

Basolateral exit of amino acids uses Na+-independent exchangers (systems y+L, asc, L) and facilitative transporters that allow amino acids to diffuse into the interstitial fluid.

PepT1 (SLC15A1) is a proton-coupled oligopeptide transporter on the apical membrane that absorbs dipeptides and tripeptides. PepT1 uses the inward proton gradient (luminal pH is slightly acidic, approximately 6.0 at the brush-border surface) to drive peptide uptake with a 1 H+ : 1 peptide stoichiometry. PepT1 has extremely broad substrate specificity -- it can transport virtually any dipeptide or tripeptide regardless of amino acid composition, which is more efficient than having individual transporters for all 20 amino acids. Inside the enterocyte, cytosolic peptidases hydrolyse the absorbed peptides to free amino acids, which then exit basolaterally.

PepT1 also transports peptidomimetic drugs, including beta-lactam antibiotics (penicillins, cephalosporins), ACE inhibitors (captopril), and the antiviral agent valacyclovir, which explains their good oral bioavailability.

Lipid absorption and chylomicron assembly

Lipid absorption is a multi-step process that differs fundamentally from carbohydrate and protein absorption because the products of lipid digestion (fatty acids, monoglycerides) are hydrophobic.

Step 1: Micelle formation. Bile salts, which are amphipathic molecules (hydrophilic face and hydrophobic face), form mixed micelles with the products of triglyceride digestion (fatty acids, 2-monoglycerides) plus cholesterol, lysolecithin, and fat-soluble vitamins. Micelles are disc-shaped particles (4-8 nm diameter) with the hydrophobic tails of the lipid products facing inward and the hydrophilic bile salt groups facing the aqueous lumen. Micelles solubilise the hydrophobic digestion products and transport them through the unstirred water layer to the brush-border surface.

Step 2: Diffusion into enterocytes. At the brush border, fatty acids and monoglycerides dissociate from the micelle and diffuse passively across the apical membrane down their concentration gradient. The lipid-soluble nature of these molecules allows them to dissolve in and cross the phospholipid bilayer directly. Bile salts remain in the lumen and are absorbed separately in the terminal ileum.

Step 3: Intracellular re-esterification. Inside the enterocyte, fatty acids are activated to fatty acyl-CoA by acyl-CoA synthetase (consuming ATP). Fatty acyl-CoA and 2-monoglyceride are then reassembled into triglyceride by monoacylglycerol acyltransferase (MGAT) and diacylglycerol acyltransferase (DGAT). This re-esterification maintains a low intracellular concentration of free fatty acids, preserving the diffusion gradient from lumen to cell.

Step 4: Chylomicron assembly. Reassembled triglycerides, cholesterol esters, phospholipids, and apolipoprotein B-48 are assembled into chylomicrons in the endoplasmic reticulum and Golgi apparatus. Apo B-48 is essential for chylomicron formation; it is synthesised exclusively by intestinal cells (the 48 refers to the fact that it is 48% of the full-length apo B-100 produced by the liver). Microsomal triglyceride transfer protein (MTP) loads the lipid core onto apo B-48. Abetalipoproteinaemia, caused by MTP mutations, results in failure to form chylomicrons, leading to fat malabsorption and fat-soluble vitamin deficiencies.

Step 5: Lymphatic secretion. Chylomicrons (75-1200 nm diameter) are released from the basolateral membrane by exocytosis into the interstitial fluid. They enter lacteals (lymphatic capillaries) because they are too large to pass through the fenestrations of blood capillaries. Chylomicrons travel through the lymphatic system to the thoracic duct, which empties into the venous circulation at the junction of the left subclavian and internal jugular veins. From there, chylomicrons circulate systemically until lipoprotein lipase (LPL) on capillary endothelial cells hydrolyses their triglycerides, releasing fatty acids for uptake by adipose tissue (storage) or skeletal muscle (energy).

Iron absorption

Iron absorption occurs primarily in the duodenum and proximal jejunum. Dietary iron exists in two forms with distinct absorption pathways.

Heme iron (from haemoglobin and myoglobin in animal products) is absorbed as an intact metalloporphyrin complex via the heme carrier protein 1 (HCP1, SLC46A1) on the apical membrane. Inside the enterocyte, heme oxygenase releases Fe2+ from the porphyrin ring. Heme iron has a higher bioavailability (approximately 15-35% absorbed) than non-heme iron because it does not require reduction and is less affected by dietary inhibitors (phytates, tannins, calcium).

Non-heme iron (from plant sources and fortified foods) is primarily Fe3+ (ferric). It must be reduced to Fe2+ (ferrous) by duodenal cytochrome B (Dcytb, a ferric reductase on the brush border) before transport. Fe2+ enters the enterocyte via DMT1 (divalent metal transporter 1, SLC11A2), a proton-coupled co-transporter. Dietary factors strongly influence non-heme iron absorption: vitamin C (ascorbic acid) enhances absorption by reducing Fe3+ to Fe2+ and chelating iron to keep it soluble; phytates (in grains and legumes), tannins (in tea), and calcium inhibit absorption.

Intracellular fate. Absorbed Fe2+ has two possible fates: (a) it is exported across the basolateral membrane by ferroportin (SLC40A1), the only known cellular iron exporter, and oxidised to Fe3+ by hephaestin (a ferroxidase) for binding to transferrin in the blood; or (b) it is stored intracellularly as ferritin and lost when the enterocyte is sloughed off into the lumen at the end of its 3-5 day lifespan.

Hepcidin regulation. Hepcidin, produced by hepatocytes, is the master regulator of systemic iron homeostasis. Hepcidin binds ferroportin on enterocytes, macrophages, and hepatocytes, inducing its internalisation and degradation. When body iron stores are adequate, hepcidin levels rise, ferroportin is degraded, iron is trapped in enterocytes (and lost in faeces as cells turnover), and dietary iron absorption is reduced. When iron stores are low, hepcidin falls, ferroportin remains on the basolateral membrane, and iron absorption increases. Inflammation (via IL-6) stimulates hepcidin production, causing the anaemia of chronic disease -- functional iron deficiency despite adequate stores.

Calcium absorption

Calcium absorption occurs via two mechanisms in the duodenum and proximal jejunum.

Transcellular (active) transport is vitamin D-dependent and dominates when dietary calcium is low. 1,25-dihydroxyvitamin D3 (calcitriol, the active form of vitamin D) upregulates three components: TRPV6 (a calcium channel on the apical membrane that allows Ca2+ entry down its electrochemical gradient), calbindin-D9k (a cytosolic calcium-binding protein that buffers Ca2+ and facilitates its diffusion across the cell without raising free cytosolic Ca2+ to toxic levels), and PMCA1b (plasma membrane Ca2+ ATPase on the basolateral membrane that pumps Ca2+ out of the cell into the interstitial fluid, consuming ATP).

Paracellular (passive) transport operates throughout the small intestine and dominates when dietary calcium is high. Ca2+ diffuses passively through tight junctions between enterocytes, driven by the electrochemical gradient. This pathway is not vitamin D-dependent.

Vitamin D deficiency impairs transcellular calcium absorption, leading to inadequate bone mineralisation: rickets in children (soft, deformed bones) and osteomalacia in adults (bone pain, fractures).

Vitamin absorption

Fat-soluble vitamins (A, D, E, K) are incorporated into mixed micelles with bile salts, dietary lipids, and cholesterol. They diffuse across the apical membrane with fatty acids and are packaged into chylomicrons for lymphatic transport. Any condition that impairs fat absorption (bile acid deficiency, pancreatic lipase deficiency, celiac disease) can produce deficiencies of fat-soluble vitamins. Vitamin K deficiency causes bleeding (impaired coagulation factor synthesis); vitamin D deficiency causes rickets and osteomalacia; vitamin A deficiency causes night blindness and xerophthalmia; vitamin E deficiency causes haemolytic anaemia and neurologic dysfunction.

Water-soluble vitamins (B complex, C) are absorbed by specific transporters: vitamin C (ascorbic acid) via SVCT1 and GLUT transporters; thiamine (B1) via THTR1 and THTR2; riboflavin (B2) via RFVT3; folate (B9) via PCFT and RFC; and vitamin B12 via the intrinsic factor-cubilin complex in the terminal ileum (see 18.06.02 pending).

Enterohepatic circulation of bile acids

The enterohepatic circulation is a highly efficient recycling system that conserves bile acids between their site of action (intestine) and their site of synthesis (liver).

Hepatic synthesis. Hepatocytes convert cholesterol to the primary bile acids cholic acid and chenodeoxycholic acid via the rate-limiting enzyme cholesterol 7-alpha-hydroxylase (CYP7A1). These are conjugated with glycine or taurine to form bile salts (glycocholate, taurocholate, etc.), which are more water-soluble and better emulsifiers than unconjugated acids.

Intestinal reabsorption. Approximately 95% of secreted bile acids are reabsorbed. The major route is active transport in the terminal ileum by ASBT (apical sodium-dependent bile acid transporter, SLC10A2), a Na+-coupled co-transporter. A smaller fraction is passively reabsorbed along the length of the small intestine and colon (unconjugated bile acids, being more lipophilic, can diffuse passively).

Portal return and resecretion. Reabsorbed bile acids bind to albumin in the portal blood (as bile acid-albumin complexes) and are efficiently extracted by hepatocytes via NTCP (Na+-taurocholate co-transporting polypeptide, SLC10A1) and OATPs (organic anion transporting polypeptides) on the basolateral hepatocyte membrane. The liver resecretts them into bile, completing the cycle.

FXR-FGF19 axis. The nuclear bile acid receptor FXR (farnesoid X receptor) in ileal enterocytes senses intracellular bile acid concentration and induces expression of FGF19 (fibroblast growth factor 19; FGF15 in mice). FGF19 travels via the portal blood to the liver, where it binds FGFR4 on hepatocytes and suppresses CYP7A1 expression via the JNK signalling pathway, inhibiting new bile acid synthesis. This negative feedback loop adjusts bile acid production to match the pool size: when reabsorption is efficient and the returning bile acid load is high, FGF19 suppresses synthesis; when reabsorption is impaired (ileal resection, ASBT deficiency), synthesis increases to compensate.

Gut microbial modification. Colonic bacteria deconjugate and dehydroxylate primary bile acids to produce secondary bile acids (deoxycholic acid from cholic acid, lithocholic acid from chenodeoxycholic acid). These secondary bile acids have distinct signalling properties (activating TGR5, modulating FXR) and are partly reabsorbed passively.

Water and electrolyte absorption

The small intestine absorbs approximately 8-9 litres of water per day (approximately 2 litres from dietary intake plus approximately 7 litres from GI secretions: saliva, gastric juice, bile, pancreatic juice, intestinal secretions). The large intestine absorbs an additional 1-2 litres, leaving approximately 100-200 mL in faeces.

Water absorption is passive, following osmotic gradients created by solute absorption. Na+ absorption is the primary driver: Na+ is absorbed by multiple mechanisms including Na+/nutrient co-transport (SGLT1), Na+/H+ exchange (NHE3), and paracellular diffusion. Cl- follows passively via paracellular pathways and via the apical Cl-/HCO3- exchanger (PAT1, SLC26A6). K+ is absorbed passively in the small intestine (paracellular, driven by the favourable electrochemical gradient) and is secreted in the colon via BK channels (contributing to faecal K+ loss).

In the colon, electrogenic Na+ absorption via ENaC (epithelial sodium channel) is aldosterone-sensitive. Aldosterone, released from the adrenal cortex in response to angiotensin II or hyperkalaemia, upregulates ENaC expression, enhancing Na+ (and water) reabsorption and K+ secretion -- a mechanism shared with the renal distal tubule (see 18.08.01).

Key experiment Intermediate+

Crane (1960-1962) -- the sodium gradient hypothesis for glucose absorption.

Before Robert Crane's work, the mechanism of intestinal glucose absorption was unknown. Glucose could be absorbed against its concentration gradient, but no ATPase had been identified on the apical membrane that could power active glucose transport directly. The prevailing view was that glucose was phosphorylated and then dephosphorylated inside the cell (a "group translocation" mechanism).

Crane, working at the University of Illinois and later the Chicago Medical School, demonstrated that glucose transport by intestinal brush-border membrane preparations was absolutely dependent on sodium. When sodium was removed from the medium, glucose uptake ceased. When sodium was restored, glucose uptake resumed. Furthermore, glucose transport was enhanced by ouabain sensitivity: inhibiting the Na+/K+ ATPase (with ouabain on the basolateral membrane) eventually abolished the sodium gradient and eliminated glucose uptake, but only after a delay consistent with the time required for the sodium gradient to dissipate.

Crane proposed the sodium gradient hypothesis: glucose is co-transported with sodium across the apical membrane, and the energy for glucose accumulation comes not from direct ATP hydrolysis but from the sodium electrochemical gradient maintained by the basolateral Na+/K+ ATPase. This was the first demonstration of secondary active transport.

Proposition (Crane's sodium gradient hypothesis). Glucose transport across the apical membrane of the intestinal enterocyte is coupled to sodium influx. The sodium electrochemical gradient, maintained by the basolateral Na+/K+ ATPase, provides the driving force for glucose accumulation against its concentration gradient. Glucose exits the cell basolaterally by facilitated diffusion via GLUT2.

Derivation. The free energy change for moving one glucose molecule and two sodium ions into the cell is: Delta-G = RT ln([glucose]_in / [glucose]_out) + 2RT ln([Na+]_in / [Na+]_out) + 2F x (psi_in - psi_out), where the last term accounts for the membrane potential (approximately -40 mV, inside negative). With typical values ([Na+]_out approximately 140 mM, [Na+]_in approximately 15 mM, membrane potential approximately -40 mV), the sodium gradient and membrane potential together provide approximately -20 kJ/mol of free energy per sodium ion, sufficient to concentrate glucose intracellularly by a factor of approximately 100-fold above the luminal concentration. $\square$

Bridge. Crane's discovery of sodium-coupled glucose transport had implications far beyond intestinal physiology. The same co-transport mechanism was subsequently found in the renal proximal tubule (SGLT2, the target of the diabetes drugs canagliflozin and dapagliflozin), in neurons (neurotransmitter reuptake transporters), and in the thyroid (sodium-iodide symporter). The oral rehydration solution (ORS) -- a mixture of glucose, sodium, and water that exploits SGLT1 co-transport to drive water absorption in cholera and other diarrhoeal diseases -- is a direct clinical application of Crane's discovery and has saved millions of lives worldwide.

Exercises Intermediate+

Advanced treatment Master

Malabsorption syndromes

Celiac disease (see 18.06.02 pending) produces malabsorption through autoimmune destruction of the duodenal and jejunal mucosa. Gliadin peptides, deamidated by tissue transglutaminase (tTG) and presented by HLA-DQ2/DQ8, activate CD4+ T cells that release IFN-gamma, driving villous atrophy, crypt hyperplasia, and intraepithelial lymphocytosis. The resulting loss of absorptive surface area impairs iron absorption (duodenal damage), folate absorption (jejunal damage), calcium and vitamin D absorption, and carbohydrate absorption (loss of disaccharidases producing secondary lactose intolerance). Fat malabsorption occurs because the reduced surface area limits micelle contact with the brush border. Diagnosis requires positive anti-tTG IgA serology and confirmation by duodenal biopsy showing Marsh stage 3 changes. Treatment is a lifelong gluten-free diet, which allows mucosal recovery over months.

Crohn's disease can affect any segment of the GI tract from mouth to anus in a skip-lesion pattern. Malabsorption results from several mechanisms: (a) mucosal inflammation and ulceration reduce absorptive surface area; (b) strictures cause stasis and bacterial overgrowth, which deconjugate bile acids and damage the brush border; (c) ileal resection disrupts the enterohepatic circulation and vitamin B12 absorption; (d) extensive small bowel resection produces short bowel syndrome. Nutritional deficiencies depend on the affected segments: duodenal Crohn's impairs iron and calcium; jejunal disease impairs carbohydrate, protein, and folate; ileal disease impairs B12 and bile acid recycling. Treatment includes corticosteroids, immunomodulators (azathioprine, methotrexate), biologics (anti-TNF agents, anti-integrin therapies), and dietary modification.

Tropical sprue is a malabsorption syndrome of unclear aetiopathogenesis endemic in tropical regions (Southeast Asia, Caribbean, Central America). It produces villous atrophy and malabsorption of folate and vitamin B12, leading to megaloblastic anaemia. The response to tetracycline and folate supplementation (but not a gluten-free diet) distinguishes it from celiac disease. The aetiology is presumed to be infectious (persistent colonisation by toxin-producing or mucosa-adherent bacteria), though no single organism has been definitively identified.

Bile acid malabsorption

Bile acid malabsorption (BAM) is an underdiagnosed cause of chronic diarrhoea. Three types are recognised: Type 1 (ileal disease or resection, impairing ASBT-mediated reabsorption), Type 2 (primary or idiopathic, caused by overproduction of bile acids exceeding ileal reabsorptive capacity or by ASBT deficiency), and Type 3 (associated with other GI disorders such as post-cholecystectomy, small bowel resection, or celiac disease).

When bile acids escape ileal reabsorption and reach the colon, they stimulate colonic water and electrolyte secretion (via FXR-independent mechanisms, possibly involving PKC activation and increased intracellular calcium) and accelerate colonic transit. Unabsorbed bile acids are deconjugated and dehydroxylated by colonic bacteria; the resulting secondary bile acids (particularly deoxycholic acid) are potent secretagogues.

Diagnosis is by 75SeHCAT (selenium-75-labeled homotaurocholic acid) retention test: a radiolabelled bile acid is administered orally and whole-body retention is measured at 7 days. Retention below 15% indicates bile acid malabsorption. Treatment is with bile acid sequestrants (cholestyramine, colestipol, colesevelam) that bind bile acids in the intestinal lumen, preventing their secretory effect on the colon. The FGF19 analogue obeticholic acid (a potent FXR agonist) is under investigation for Type 2 BAM.

Iron overload: haemochromatosis

Hereditary haemochromatosis (HH) is the most common genetic disorder in populations of northern European descent (carrier frequency approximately 1 in 8-10 for the C282Y HFE mutation). HFE protein normally interacts with transferrin receptor 1 (TfR1) on hepatocytes and enterocytes, contributing to iron sensing and hepcidin regulation. When HFE is mutated (C282Y homozygosity accounts for approximately 80-90% of clinical HH), hepcidin production is inappropriately low relative to body iron stores. The resulting unchecked ferroportin activity causes excessive dietary iron absorption (1-3 mg/day above the normal 1 mg/day, accumulating over decades).

Iron deposits in parenchymal organs: liver (hepatocyte iron loading causing fibrosis, cirrhosis, and a 200-fold increased risk of hepatocellular carcinoma), pancreas (beta-cell iron toxicity causing diabetes mellitus), heart (dilated cardiomyopathy, arrhythmias), pituitary (hypogonadotropic hypogonadism), joints (arthritis, particularly of the 2nd and 3rd MCP joints), and skin (hyperpigmentation, producing the classic "bronze diabetes" appearance).

Diagnosis: transferrin saturation greater than 45% (the most sensitive screening test) followed by genetic testing for HFE mutations. Ferritin is elevated but is an acute-phase reactant and less specific. MRI can quantify hepatic iron concentration non-invasively. Treatment is simple and effective: regular phlebotomy (500 mL blood removes approximately 250 mg iron) to deplete iron stores, then maintenance phlebotomy every 2-4 months. Chelation therapy (deferoxamine, deferasirox) is reserved for patients who cannot tolerate phlebotomy. Early diagnosis and treatment prevent organ damage and normalise life expectancy.

Vitamin deficiencies

Vitamin B12 deficiency and pernicious anaemia. Vitamin B12 (cobalamin) absorption requires intrinsic factor (IF), produced by gastric parietal cells. The IF-B12 complex is absorbed in the terminal ileum by the cubilin/amnionless receptor complex. Pernicious anaemia is an autoimmune condition: autoantibodies target either intrinsic factor itself (blocking antibodies that prevent B12 binding, or binding antibodies that prevent ileal uptake) or gastric parietal cells (causing atrophic gastritis and IF deficiency). B12 deficiency produces megaloblastic anaemia (impaired DNA synthesis due to methylmalonyl-CoA mutase and methionine synthase dysfunction), subacute combined degeneration of the spinal cord (demyelination of the posterior and lateral columns, causing loss of proprioception and vibration sense, weakness, and spasticity), and glossitis (beefy red, sore tongue). Diagnosis: low serum B12, elevated methylmalonic acid, and elevated homocysteine. Treatment is B12 injection (bypassing the GI tract) or high-dose oral B12 (approximately 1-2 mg/day, exploiting passive diffusion at high concentrations).

Vitamin D deficiency and osteomalacia. Vitamin D is absorbed with dietary fat via micelles. Deficiency impairs transcellular calcium absorption by reducing TRPV6, calbindin-D9k, and PMCA1b expression. Inadequate calcium absorption leads to secondary hyperparathyroidism (PTH mobilises calcium from bone), resulting in impaired bone mineralisation: osteomalacia in adults (bone pain, proximal myopathy, Looser zones on X-ray), rickets in children (growth plate widening, bowed legs, rachitic rosary). Risk factors include malabsorption syndromes, limited sun exposure, dark skin, obesity (vitamin D sequestration in adipose tissue), and chronic kidney disease (impaired 1-alpha-hydroxylation of 25-OH vitamin D to calcitriol).

SIBO and bile acid deconjugation

Small intestinal bacterial overgrowth (see 18.06.02 pending) produces malabsorption through several mechanisms that directly relate to nutrient absorption. Colonic-type bacteria that colonise the small intestine in SIBO possess bile salt hydrolase (BSH), an enzyme that deconjugates bile salts (removing the glycine or taurine moiety). Deconjugated bile acids are less effective emulsifiers than conjugated bile salts, reducing micelle formation and fat absorption. The resulting steatorrhea is characteristic of SIBO-associated malabsorption.

Bacterial overgrowth also damages the brush border, reducing disaccharidase activity (producing secondary carbohydrate malabsorption) and competing for nutrients (bacteria consume amino acids and vitamins before the host can absorb them). B12 deficiency is particularly common in SIBO because bacteria bind and utilise B12, and deconjugation of bile salts impairs the formation of the IF-B12 complex.

Short-chain fatty acid production by the intestinal microbiota

The human gut microbiota ferments indigestible dietary polysaccharides (dietary fibre, resistant starch, inulin, pectin) to produce three major short-chain fatty acids (SCFAs): acetate (approximately 60%), propionate (approximately 20%), and butyrate (approximately 20%). Total SCFA production is approximately 500-600 mmol/day.

Butyrate is the primary energy source for colonocytes, providing approximately 70% of their oxidative energy. Butyrate also regulates gene expression through inhibition of histone deacetylases (HDACs), promoting a anti-inflammatory phenotype in colonic macrophages and regulatory T cells. It enhances intestinal barrier function by upregulating tight junction protein expression (claudin-1, occludin, ZO-1) and stimulates mucin production by goblet cells. Butyrate deficiency (from low-fibre diets) impairs colonocyte energy metabolism, weakens the intestinal barrier, and promotes inflammation -- factors linked to inflammatory bowel disease and colorectal cancer.

Propionate is absorbed into the portal circulation and taken up by the liver, where it serves as a substrate for gluconeogenesis (contributing approximately 5-10% of hepatic glucose production in the fasted state). Propionate also activates GPR43 on enteroendocrine L cells, stimulating GLP-1 and PYY secretion, which may contribute to the appetite-suppressing effects of high-fibre diets.

Acetate reaches the peripheral circulation and serves as a substrate for hepatic lipogenesis and cholesterol synthesis. It is also metabolised by peripheral tissues (skeletal muscle, brain) and contributes approximately 10% of total body energy expenditure. Acetate activates GPR41 on sympathetic neurons and has been shown to influence appetite regulation and energy expenditure.

GLP-2 and intestinal adaptation

GLP-2 (glucagon-like peptide-2) is co-secreted with GLP-1 from intestinal L cells in response to luminal nutrients. Unlike GLP-1 (which is an incretin hormone targeting the pancreas), GLP-2 is an intestinotrophic factor: it stimulates crypt cell proliferation, increases villus height, upregulates nutrient transporter expression (SGLT1, PepT1, GLUT2), enhances intestinal blood flow, and inhibits gastric acid secretion and motility (the "ileal brake").

Intestinal adaptation is the process by which the remaining small intestine increases its absorptive capacity after resection. Over weeks to months, villi lengthen, crypt depth increases, and nutrient transporter density rises. This adaptation is mediated largely by GLP-2 and enteral nutrition (luminal nutrients themselves stimulate mucosal growth through direct trophic effects and via stimulation of GLP-2 and other growth factors). Teduglutide, a recombinant GLP-2 analogue (degly-Glu2-GLP-2, resistant to DPP-4 degradation), is approved for the treatment of short bowel syndrome. In clinical trials, teduglutide increased villus height, reduced parenteral nutrition requirements, and improved fluid and nutrient absorption.

Fecal fat testing and 72-hour faecal collection

The gold standard for quantifying fat malabsorption is the 72-hour faecal fat collection (van de Kamer method). The patient consumes a diet containing 100 g fat per day for 3 days while collecting all stool. Faecal fat exceeding 7 g/day on this diet indicates steatorrhea. The test is technically demanding (complete collection is essential, and the analysis requires saponification of faecal triglycerides, acidification, and titration of fatty acids), but it remains the benchmark for diagnosing fat malabsorption.

Qualitative screening tests include the Sudan III stain (microscopic examination of stool for fat droplets; sensitivity approximately 75-90%) and the acid steatocrit (a centrifugation-based method). The 13C-mixed triglyceride breath test is a non-invasive alternative: the patient ingests 13C-labelled triglyceride, and 13CO2 in exhaled breath is measured; reduced 13CO2 recovery indicates fat malabsorption.

Differential diagnosis of steatorrhea follows the sequence of fat digestion and absorption: (a) intraluminal phase (pancreatic lipase deficiency -- chronic pancreatitis, cystic fibrosis; bile acid deficiency -- ileal resection, biliary obstruction); (b) mucosal phase (celiac disease, tropical sprue, Crohn's); (c) delivery phase (abetalipoproteinaemia, lymphangiectasia).

Connections Master

1. 18.06.01 Digestive physiology and nutrition. This unit extends the overview of digestion from 18.06.01 into the specific mechanisms by which digested nutrients cross the intestinal epithelium. That unit introduced the structure of villi, microvilli, and the hepatic portal system; this unit details the transporters (SGLT1, GLUT2, GLUT5, PepT1, DMT1, TRPV6) and processes (micelle formation, chylomicron assembly, enterohepatic circulation) that operate at those anatomical sites.

2. 18.06.02 pending GI motility and secretion. Motility patterns (segmentation, peristalsis, MMC) and secretions (bile, pancreatic enzymes, brush-border enzymes) described in 18.06.02 pending prepare nutrients for the absorption mechanisms described here. Impaired motility (as in scleroderma or diabetic autonomic neuropathy) causes SIBO, which disrupts bile acid conjugation and nutrient absorption. Impaired secretion (pancreatic insufficiency, bile acid deficiency) prevents the luminal digestion steps that are prerequisites for absorption.

3. 17.04.01 Cellular respiration. The monosaccharides, amino acids, and fatty acids absorbed by the intestinal epithelium are the substrates for glycolysis, beta-oxidation, and the citric acid cycle. The energetic cost of nutrient absorption itself is substantial: intestinal Na+/K+ ATPase activity accounts for approximately 15-20% of total body oxygen consumption, reflecting the active transport of sodium-coupled nutrients across the epithelium.

4. 18.08.01 Renal physiology. The sodium-coupled co-transport mechanisms (SGLT1, SGLT2) that absorb glucose in the intestine and kidney share a common principle: secondary active transport powered by the Na+/K+ ATPase. SGLT2 inhibitors (dapagliflozin, empagliflozin), developed to block renal glucose reabsorption in diabetes, also have off-target effects on intestinal SGLT1 at high doses. Iron regulation by hepcidin and ferroportin operates in both enterocytes and renal tubular cells. The ENaC channel, aldosterone-regulated in the distal nephron, also mediates electrogenic sodium absorption in the colon.

5. 17.07.01 Cell signalling -- GPCRs. The FXR receptor (a nuclear receptor, not a GPCR) regulates bile acid synthesis via the FGF19-FGFR4 pathway. The TGR5 receptor (a GPCR activated by bile acids) regulates energy expenditure and GLP-1 secretion. GLP-1 and GIP act through Gs-coupled GPCRs on pancreatic beta cells. The sweet taste receptor T1R2/T1R3 (a GPCR) on enteroendocrine cells regulates apical GLUT2 insertion. Understanding nutrient absorption requires integrating transport physiology with receptor signalling.

6. 18.07.01 Endocrine hormones and regulation. Several hormones regulate nutrient absorption directly: vitamin D (a steroid hormone) upregulates calcium transport proteins (TRPV6, calbindin, PMCA1b); hepcidin (a peptide hormone) regulates iron absorption by controlling ferroportin; GLP-2 (an intestinotrophic hormone) promotes intestinal adaptation by stimulating crypt cell proliferation and transporter expression; aldosterone (a mineralocorticoid) upregulates ENaC in the colon, enhancing sodium and water reabsorption.

Historical & philosophical context Master

The understanding of intestinal absorption evolved through several conceptual revolutions, each driven by new experimental techniques.

Claude Bernard's discovery of the hepatic glycogenic function in the 1850s established that the liver does not merely filter nutrients from portal blood but actively metabolises and regulates them. This was the first demonstration that the liver serves as a metabolic gatekeeper between intestinal absorption and systemic circulation -- the physiological rationale for the hepatic portal system.

The mechanism of glucose absorption remained mysterious until Robert Crane proposed the sodium gradient hypothesis in 1960. Working with intestinal brush-border preparations, Crane demonstrated that glucose uptake was sodium-dependent and ouabain-sensitive, establishing that glucose accumulation was powered not by direct ATP hydrolysis but by the sodium electrochemical gradient maintained by the Na+/K+ ATPase. This was the first description of secondary active transport, a principle now known to apply to hundreds of transporters across all cell types. Crane's work directly enabled the development of oral rehydration therapy: in the late 1960s, David Nalin and Richard Cash, working in Bangladesh and India, demonstrated that a glucose-salt solution could prevent death from cholera-related dehydration by exploiting SGLT1 co-transport to drive water absorption. ORS was adopted by the WHO in 1978 and is estimated to have saved over 50 million lives.

The discovery of the enterohepatic circulation of bile acids was elucidated by Alan Hofmann and colleagues in the 1960s and 1970s. Hofmann's 1972 review in the Journal of Clinical Investigation synthesised decades of work showing that bile acids cycle between liver and intestine with approximately 95% reabsorption efficiency. His group identified ASBT as the terminal ileal transporter and demonstrated that bile acid sequestrants (cholestyramine) could exploit the enterohepatic circulation to lower serum cholesterol by forcing the liver to convert more cholesterol to bile acids. The subsequent discovery of FXR (1995) and the FXR-FGF19 axis (2003 by Inagami and colleagues) revealed the molecular feedback loop that adjusts bile acid synthesis to match pool size, opening the door to FXR-targeted therapies (obeticholic acid for primary biliary cholangitis).

The molecular characterisation of iron absorption progressed from the identification of DMT1 by Nancy Andrews and colleagues (1997, cloning the gene responsible for the microcytic anaemia mk mouse and the Belgrade rat) to the discovery of ferroportin by three independent groups in 2000 and the identification of hepcidin as the iron-regulatory hormone by Sophie Vaulont's group in 2001. Hepcidin was independently discovered as a liver-produced antimicrobial peptide (hence the name: hepatic bactericidal protein) before its role in iron regulation was recognised. The discovery that hepcidin expression is regulated by HFE (the protein mutated in hereditary haemochromatosis) linked the most common genetic disorder of European populations to a defined molecular pathway: HFE normally facilitates BMP6-mediated hepcidin transcription; mutant HFE fails to signal iron sufficiency, hepcidin remains inappropriately low, ferroportin remains active, and iron absorption proceeds unchecked.

The understanding of chylomicron assembly was transformed by the identification of microsomal triglyceride transfer protein (MTP) in 1986 and the recognition that mutations in MTP cause abetalipoproteinaemia (the Bassen-Kornzweig syndrome, described in 1950). This rare disease -- characterised by fat malabsorption, acanthocytosis (spiky red blood cells due to membrane lipid abnormalities), retinal degeneration, and progressive neurologic deterioration -- demonstrated that chylomicron assembly is an essential, genetically programmed process, not merely passive lipid aggregation.

The intestinal microbiome's role in nutrient absorption and energy harvest was highlighted by Jeffrey Gordon's laboratory at Washington University in the mid-2000s. Their landmark 2006 paper in Nature demonstrated that the gut microbiome of obese humans and mice had an increased ratio of Firmicutes to Bacteroidetes and that transplantation of the "obese microbiome" into germ-free mice caused greater weight gain than transplantation of a "lean microbiome," establishing that microbial composition directly influences energy harvest from the diet.

Bibliography Master

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