Digestion & Nutrient Absorption

Digestion is the process of breaking large food molecules — proteins, fats, and complex carbohydrates — down into small enough units to be absorbed through the gut wall into the bloodstream. This requires both mechanical breakdown (chewing, stomach churning) and chemical breakdown (enzymes and acids). Think of the digestive system as a long production line, with each station specialising in a different set of chemical reactions: | Region | Key roles | |--------|-----------| | Mouth | Amylase begins starch digestion; mechanical grinding | | Stomach | HCl kills bacteria, denatures proteins; pepsin begins protein digestion | | Small intestine | Main site of digestion AND absorption; receives bile and pancreatic enzymes | | Large intestine | Water reabsorption; bacterial fermentation of fibre | Why does digestion need to be so thorough? Large food molecules cannot cross the gut wall. A triglyceride (fat) molecule is 850 daltons — far too big. Starch is thousands of glucose units linked together. Proteins are chains of hundreds of amino acids. All of these must be broken down to their monomers before absorption: - Proteins → amino acids - Complex carbohydrates → monosaccharides (glucose, fructose, galactose) - Triglycerides → fatty acids + glycerol (or monoglycerides)

Mouth: Digestion begins the moment food enters the mouth. Salivary amylase (also called ptyalin) is secreted by the salivary glands and begins breaking down starch → maltose and dextrins. It has a pH optimum of ~7 and is rapidly inactivated by stomach acid when food reaches the stomach. Saliva also contains lingual lipase (minor fat digestion) and mucins (glycoproteins that lubricate food for swallowing). Stomach: The stomach serves two main digestive functions: 1. Protein denaturation and initial digestion: - Parietal cells secrete HCl, making gastric juice pH 1–2. This acid denatures proteins (unfolds them, exposing peptide bonds) and converts pepsinogen → pepsin (by cleaving off an inhibitory peptide — this is autocatalytic at low pH) - Pepsin is an endopeptidase (cleaves within the protein chain rather than from the ends) with a pH optimum of 1.5–2. It begins breaking proteins into smaller polypeptides - Chief cells secrete pepsinogen (inactive precursor — a zymogen); parietal cells secrete HCl and intrinsic factor 2. Gastric lipase: secreted by gastric chief cells — responsible for ~10–30% of fat digestion. Important in neonates whose pancreatic lipase is immature. Gastric emptying is regulated: The pyloric sphincter controls the rate at which chyme (the acidic, semi-liquid mixture of food and gastric secretions) enters the duodenum. Fatty meals slow gastric emptying — CCK (cholecystokinin) released from the duodenum signals the stomach to slow down, giving the small intestine time to deal with the fat. Protection from self-digestion: The stomach could digest itself — it has the acid and pepsin to do so. It is protected by a layer of bicarbonate-rich mucus secreted by surface mucous cells. This creates a pH gradient from ~2 at the lumen surface to ~7 at the cell surface. NSAIDs (ibuprofen, aspirin) inhibit prostaglandins that stimulate this protective mucus → chronic NSAID use can cause gastric ulceration.

The small intestine is where most digestion and virtually all absorption takes place. It is ~6 metres long and has a surface area of ~250 m² — the size of a tennis court — thanks to three levels of folding: 1. Plicae circulares — circular folds of the mucosa 2. Villi — finger-like projections (~1 mm tall) 3. Microvilli — tiny projections on each enterocyte forming the "brush border" Duodenal neutralisation: Chyme arriving from the stomach (pH 1–2) is neutralised by bicarbonate secreted by the pancreas and by duodenal Brunner's glands. The pancreas secretes ~1.5–2 litres of bicarbonate-rich juice per day, raising duodenal pH to ~6–7 — the optimal range for pancreatic enzymes. Pancreatic enzymes — the main digestive workhorses: All secreted as inactive zymogens (preventing autodigestion of the pancreas): - Trypsinogen → trypsin (activated by enterokinase on brush border). Trypsin then activates all other zymogens (chymotrypsinogen, proelastase, prolipase, prophospholipase A2) - Trypsin + chymotrypsin + elastase — endopeptidases that cleave proteins at different amino acids - Carboxypeptidase — exopeptidase; cleaves amino acids from the C-terminal end - Pancreatic amylase — digests remaining starch → maltose, maltotriose - Pancreatic lipase — the main fat-digesting enzyme (with colipase as cofactor) - Phospholipase A2 — digests phospholipids Brush border enzymes: Embedded in the microvilli membrane — the final step of digestion: - Lactase — lactose → glucose + galactose - Sucrase — sucrose → glucose + fructose - Maltase — maltose → 2 glucose - Peptidases — digest dipeptides and tripeptides → amino acids Bile — essential for fat digestion: Bile is produced by the liver and stored/concentrated in the gallbladder. Released into the duodenum after a fatty meal (triggered by CCK). Bile salts act as detergents — they are amphipathic (part hydrophobic, part hydrophilic) and emulsify fats: breaking large fat globules into tiny droplets, massively increasing surface area for lipase to work on. Acute pancreatitis — premature activation of pancreatic zymogens WITHIN the pancreas (caused by gallstones blocking the duct, or by alcohol damaging pancreatic cells) → trypsin activated inside pancreas → autodigestion → severe inflammatory destruction. Features: severe epigastric pain, raised amylase/lipase, potentially fatal.

Carbohydrate absorption: Monosaccharides (glucose, galactose, fructose) are absorbed by enterocytes. - Glucose and galactose enter via SGLT1 (sodium-glucose co-transporter 1) — an active process that uses the Na⁺ gradient (maintained by Na⁺/K⁺-ATPase on the basolateral side) to bring glucose in against its concentration gradient. Then exit via GLUT2 on the basolateral side into the portal blood. - Fructose enters passively via GLUT5 and exits via GLUT2 Amino acid absorption: Multiple specific transporters (by amino acid type) co-transport amino acids with Na⁺ — similar to glucose. Dipeptides and tripeptides can also enter via PepT1 (a H⁺-peptide co-transporter) and are hydrolysed inside the enterocyte. Fat absorption — the most complex process: 1. Bile salts emulsify fat → small droplets 2. Pancreatic lipase (with colipase) cleaves triglycerides → 2 fatty acids + 1 monoglyceride 3. Fatty acids + monoglycerides are incorporated into micelles (tiny spherical structures stabilised by bile salts) for transport to the brush border 4. At the membrane, fatty acids and monoglycerides diffuse passively into enterocytes (being fat-soluble) 5. Inside the enterocyte, they are reassembled into triglycerides in the smooth ER 6. Triglycerides are packaged with cholesterol, phospholipids, and apolipoprotein B-48 into chylomicrons — large lipoprotein particles 7. Chylomicrons are secreted into lacteals (lymphatic vessels in each villus), not directly into blood. They travel via the thoracic duct and enter the bloodstream at the subclavian vein. This is why dietary fat appears as milky white lymph (chyle) in the lacteals after a fatty meal — and why fat absorption is disrupted by fat-soluble vitamin deficiencies (A, D, E, K all travel with dietary fat in chylomicrons). Vitamin B12 absorption (unique): Requires intrinsic factor (IF) — a glycoprotein secreted by gastric parietal cells. IF binds B12 in the stomach; the B12-IF complex is absorbed in the terminal ileum via specific receptors. This is why ileal disease (Crohn's disease) or terminal ileum resection causes B12 deficiency, and why pernicious anaemia (no IF) requires injectable B12.

Digestion is not a simple mechanical process — it is precisely orchestrated by a family of gut hormones that coordinate the activities of the stomach, pancreas, gallbladder, and small intestine. Gastrin: - Secreted by: G cells in the stomach antrum - Trigger: peptides in stomach, stomach distension, vagal stimulation - Actions: stimulates parietal cells to secrete HCl; promotes gastric motility; trophic (growth-promoting) effect on gastric mucosa - Clinical: Zollinger-Ellison syndrome — a gastrin-secreting tumour (gastrinoma) causes massively elevated gastrin → uncontrolled HCl hypersecretion → multiple peptic ulcers in unusual locations (jejunum), diarrhoea, oesophageal damage. Treated with high-dose PPIs and surgical removal. Secretin: - Secreted by: S cells in the duodenum - Trigger: acid (low pH) arriving from the stomach - Actions: stimulates pancreas to secrete bicarbonate-rich fluid (to neutralise acid); inhibits gastric acid secretion; stimulates bile flow Cholecystokinin (CCK): - Secreted by: I cells in the duodenum and jejunum - Trigger: fat and protein in the duodenum - Actions: stimulates pancreatic enzyme secretion; causes gallbladder contraction → bile release into duodenum; relaxes sphincter of Oddi; slows gastric emptying; induces satiety (feeling full) - Clinical: gallstones can block the common bile duct → CCK triggers gallbladder contraction → severe right upper quadrant pain (biliary colic). No bile enters duodenum → fat malabsorption → pale fatty stools (steatorrhoea), fat-soluble vitamin deficiencies. GLP-1 (Glucagon-Like Peptide-1): - Secreted by: L cells in the ileum and colon - Trigger: nutrients (especially carbohydrates) reaching the distal gut - Actions: stimulates insulin secretion (incretin effect); suppresses glucagon; slows gastric emptying (reduces post-meal glucose spike); reduces appetite - Clinical: GLP-1 receptor agonists (semaglutide/Ozempic, liraglutide) mimic GLP-1 → used for Type 2 diabetes AND obesity. Semaglutide causes ~15% body weight loss in trials — one of the most effective obesity treatments ever discovered. They work by slowing gastric emptying, reducing appetite, and enhancing insulin release.