4.1 Gastrointestinal Physiology: Secretion, Motility, Digestion & Absorption

Why this area matters

The 2025 TOS lists:

• "sites and processes in the intake, digestion, absorption, metabolism and excretion of carbohydrates, fats and protein";
• the gut-brain axis and the main enzymes;
• the regulation of gut motility and the mechanism of stomach acidity, including the "alkaline tide";
• the effects of Helicobacter pylori on the gastric mucosal barrier;
• fluid exchange in the gut.

This physiology explains peptic ulcer, diarrhea, malabsorption and dehydration in the clinical subjects.

Fluid handling in the gut

About 9 L of fluid enters the gut each day: roughly 2 L from food and drink and 7 L from saliva, gastric, biliary, pancreatic and intestinal secretions. The small intestine absorbs most of it, about 7 to 8 L. The colon absorbs about 1 to 1.5 L and can absorb up to about 5 to 8 L a day, so stool water is normally only about 100 to 200 mL.

• Secretory diarrhea, such as cholera, occurs when cholera toxin permanently activates Gs, raises cAMP and opens CFTR chloride channels in crypt cells. The gut's secretory output then exceeds its absorptive capacity.
• Glucose-coupled sodium absorption through SGLT1 still works in cholera. That is the physiological basis of oral rehydration solution.

Gastric, Pancreatic and Biliary Secretion

Gastric Acid Secretion by Parietal Cells

Gastric acid ($HCl$) is secreted by oxyntic parietal cells in the gastric body and fundus via the apical $H^+/K^+$ ATPase pump (proton pump), which extrudes $H^+$ into the lumen in exchange for $K^+$ against a 3-million-to-1 gradient. Carbonic anhydrase supplies protons while extruding $HCO_3^-$ into peritubular capillaries across the basolateral membrane (postprandial "alkaline tide").

1. Secretory Stimuli (Potentiating Synergy):
   • Histamine: Released by Enterochromaffin-Like (ECL) cells in the lamina propria; binds parietal cell $H_2$ receptors $\rightarrow G_s \rightarrow$ adenylyl cyclase $\rightarrow \uparrow \text{cAMP} \rightarrow \text{PKA}$.
   • Gastrin: Secreted by antral G cells into the bloodstream; binds $CCK_B$ receptors on parietal cells and ECL cells $\rightarrow G_q \rightarrow PLC \rightarrow \uparrow IP_3 / Ca^{2+}$.
   • Acetylcholine (ACh): Released by vagal postganglionic parasympathetic efferents; binds parietal cell $M_3$ receptors $\rightarrow G_q \rightarrow PLC \rightarrow \uparrow IP_3 / Ca^{2+}$.
   • Physiological Potentiation: Simultaneous activation of the cAMP and $Ca^{2+}$ pathways generates an acid secretory response far greater than the sum of each stimulus alone. This explains why $H_2$ receptor antagonists (famotidine) markedly suppress acid output even when gastrin or vagal tone is elevated.
2. Inhibitory Regulators:
   • Somatostatin: Secreted by antral D cells when luminal pH drops below $3.0$; binds $SST_2$ receptors ($G_i$-coupled) on G cells, ECL cells, and parietal cells, shutting down adenylyl cyclase.
   • Prostaglandin $E_2$ ($PGE_2$): Binds $EP_3$ receptors ($G_i$) on parietal cells to inhibit cAMP, while stimulating mucous and bicarbonate secretion by superficial mucous cells. NSAIDs block COX-1, depleting $PGE_2$ and predisposing to peptic ulcer disease.
3. Proton Pump Inhibitors (PPIs): Omeprazole and pantoprazole covalently bind and irreversibly inactivate the $H^+/K^+$ ATPase pump, providing the most potent suppression of gastric acid secretion.

Pancreatic & Biliary Secretions

• Acinar Cells: Secrete enzyme-rich fluid containing proteases (trypsinogen, chymotrypsinogen, procarboxypeptidase), pancreatic lipase, colipase, and amylase. Secretion is strongly stimulated by Cholecystokinin (CCK) (released by duodenal I cells in response to luminal peptides and fatty acids) and vagal ACh ($M_3$).
  • Activation Cascade: Pancreatic zymogens remain inactive until they reach the duodenum, where brush-border enteropeptidase (enterokinase) cleaves trypsinogen to active trypsin. Trypsin then autocatalytically cleaves and activates all other pancreatic proteases. Premature intrapancreatic activation of trypsin leads to acute pancreatitis.
• Ductal Cells: Secrete high-volume, alkaline fluid rich in bicarbonate ($[HCO_3^-]$ up to $140\text{ mEq/L}$, pH $\sim 8.0\text{--}8.3$) to neutralize acidic gastric chyme entering the duodenum. Stimulated by Secretin (released by duodenal S cells when luminal pH $< 4.5$). Secretin binds $G_s$-coupled receptors, elevating cAMP and opening apical CFTR chloride channels. Chloride exit drives apical $Cl^-/HCO_3^-$ antiporters. In cystic fibrosis, defective CFTR impairs ductal bicarbonate secretion, producing thick plugs and exocrine pancreatic insufficiency.
• Biliary Secretion & Enterohepatic Circulation: Primary bile acids (cholic and chenodeoxycholic acids) are synthesized from cholesterol in hepatocytes via rate-limiting cholesterol $7\alpha$-hydroxylase (CYP7A1) and conjugated with glycine or taurine to form amphipathic bile salts. Stored and concentrated in the gallbladder; CCK triggers gallbladder contraction and relaxation of the Sphincter of Oddi. Over 95% of bile salts are reabsorbed in the terminal ileum via the Apical Sodium-Dependent Bile Acid Transporter (ASBT) and recycled back to the liver via the portal vein several times a day.

Digestion and absorption of the macronutrients

Absorption sites:

• Duodenum and jejunum absorb most nutrients. Iron (as Fe2+, via DMT1) and calcium are absorbed mainly in the duodenum, and folate in the jejunum.
• The terminal ileum absorbs vitamin B12 bound to intrinsic factor (from gastric parietal cells) and bile salts.

Malabsorption patterns:

• Lactase deficiency, which is common in Filipino adults, causes osmotic diarrhea, bloating and a low stool pH after milk.
• Pancreatic insufficiency (chronic pancreatitis, cystic fibrosis) causes steatorrhea with loss of the fat-soluble vitamins A, D, E and K.
• Ileal resection causes B12 deficiency and bile-acid diarrhea.

Motility

• Swallowing and the esophagus. Primary peristalsis carries the bolus, and the lower esophageal sphincter relaxes through vagal inhibitory neurons that release nitric oxide and VIP. Loss of these neurons causes achalasia.
• Stomach. Receptive relaxation of the fundus accommodates a meal. Antral contractions grind food and empty it through the pylorus. Fat and acid in the duodenum slow gastric emptying through CCK, secretin and the enterogastric reflex. Liquids empty faster than solids.
• Small intestine.
  • After a meal, segmentation mixes chyme and peristalsis propels it.
  • During fasting, the migrating motor complex sweeps residue toward the colon about every 90 minutes. Motilin drives it, which is why erythromycin, a motilin agonist, speeds gastric emptying.
• Colon and defecation. Haustral mixing and mass movements, often triggered by the gastrocolic reflex after meals, fill the rectum. Rectal distension relaxes the internal anal sphincter (the rectoanal inhibitory reflex). The external sphincter, which is skeletal muscle under pudendal nerve control, allows voluntary delay. In Hirschsprung disease, ganglion cells are missing, so the affected segment cannot relax.

The enteric nervous system and the gut-brain axis

The myenteric (Auerbach) plexus controls motility and the submucosal (Meissner) plexus controls secretion and blood flow. Both work on their own but are modulated by the vagus nerve (stimulatory) and sympathetic nerves (inhibitory). The gut-brain axis links:

• enteric neurons;
• vagal afferents;
• enteroendocrine hormones (GLP-1, PYY, ghrelin);
• the gut microbiota;
• the central nervous system.

Ghrelin from the stomach stimulates hunger, while PYY and GLP-1 promote satiety. Stress alters motility and visceral sensitivity, which is the basis of functional disorders such as irritable bowel syndrome.

Helicobacter pylori and the mucosal barrier

The stomach is protected by:

• surface mucus and the bicarbonate layer;
• tight junctions between epithelial cells;
• rapid epithelial renewal;
• mucosal blood flow;
• prostaglandins.

H. pylori survives by producing urease, which splits urea into ammonia and buffers the acid around it. Its urease, cytotoxins (VacA, CagA) and the inflammation it provokes damage this barrier.

• Antral-predominant infection reduces somatostatin from D cells. Gastrin and acid rise, which promotes duodenal ulcers.
• Body-predominant (pangastritis) infection destroys parietal cells, lowers acid output and leads to atrophic gastritis, gastric ulcer, gastric adenocarcinoma and MALT lymphoma.

NSAIDs damage the barrier through a different route: they block COX-1 and remove protective prostaglandins.