Gastrointestinal hormones
GI hormones: gastrin, secretin, CCK, GIP, GLP-1, motilin and somatostatin
Source cells, stimuli, actions and feedback of the gut hormones, with their clinical links, for FCPS Part 1. Explains why PPIs and H. pylori raise gastrin, how somatostatin switches secretion off, and which hormones slow the stomach.
The classic gut hormones
Gut hormones are peptides released from scattered enteroendocrine cells in the mucosa. Each responds to a particular component of the meal in a particular segment, and each adjusts secretion or motility so that the next stage of digestion is ready.
| Hormone | Source | Main stimulus | Main actions | Clinical link |
|---|---|---|---|---|
| Gastrin | G cells, gastric antrum (some in duodenum) | Peptides and amino acids in the stomach, distension, vagus (via GRP) | Acid secretion (mainly by releasing histamine from ECL cells), trophic to gastric mucosa, gastric motility, raises LOS tone | Zollinger–Ellison syndrome; high in PPI use and atrophic gastritis |
| Secretin | S cells, duodenum | Acid (pH below about 4.5) in the duodenum | Pancreatic and biliary bicarbonate; inhibits gastric acid and gastrin; slows gastric emptying | Secretin test: gastrin paradoxically rises in gastrinoma |
| CCK | I cells, duodenum and jejunum | Fatty acids, monoglycerides and amino acids | Pancreatic enzymes, gallbladder contraction, relaxes sphincter of Oddi, slows gastric emptying, satiety | Fatty meals trigger biliary colic |
| GIP | K cells, duodenum and jejunum | Glucose, fat, amino acids | Insulin release (incretin); weakly inhibits acid | Oral glucose releases more insulin than IV glucose |
| GLP-1 | L cells, ileum and colon | Nutrients | Insulin up, glucagon down, slows gastric emptying, satiety | Liraglutide, semaglutide; DPP-4 inhibitors prolong it |
| Motilin | M cells, duodenum and jejunum | Fasting (cyclic) | Starts the migrating motor complex | Erythromycin is a motilin agonist |
| Somatostatin | D cells of stomach, intestine, pancreatic islets | Acid in the antrum, fat, other hormones | Inhibits almost all gut hormones, acid, pancreatic and biliary secretion, gallbladder contraction, splanchnic blood flow; also GH, insulin, glucagon | Octreotide; somatostatinoma |
- Hormone families: gastrin and CCK share the same C-terminal amino acids, so CCK has weak gastrin-like activity. The secretin family includes secretin, glucagon, GIP, GLP-1 and VIP.
Control of gastrin: the acid feedback loop
- Food protein buffers acid and supplies peptides, so gastrin release and acid output peak during the gastric phase after a protein meal. Vagal fibres release GRP (bombesin) onto G cells; atropine does not block this route.
- Acid switches gastrin off. When antral pH falls below about 3, D cells release somatostatin, which acts on neighbouring G cells (paracrine) to stop gastrin release. Decreasing gastric pH therefore decreases gastrin.
- Proton pump inhibitors: acid suppression removes this negative feedback, so G cells release more gastrin; long-term users have raised serum gastrin and ECL cell hyperplasia, and rebound acid hypersecretion on stopping.
- Atrophic (autoimmune) gastritis: parietal cells are lost, the stomach is achlorhydric, and gastrin is very high; ECL hyperplasia can lead to carcinoid tumours.
- Antral-predominant *H. pylori* gastritis: infection damages antral D cells, reducing somatostatin. Gastrin rises, the healthy body produces excess acid, and duodenal ulcers result. A raised gastrin here does not mean gastrinoma, and it falls after eradication.
- Gastrinoma (Zollinger–Ellison): tumour in the duodenum or pancreas (the "gastrinoma triangle"), part of MEN1 in about a quarter. Gastrin secretion is autonomous, so acid continues despite low pH: multiple, recurrent or post-bulbar ulcers, and diarrhoea because acid inactivates pancreatic lipase. Fasting gastrin is high with a low gastric pH; secretin raises gastrin further, unlike in normal people.
| Cause of high gastrin | Gastric acid | Why |
|---|---|---|
| Gastrinoma | High | Autonomous tumour ignores feedback |
| Antral H. pylori | High | Fewer somatostatin-producing D cells |
| PPI therapy | Low | Feedback removed by drug |
| Atrophic gastritis | Absent | Parietal cell loss; no acid to brake G cells |
Exam trap A high gastrin with low acid is a feedback response; a high gastrin with high acid suggests gastrinoma.
Hormones after a meal
- Fat in the duodenum releases CCK: the gallbladder contracts, the sphincter of Oddi relaxes, pancreatic enzymes flow, and gastric emptying slows so fat can be emulsified and digested.
- Acid in the duodenum releases secretin: pancreatic and biliary bicarbonate neutralise it; gastric acid and emptying fall.
- Glucose releases GIP and GLP-1: insulin rises before blood glucose climbs much (the incretin effect).
- Hormones that slow gastric emptying: CCK (most important), secretin, GIP, GLP-1, peptide YY, somatostatin. Hormones that speed it: gastrin and motilin.
- Gallbladder: CCK contracts it; somatostatin relaxes it (somatostatinoma and long-term octreotide cause gallstones). Gastrin does not contract the sphincter of Oddi.
Somatostatin and its analogues
- Somatostatin inhibits gastrin, secretin, CCK, VIP, insulin, glucagon and GH; reduces acid, pancreatic and intestinal secretion; and constricts splanchnic vessels, lowering portal pressure.
- Octreotide (a long-acting analogue) is used for: bleeding oesophageal varices; pancreatic and enterocutaneous fistulae, where it reduces the volume of pancreatic secretion and may speed closure; VIPoma and carcinoid symptoms; acromegaly.
- Somatostatinoma: diabetes, gallstones, steatorrhoea and hypochlorhydria, the result of inhibiting everything.
Paracrine and neural messengers
- Histamine (ECL cells): main amplifier of acid via H2 receptors.
- VIP (enteric neurons): relaxes smooth muscle and sphincters and stimulates intestinal water and chloride secretion. VIPoma causes watery diarrhoea, hypokalaemia and achlorhydria (WDHA).
- Nitric oxide: receptive relaxation and LOS relaxation.
- Ghrelin (gastric fundus): stimulates appetite and GH; rises before meals. Leptin (adipose tissue) and peptide YY (ileum, colon) signal satiety.
- Serotonin (enterochromaffin cells): stimulates motility and secretion; carcinoid syndrome appears once tumour has spread to the liver.
- Dopamine in the gut inhibits motility; D2 blockers (domperidone, metoclopramide) are prokinetic.
Remember Gastrin from the antrum, secretin for acid, CCK for fat, motilin for fasting, somatostatin stops them all.
How FCPS asks about this
- Site of gastrin secretion: G cells of the gastric antrum.
- Stimulus for maximal gastrin release: peptides and amino acids in the stomach, plus distension and vagal GRP.
- Effect of lower gastric pH on gastrin: decreased, through antral somatostatin.
- Raised gastrin on long-term PPI: low acid removes negative feedback on G cells.
- Duodenal ulcer with antral H. pylori and high gastrin: reduced somatostatin from damaged antral D cells.
- Hormone for pancreatic enzymes and gallbladder contraction: CCK, released by fat and protein.
- Role of somatostatin or octreotide in a pancreatic fistula: reduces pancreatic secretion and fistula output.
Exam trap Secretin is released by acid, CCK by fat and protein; both slow gastric emptying.
Test yourself on this topic
5 of the 18 questions in our bank on this topic. Choose an answer to see why every option is right or wrong.
A man with acromegaly develops gallstones after two years of octreotide injections. How does the drug promote stone formation?
Answer: It inhibits CCK release and gallbladder emptying
Somatostatin is an inhibitory hormone of the gut. It reduces release of CCK from duodenal I cells and directly reduces gallbladder contraction, so bile stays in the gallbladder for long periods, forming sludge and cholesterol stones. It also slows intestinal transit. Gallstones and sludge are common in long-term users of octreotide or lanreotide, though most stay silent. The same effect is seen in patients with somatostatin-secreting tumours.
Somatostatin and the gallbladder
- Somatostatin inhibits CCK
- Gallbladder does not empty
- Bile stasis: sludge, stones
- Seen with octreotide, lanreotide
Remember A gallbladder that never squeezes makes stones.
Exam trap Octreotide treats acromegaly well, but ask about biliary pain during follow-up.
Why the other options are wrong
- It increases hepatic cholesterol secretion Not the main mechanism.
- It causes haemolysis and pigment load Octreotide does not cause haemolysis.
- It blocks bile acid reabsorption in ileum Not an action of octreotide.
- It stimulates excess bile acid synthesis Not an action of octreotide.
Six months after a sleeve gastrectomy that removed most of the gastric fundus, a woman reports much less hunger before meals. Loss of which hormone mainly explains this?
Answer: Ghrelin
Ghrelin is made mainly by endocrine cells in the oxyntic mucosa of the gastric fundus. Its level rises before meals and falls after eating, and it acts on the arcuate nucleus of the hypothalamus to stimulate hunger; it also stimulates growth hormone release. Removing the fundus in a sleeve gastrectomy lowers ghrelin, which partly explains the reduced appetite. Leptin from fat, and CCK and peptide YY from the gut, reduce appetite rather than increase it.
Ghrelin
- Made in the gastric fundus
- Rises before meals
- Acts on arcuate nucleus: hunger
- Also stimulates GH release
Remember Ghrelin growls before meals.
Exam trap Ghrelin is the only major gut hormone that increases appetite.
Why the other options are wrong
- Leptin Made by fat; it suppresses appetite.
- Cholecystokinin A satiety hormone from the duodenum.
- Peptide YY A satiety hormone from the ileum and colon.
- Insulin Not the hunger hormone.
A 35-year-old man with a duodenal ulcer has antrum-predominant Helicobacter pylori gastritis and a raised fasting gastrin. Which of the following explains his increased acid output?
Answer: Reduced somatostatin from antral D cells
In the antrum, D cells release somatostatin, which acts locally to restrain gastrin release from G cells. Antral H. pylori infection reduces D cells and somatostatin, so gastrin rises, parietal cells are driven harder and acid output increases. More acid enters the duodenum, causing gastric metaplasia there, which H. pylori can then colonise, leading to duodenal ulcer. Eradication restores somatostatin and gastrin. Body-predominant infection instead causes atrophy and low acid.
H. pylori and acid
- Antral infection: fewer D cells
- Less somatostatin, more gastrin
- More acid: duodenal ulcer
- Body infection: atrophy, low acid
Remember Antral H. pylori removes the gastrin brake.
Exam trap Raised gastrin in a duodenal ulcer patient with H. pylori does not mean a gastrinoma.
Why the other options are wrong
- Gastrin-secreting tumour in the pancreas No tumour is needed to explain this.
- Destruction of parietal cells Would lower acid, as in body gastritis.
- Bacterial urease stimulating parietal cells Urease makes ammonia; it does not stimulate parietal cells.
- Increased secretin release Secretin inhibits acid secretion.
A year after a Roux-en-Y gastric bypass, a man notices that he feels full sooner and stays full longer, because food now reaches his distal small bowel quickly. Which hormones from intestinal L cells mainly explain this?
Answer: Peptide YY and GLP-1
L cells in the ileum and colon release peptide YY and GLP-1 when nutrients reach them. After a bypass, food arrives in the distal bowel early and in larger amounts, so both hormones rise steeply after meals. Peptide YY acts on the hypothalamus to reduce appetite, and GLP-1 slows gastric emptying, increases satiety and enhances insulin release. These changes contribute to weight loss and to the remission of type 2 diabetes after surgery. CCK and secretin come from the duodenum, which is bypassed.
Bypass and gut hormones
- Food reaches L cells early
- Big rise in PYY and GLP-1
- PYY: less appetite
- GLP-1: satiety, insulin
Remember Bypass surgery turns up the ileal brake.
Exam trap Bypass reduces duodenal hormones such as CCK and GIP; the satiety effect comes from L cells.
Why the other options are wrong
- Ghrelin and motilin Ghrelin increases hunger; motilin drives fasting motility.
- Gastrin and histamine Drive acid secretion, not satiety.
- Secretin and CCK Duodenal hormones; the duodenum is bypassed.
- Insulin and glucagon Pancreatic, not L-cell, hormones.
An obese 50-year-old woman with type 2 diabetes starts weekly semaglutide. She feels full after small meals and loses weight, but has nausea in the first weeks. Which action of the drug mainly explains these effects?
Answer: Slowed gastric emptying and central satiety
GLP-1 is an incretin released from intestinal L cells after meals. Semaglutide, a long-acting GLP-1 receptor agonist, increases glucose-dependent insulin release and suppresses glucagon, but it also slows gastric emptying and acts on the hypothalamus and brainstem to increase satiety. These last two effects cause early fullness, weight loss and the nausea and vomiting that are its commonest side effects, which usually settle with time. Orlistat blocks fat absorption, and SGLT2 inhibitors cause glycosuria.
GLP-1 agonist effects
- More glucose-dependent insulin
- Less glucagon
- Slow gastric emptying
- Satiety: weight loss, nausea
Remember GLP-1 drugs fill the stomach longer and quiet the hunger centre.
Exam trap Hypoglycaemia is uncommon with GLP-1 agonists alone because their insulin effect is glucose-dependent.
Why the other options are wrong
- Increased insulin-independent glucose uptake Not an action of GLP-1 agonists.
- Inhibition of intestinal fat absorption That is orlistat.
- Glucose loss in the urine That is an SGLT2 inhibitor.
- Increased thyroid hormone secretion Not an action of GLP-1.
Where this sits in the CPSP syllabus
- Paper 1: Gastrointestinal system and liver, GI hormones
- Surgery & Allied, Paper 2: Gastrointestinal system and liver, GI hormones
- Medicine & Allied, Paper 2: Gastrointestinal system and liver, GI hormones
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