Intestinal Absorption

Absorption is the transfer of digested nutrients, water, electrolytes and vitamins from the gut lumen into blood or lymph. For NEET PG, the highest yield lies in the specific transporters, the site of absorption of each nutrient, and the regulatory hormones (hepcidin, intrinsic factor). Master the transporter names and you have won half the questions.

Overview & general principles

The small intestine is the principal absorptive organ, with the duodenum and jejunum doing most of the work. Surface area is amplified ~600-fold by three devices:

1. Plicae circulares (valves of Kerckring) → ×3
2. Villi → ×10
3. Microvilli (brush border) → ×20

Routes of absorption: transcellular (through the enterocyte, requires transporters) and paracellular (between cells, through tight junctions, driven by solvent drag and concentration gradients). The jejunum has "leaky" tight junctions (high paracellular flux); the colon has "tight" junctions (low permeability, allowing it to scavenge the last Na⁺ and water).

High-yield: The basolateral Na⁺-K⁺-ATPase is the master pump. By keeping intracellular Na⁺ low, it generates the electrochemical gradient that powers virtually every secondary active transporter at the apical brush border (SGLT1, PepT1, amino-acid carriers). Ouabain blocks it → all coupled absorption fails.

Region	Primary absorptive role
Duodenum	Iron, calcium, folate, most water-soluble vitamins
Jejunum	Carbohydrates, amino acids, fats (peak), water-soluble vitamins
Ileum	Vitamin B12, bile salts (enterohepatic), fat-soluble vitamins
Colon	Water, Na⁺, K⁺ secretion, short-chain fatty acids

Carbohydrate digestion & absorption

Dietary carbohydrate is mostly starch (amylose + amylopectin), sucrose and lactose. Only monosaccharides can be absorbed.

Digestion flow: Starch → salivary & pancreatic α-amylase → maltose, maltotriose, α-limit dextrins → brush-border enzymes (maltase, isomaltase, lactase, sucrase) → glucose, galactose, fructose.

Absorption:

• Glucose & galactose enter the enterocyte apically via SGLT1 (SLC5A1) — a secondary active, Na⁺-coupled symporter (2 Na⁺ : 1 glucose).
• Fructose enters apically via GLUT5 (SLC2A5) — facilitated diffusion, Na⁺-independent. This is why fructose is absorbed more slowly and excess causes osmotic diarrhoea.
• All three monosaccharides exit basolaterally via GLUT2 (SLC2A2) into the portal blood.

High-yield: SGLT1 is the molecular basis of oral rehydration solution (ORS) — glucose-coupled Na⁺ absorption continues even in cholera because the enterotoxin does not damage SGLT1. This drives water reabsorption and is the single most life-saving physiological fact in GI.

Sugar	Apical transporter	Mechanism	Energy source
Glucose	SGLT1	Secondary active (symport)	Na⁺ gradient
Galactose	SGLT1	Secondary active (symport)	Na⁺ gradient
Fructose	GLUT5	Facilitated diffusion	None
(Basolateral exit, all)	GLUT2	Facilitated diffusion	None

Clinical correlate: Lactase is the first brush-border enzyme to fall and the last to recover after gut injury → secondary lactose intolerance after gastroenteritis. Glucose-galactose malabsorption = SGLT1 mutation (osmotic diarrhoea from birth, fructose tolerated).

Protein digestion & absorption

Proteins are digested by gastric pepsin (optimum pH 1.6–3.2; activated from pepsinogen by HCl), then pancreatic proteases. Trypsinogen is activated by enteropeptidase (enterokinase) on the brush border → trypsin, which then activates chymotrypsinogen, proelastase and procarboxypeptidases (autocatalytic cascade).

End products: free amino acids + di- and tripeptides.

• Di- and tripeptides are absorbed apically by PepT1 (SLC15A1), an H⁺-coupled symporter (uses the proton gradient from the apical Na⁺/H⁺ exchanger). PepT1 is highly relevant pharmacologically — it transports β-lactam antibiotics, ACE inhibitors and valaciclovir.
• Free amino acids use multiple Na⁺-dependent (and some Na⁺-independent) carriers, grouped by amino-acid class (neutral, basic, acidic, imino).

High-yield: Peptide absorption (di/tripeptides via PepT1) is faster and more efficient than free amino-acid absorption — a favourite MCQ contrast. Inside the cell, cytoplasmic peptidases split peptides into amino acids before basolateral exit.

Inborn errors (named, high-yield):

Disease	Defective transporter	Amino acids affected	Hallmark
Hartnup disease	Neutral AA transporter (B⁰AT1/SLC6A19)	Tryptophan & other neutral AAs	Pellagra-like rash, cerebellar ataxia
Cystinuria	Dibasic AA transporter (SLC3A1/SLC7A9)	Cystine, Ornithine, Lysine, Arginine ("COLA")	Cystine renal stones

Mnemonic for cystinuria: "COLA" stones = Cystine, Ornithine, Lysine, Arginine.

Fat digestion & absorption

This is the most multi-step pathway and a perennial favourite.

Stepwise approach:

1. Emulsification — bile salts + mechanical churning break fat into small droplets (↑ surface area).
2. Lipolysis — pancreatic lipase (with colipase, which anchors lipase to the droplet against bile salt displacement) hydrolyses triglycerides → 2 free fatty acids + 1 2-monoglyceride.
3. Micelle formation — products + bile salts + fat-soluble vitamins + cholesterol form mixed micelles that ferry lipids across the unstirred water layer to the brush border.
4. Diffusion — fatty acids and monoglycerides diffuse passively into the enterocyte (bile salts stay behind and are reabsorbed in the ileum).
5. Re-esterification — within smooth ER, triglycerides are resynthesised (monoglyceride pathway).
6. Chylomicron assembly — TG + cholesterol + phospholipid + apoB-48 packaged via MTP (microsomal triglyceride transfer protein).
7. Exocytosis into lacteals (lymphatics) → thoracic duct → systemic circulation.

High-yield: Long-chain fatty acids → chylomicrons → lymphatics. Short- and medium-chain fatty acids are water-soluble, bypass micelles and chylomicrons, and pass directly into portal blood bound to albumin. This is why MCT oil is used in fat malabsorption (e.g. chylomicron retention disease, lymphangiectasia).

High-yield: Abetalipoproteinaemia = defective MTP → no chylomicron/VLDL assembly → fat-laden enterocytes, acanthocytes, retinitis pigmentosa, spinocerebellar degeneration, fat-soluble vitamin deficiency (esp. vitamin E). Low TG, low cholesterol, absent apoB.

Cholesterol is absorbed apically via NPC1L1 — the target of ezetimibe. Plant sterols are pumped back out by ABCG5/G8 (mutated in sitosterolaemia).

Iron absorption

Iron exists as haem and non-haem (ionic) iron. Absorption occurs chiefly in the duodenum.

Flow: Dietary Fe³⁺ → reduced to Fe²⁺ by duodenal cytochrome b (DcytB) & gastric acid/ascorbate → enters enterocyte apically via DMT1 (divalent metal transporter 1) → either stored as ferritin (lost when cell sheds) or exported basolaterally via ferroportin → oxidised back to Fe³⁺ by hephaestin → binds transferrin in plasma.

High-yield: Hepcidin (from liver) is the master negative regulator. It binds and degrades ferroportin, blocking iron export from enterocytes and macrophages. ↑Hepcidin (inflammation, IL-6) → anaemia of chronic disease (iron trapped, low serum iron, high ferritin). ↓Hepcidin → iron overload (hereditary haemochromatosis, HFE/HJV mutations).

• Haem iron is absorbed intact (more efficient, ~20–30% vs ~5–10% non-haem) and iron is freed inside the cell by haem oxygenase.
• Enhancers of non-haem absorption: vitamin C, gastric acid, meat. Inhibitors: phytates, tannins (tea), phosphates, antacids/PPIs, calcium.

Factor	Effect on iron absorption
Ferrous (Fe²⁺) form, vitamin C, HCl	↑
Hepcidin, inflammation	↓ (ferroportin degraded)
Phytates, tannins, PPIs	↓
Iron deficiency, hypoxia, ↑erythropoiesis	↑ (hepcidin suppressed)

Vitamin B12 (cobalamin) absorption

A classic multi-step, multi-site question.

Flow: Dietary B12 (protein-bound) → freed by gastric acid & pepsin → binds R-protein (haptocorrin/transcobalamin I) in stomach → pancreatic proteases degrade R-protein in duodenum → B12 transfers to intrinsic factor (IF) (secreted by gastric parietal cells) → IF–B12 complex absorbed in terminal ileum via cubilin (cubam) receptor → in blood B12 carried by transcobalamin II.

High-yield: Site of B12 absorption = terminal ileum, and it requires intrinsic factor from parietal cells. Loss of parietal cells (autoimmune pernicious anaemia, gastrectomy) or ileal disease/resection (Crohn's, ileal resection) → B12 deficiency → megaloblastic anaemia + subacute combined degeneration of the cord.

Other causes: fish tapeworm (Diphyllobothrium latum), blind-loop bacterial overgrowth, terminal ileal TB.

Other key absorption facts

• Folate absorbed in the proximal jejunum (deconjugated to monoglutamate first); transported by PCFT/RFC.
• Calcium absorbed mainly in duodenum — active, vitamin D (calcitriol)-dependent via TRPV6 channel and calbindin; passive paracellular route in jejunum/ileum.
• Fat-soluble vitamins (A, D, E, K) require micelles & bile → deficient in cholestasis, fat malabsorption.
• Water-soluble vitamins generally absorbed in upper small bowel (B12 the exception → ileum).
• Bile salts reabsorbed by ASBT (apical sodium-dependent bile acid transporter) in the terminal ileum — the enterohepatic circulation (recycles ~95%, 6–8 cycles/day).
• Water absorption is entirely passive, secondary to solute (mainly Na⁺ and glucose) absorption — the osmotic engine of ORS.

Diagnosis & investigation of malabsorption

When a stem describes steatorrhoea, weight loss and deficiencies, think malabsorption and know the investigation of choice:

Test	What it assesses
D-xylose test	Mucosal (small-bowel) absorption — abnormal in mucosal disease (coeliac), normal in pancreatic causes
Faecal elastase / faecal fat (Sudan III)	Pancreatic exocrine insufficiency / steatorrhoea
Schilling test (historical)	Localises cause of B12 malabsorption (IF vs ileal vs bacterial)
Hydrogen breath test	Lactose intolerance, bacterial overgrowth
Duodenal/jejunal biopsy	Coeliac (villous atrophy), Whipple, lymphangiectasia

High-yield: The D-xylose test differentiates mucosal from pancreatic malabsorption — it is abnormal in coeliac disease but normal in chronic pancreatitis (because xylose needs no enzymes, only intact mucosa).

Management / clinical pearls (drug & nutrient targets)

• ORS (WHO low-osmolarity) exploits SGLT1 — first-line in acute diarrhoea.
• Ezetimibe blocks NPC1L1 → ↓cholesterol absorption.
• PepT1 drug delivery: valaciclovir (prodrug) is absorbed via PepT1 far better than aciclovir.
• MCT oil for fat malabsorption (bypasses lymphatics).
• Pancreatic enzyme replacement for exocrine insufficiency; parenteral B12 for pernicious anaemia/ileal disease.
• Oral iron (ferrous sulphate) best on empty stomach with vitamin C; alternate-day dosing improves absorption (less hepcidin spike).

Complications & associated syndromes

• Bile salt diarrhoea after ileal resection (<100 cm) → cholestyramine; larger resection → fatty diarrhoea + oxalate stones.
• Enteric hyperoxaluria — unabsorbed fatty acids bind calcium, freeing oxalate for absorption → calcium oxalate renal stones (a classic link in fat malabsorption).
• Fat-soluble vitamin deficiencies — night blindness (A), osteomalacia (D), neuropathy/haemolysis (E), bleeding (K).
• Megaloblastic anaemia + neuropathy in B12 deficiency.

Key differentials of malabsorption

• Coeliac disease — villous atrophy, anti-tTG/EMA antibodies, HLA-DQ2/DQ8, duodenal biopsy; D-xylose abnormal.
• Chronic pancreatitis — enzyme deficiency; D-xylose normal, faecal elastase low.
• Crohn's / ileal disease — B12 and bile-salt malabsorption.
• Bacterial overgrowth (blind loop) — deconjugated bile salts, B12 low but folate often high (bacteria synthesise folate).
• Tropical sprue / Whipple's disease — chronic tropical malabsorption; PAS-positive macrophages (Tropheryma whipplei).

Recently asked / exam angle

• "Transporter for glucose at apical membrane of enterocyte?" → SGLT1 (Na⁺-coupled). Basolateral exit → GLUT2.
• "Fructose absorption transporter?" → GLUT5 (facilitated, Na⁺-independent).
• "Most efficient form of protein absorption?" → Di/tripeptides via PepT1 (H⁺-coupled).
• "Site of vitamin B12 absorption?" → Terminal ileum, needs intrinsic factor.
• "Hormone regulating iron absorption / degrades ferroportin?" → Hepcidin.
• "Iron absorbed in?" → Duodenum, via DMT1 (apical), exported by ferroportin.
• "Test to differentiate mucosal vs pancreatic malabsorption?" → D-xylose.
• "Defect in abetalipoproteinaemia?" → MTP; "ezetimibe target?" → NPC1L1; "cystinuria amino acids?" → COLA.
• "Why does ORS work in cholera?" → SGLT1-mediated glucose-Na⁺ co-transport is intact.

Rapid revision

1. SGLT1 = apical Na⁺-glucose/galactose symporter; GLUT5 = fructose; GLUT2 = basolateral exit of all three.
2. Na⁺-K⁺-ATPase (basolateral) powers all secondary active transport; ouabain blocks it.
3. PepT1 absorbs di/tripeptides (H⁺-coupled) — faster than free amino acids; also carries β-lactams, ACE inhibitors, valaciclovir.
4. Hartnup = neutral AA transporter defect (pellagra-like); Cystinuria = COLA stones.
5. Long-chain fats → chylomicrons → lymphatics; MCFA/SCFA → portal blood directly.
6. Lipase needs colipase; MTP assembles chylomicrons; NPC1L1 absorbs cholesterol (ezetimibe target).
7. Abetalipoproteinaemia = MTP defect → acanthocytes, vitamin E deficiency, retinitis pigmentosa.
8. Iron: duodenum, DMT1 in, ferroportin out, hepcidin degrades ferroportin (↑ in chronic disease).
9. Vitamin B12: terminal ileum, needs intrinsic factor (parietal cells), receptor = cubilin.
10. Folate → jejunum; Calcium → duodenum (vitamin D/TRPV6); bile salts → terminal ileum (ASBT, enterohepatic).
11. D-xylose abnormal in mucosal disease, normal in pancreatic insufficiency.
12. ORS works because cholera toxin spares SGLT1 glucose-coupled Na⁺ (and water) absorption.