Stomach

The stomach is a muscular, sac-like organ of the digestive system that lies between the esophagus and the small intestine. It receives swallowed food and liquid, stores them temporarily, mixes them with gastric juice, and converts them into a semi-liquid mass called chyme that is released into the duodenum. Its main work is mechanical churning and chemical breakdown: hydrochloric acid and enzymes begin the digestion of proteins, while the stomach itself absorbs very little, so most nutrient uptake happens later in the digestive tract.

The stomach matters for health because its secretions and muscular activity affect nutrition, drug absorption and defence against ingested microbes, and because its lining is the site of common and serious disorders, including peptic ulcer and stomach cancer. Its structure is also a standard example in anatomy and physiology of how a tissue-layered digestive tube is specialised for a particular function.

This entry first describes the stomach's location and regions, then its four-layered wall and specialised glands. It next covers the two digestive processes, mechanical churning and acid-enzyme chemistry, followed by the mucosal defences and hormonal and nervous control that regulate them. The entry then considers the stomach's limited absorptive role, the main disorders of the organ, the clinical methods used to examine and treat it, and the developmental, comparative and historical background of research on gastric function.

Location and regions

The stomach is a hollow, muscular organ in the upper left of the abdomen. It lies largely beneath the left dome of the diaphragm, with its upper part tucked under the lower ribs and its lower part extending toward the umbilical region. Its neighbours include the spleen, the left lobe of the liver, the pancreas and the transverse colon. Its position shifts with posture, body build and how full it is, so the organ is usually described relative to these structures rather than to fixed landmarks. As part of the digestive system, it links two tubes: the oesophagus enters at the upper opening, and the duodenum, the first part of the small intestine, begins at the lower opening.

The upper opening is the cardia, the region that surrounds the junction where the oesophagus joins the stomach. Above and to the left of the cardia is the fundus, a dome-shaped region that often contains gas when a person is upright. The body is the large central portion that makes up most of the organ's volume. The lower part is the antrum, which narrows into a short pyloric canal and ends at the pylorus, the connection to the duodenum.

The stomach has two curvatures. The greater curvature is the long, convex left and lower border, to which the greater omentum (a peritoneal fold) attaches. The lesser curvature is the shorter, concave right and upper border, where the lesser omentum attaches and where the stomach meets the liver. These folds of peritoneum help anchor the stomach and carry its blood vessels.

Two muscular rings control passage at either end. The lower oesophageal sphincter, often called the cardiac sphincter, is a zone of raised pressure at the junction with the oesophagus. It is not a sharply separate muscle in the way the pyloric sphincter is, and it relies partly on the surrounding diaphragmatic crura to keep stomach contents from moving back up. Its failure underlies gastro-oesophageal reflux disease. The pyloric sphincter is a thickened ring of circular smooth muscle at the end of the pyloric canal. It regulates the release of stomach contents into the duodenum.

The stomach's size and shape are highly variable. When empty, its walls collapse into folds and the organ is relatively small and contracted. As food and liquid enter, the organ distends, its wall stretches, and its shape changes from a collapsed tube to a larger, often J-shaped sac. A typical adult stomach holds roughly one to one and a half litres, but it can expand considerably further after a large meal. Much of this expansion happens without a proportionate rise in internal pressure, a feature governed by the proximal stomach's relaxation, which is described in the section on mechanical digestion. The organ then gradually returns to a smaller size as its contents are emptied into the small intestine.

Because of this flexibility, the stomach's position and dimensions are often assessed on imaging, and changes in its size or shape can reflect either normal filling or disease processes discussed elsewhere in this entry, such as stomach cancer or obstruction.

Wall layers and rugae

Four layers of the wall

The stomach wall follows the same basic plan as the rest of the gastrointestinal tract and has four concentric layers. From the lumen outward these are the mucosa, the submucosa, the muscularis externa and the serosa. The innermost mucosa is lined by simple columnar epithelium, which dips into gastric pits and glands. Beneath the glands lie a lamina propria and a thin muscularis mucosae. The submucosa lies outside the mucosa and provides most of the wall's structural support. The muscularis externa surrounds the submucosa and is composed of smooth muscle, arranged in three layers (described in the section on mechanical digestion). The serosa forms the outermost covering.

Rugae

The rugae are large, longitudinal folds of the mucosa and submucosa, visible to the naked eye when the stomach is empty or contracted. They are most prominent in the body and fundus, where they run roughly parallel to the lesser and greater curvatures, and they are less evident in the antrum. Because the folds contain both the mucosa and the submucosa, they can be stretched or smoothed out as the organ fills. As food enters, the rugae gradually flatten, which allows the stomach to increase its volume without a large rise in internal pressure. Unlike the villi of the small intestine, rugae are not permanent structures; their shape changes with gastric volume and muscle tone. The folds also enlarge the internal surface area, giving the gastric glands a larger area from which to release acid and enzymes for digestion.

Contents of the submucosa

The submucosa is a dense, irregular layer of connective tissue. Its amount of adipose tissue varies between individuals and regions. It carries the blood vessels that supply the overlying mucosa and the lymphatic vessels that drain it. Nerve fibres run through this layer to supply the vessels and the muscularis mucosae. The submucosal (Meissner) plexus, a network of nerve cells, sits within the submucosa. It helps regulate local blood flow and gastric secretion. The myenteric (Auerbach) plexus lies in the muscularis externa instead, between the muscle layers.

Serosa and peritoneal connections

The serosa is the outermost layer and is continuous with the visceral layer of the peritoneum, the serous membrane that lines the abdominal cavity. Because of this, the stomach sits within the peritoneal cavity rather than being fixed firmly to the wall of the abdomen. Peritoneal folds, known as the greater and lesser omenta, pass from the stomach to neighbouring structures such as the spleen, liver and transverse colon. These folds attach the stomach to these organs and carry its blood vessels and nerves. The surface of the serosa is smooth and moist, which allows the stomach to slide against adjacent organs as it changes shape with the amount of food it contains.

Gastric glands and secretory cells

The stomach lining is a simple columnar epithelium that is pierced by numerous invaginations called gastric pits, and these pits open into a variety of glands. The gastric pits lead into a variety of glandular types (cardiac, fundic and antral). Glands in the cardia and pylorus are built mainly from mucus-producing cells. The much larger glands of the fundus and body are where most gastric secretions are made and where most chemical digestion begins. The glands of the cardia and pylorus are composed primarily of mucus-secreting cells. The much larger glands of the fundus and body of the stomach, the site of most chemical digestion, produce most of the gastric secretions.

The cardiac glands are the simplest. They secrete only mucus, which is alkaline and probably protects the adjacent esophageal lining from the stomach's acid. Pyloric glands differ in a different way: they lack the acid-making cells found elsewhere, yet they contain the hormone-producing cells that regulate acid output. The pyloric glands have no parietal cells but contain the gastrin-producing G cells.

The fundic glands contain several distinct cell populations, arranged roughly by depth. Near the neck of each gland, mucous neck cells divide, and their daughters move either toward the surface pits or deeper into the gland, maturing into the other cell types along the way. As they divide, they migrate either down into the glands or up into the pits and onto the surface epithelium. As they migrate, the mucous neck cells differentiate into any of the several types of mature cells of the gastric surface and glands. In the middle of the gland sit the parietal cells. These large, highly specialised cells make hydrochloric acid and intrinsic factor, the latter being required later for vitamin B12 uptake in the small intestine. Parietal cells are among the most highly differentiated of the body's epithelial cells, and these relatively large cells produce both hydrochloric acid and intrinsic factor. At the base of the glands, chief cells release pepsinogen, the inactive form of the protein-digesting enzyme pepsin. Chief cells, which are located primarily in the basal regions of gastric glands, secrete pepsinogen, the inactive proenzyme form of pepsin.

Interspersed between the exocrine cells are enteroendocrine cells, which secrete hormones into the surrounding tissue and blood rather than into the gastric lumen. Enteroendocrine (enterochromaffin-like) cells are scattered between the gastric glands. The main types in the stomach include histamine-producing enterochromaffin-like (ECL) cells, gastrin-secreting G cells, somatostatin-producing D cells and ghrelin-producing cells. In the stomach, EECs include histamine-producing (enterochromaffin-like (ECL)) cells, gastrin-secreting (G-) cells, somatostatin (SST)-producing D-cells, and ghrelin-producing cells (P/D1)-cells.

G cells are concentrated in the antrum, and their product acts on acid-secreting cells in more than one way. Gastrin-producing G cells are specifically localized in the antrum. Gastrin secreted from G cells binds directly on parietal cells or stimulates acid secretion mediated by histamine release from ECL cells. D cells, by contrast, act as a brake. They occur in both the oxyntic and pyloric regions, where they provide a tonic inhibitory tone that regulates activity of neighboring enteroendocrine cells and gastric acid secretion. The system is also self-limiting. Accumulation of HCl and lowering of the pH in the gastric lumen stimulate D-type enteroendocrine cells in the gastric mucosa to secrete somatostatin, which in turn feeds back in negative fashion to suppress the release of gastrin.

The gastric epithelium is replaced continually, a necessity imposed by the corrosive conditions of the lumen. Due to the harsh luminal environment, replenishment of new epithelial cells is essential to maintain organ structure and function during routine turnover and injury repair. The antral lining is among the tissues that renew most quickly. The gastric antral, intestinal and colonic epithelium are rapidly renewed on a continual basis. Lineage-tracing work has identified stem populations that feed this process. Lgr5 marks long-lived cells that give rise to all the cells within the adult gastric antrum, small intestine and colonic crypts. Chief cells, by contrast, turn over slowly during homeostasis. In experimental models, however, they can re-enter the cell cycle after injury, and some clones regenerate a whole gastric unit within about a month. Upon 5-fluorouracil-mediated ablation of proliferative cells, Troy-positive chief cells begin to proliferate and undergo clonal expansion at a much higher rate than under homeostatic conditions, with some clones regenerating the entire gastric unit within 1 month.

Mechanical digestion and gastric emptying

Muscular layers and mixing

The muscularis externa of the stomach has three smooth muscle layers. The outer longitudinal layer runs lengthwise, the circular layer wraps around the organ, and the oblique layer runs diagonally. The oblique layer is the feature that sets the stomach apart. Its fibres arise mainly around the cardiac region and spread obliquely across the anterior and posterior walls, blending with the circular layer as they descend toward the pylorus. This orientation gives an extra plane of contraction that is not found elsewhere in the gastrointestinal tract.

Together the layers produce two kinds of movement. The first is peristaltic waves. The initial mixing waves are relatively gentle, but they are followed by more intense waves, starting at the body of the stomach and increasing in force as they reach the pylorus. The second is churning. The combined activity of peristalsis and retropulsion mixes food with stomach acid and enzymes, breaking it into smaller and smaller pieces. The distal stomach, often called the antral pump, has the main role here. After a meal, muscular contractions sweep down the antrum in a ring-like pattern, squeezing food toward the pylorus. Solid food is reduced in size and softened by contact with acid and enzymes as well as by mechanical grinding. Particles become progressively smaller until they can pass through the pyloric sphincter, which is about 1–2 mm. Other sources give a smaller threshold of about 1 mm³, so the exact figure varies between descriptions.chyme

Receptive relaxation and gastric accommodation

The first mechanical response to a meal is relaxation rather than contraction. Swallowing starts receptive relaxation of the proximal stomach through a vagovagal reflex, so the fundus and proximal body can begin receiving the bolus. This mechanism is mediated by a vago-vagal reflex. Receptive relaxation describes the fundus relaxing in response to swallowing, and it is followed by gastric accommodation, in which the proximal stomach relaxes so that a progressive increase in meal volume is not accompanied by a major rise in intragastric pressure. Accommodation is driven by stretch within the wall rather than by swallowing alone. When the food bolus reaches the stomach, relaxation is maintained by a second reflex starting from mechanoreceptors in the gastric wall, which is named adaptive relaxation or gastric accommodation. The inhibitory signals are carried by vagal pathways that recruit inhibitory enteric neurons releasing NO and VIP, allowing the proximal stomach to expand around the meal with relatively little increase in pressure. The proximal stomach works as a reservoir. Its muscles maintain continuous tonic contraction and do not contract in phasic bursts; phasic contractions come from the antral pump. The effect is quantitative: a 1.5 L increase in volume causes only a small increase in pressure inside the stomach.

Pyloric control and gastric emptying

After a meal, tonic contraction resumes in the proximal stomach and pushes food distally toward the antrum. There the antral pump mixes and grinds food into smaller particles and generates peristaltic contractions that control flow into the duodenum. Material that reaches the pylorus while it is still large is held back. Strong antral contractions push the chyme against the closed pyloric sphincter, which produces retropulsion, so food is repelled backward for further mixing. A contracted pylorus does not allow chyme to pass, which promotes retropulsion and further trituration of the bolus in the antrum.

The pyloric sphincter therefore acts as a filter. It stays mostly closed, allowing only liquids and small particles to pass. Each time chyme is pressed against the sphincter, a small volume, roughly 2–7 mL, may escape into the duodenum. Rhythmic mixing waves force about 3 mL of chyme at a time through the pyloric sphincter. The output is a semi-fluid mixture called chyme, and emptying is limited to match what the small intestine can manage. Releasing a greater amount at one time would overwhelm the capacity of the small intestine to handle it. The rate also depends on what is being emptied. Liquids empty much faster than solids. Water and other nutrient-poor liquids leave the stomach soon after arriving there. Because solids depend on being reduced to small particles first, their emptying is slower and more easily disrupted. Some accounts also argue that the pylorus is not a true sphincter in the anatomical sense, since the muscles across the pylorus are not electrically connected by gap junctions.

Emptying is also controlled from the other side. Retrograde duodenal peristalsis occurs frequently in the proximal duodenum, moving chyme back into the distal antrum and slowing gastric emptying. The rate of gastric emptying is matched to the duodenum's ability to buffer acid, which helps prevent acid damage to the duodenal mucosa. Overall, complete gastric emptying usually takes about 4 hours, though meal composition and intestinal hormones such as cholecystokinin can change this.

Acid, enzymes and chemical digestion

Chemical digestion in the stomach depends mainly on parietal cells, which line the gastric glands of the fundus and body and secrete hydrochloric acid. Acid output rests on the H⁺/K⁺-ATPase, a P-type pump related to the Na⁺/K⁺-ATPase. The pump is an α/β heterodimer in which a large catalytic α subunit carries the transport activity and a heavily glycosylated β subunit supports it. At rest, most pumps sit in tubulovesicles inside the cell. When the cell is stimulated, the tubulovesicles fuse into an intracellular canalicular network and the pumps move to the apical membrane, where they push hydrogen ions into the gastric lumen in exchange for potassium ions that are recycled back. Acetylcholine, histamine and gastrin act on the cell through separate receptor pathways that converge on this same step.

Each hydrogen ion released leaves behind a hydroxide ion inside the cell. Carbonic-acid chemistry turns this into bicarbonate, which is exchanged across the basolateral membrane for chloride drawn from the blood. Chloride then leaves the cell through an apical chloride channel. Studies of cultured human gastric cells (HGT-1 line) identified a cAMP-activated chloride channel with properties similar to chloride channels in intestinal epithelium, and this channel is thought to be the route in parietal cells. In the lumen, hydrogen and chloride ions combine to form hydrochloric acid. The secreted fluid is roughly 0.15 M HCl with about 7 mM KCl, and its hydrogen ion concentration exceeds that of plasma by more than a million-fold. The bicarbonate that enters the blood produces a transient rise in blood alkalinity after meals, sometimes called the alkaline tide. The result is a luminal pH that is typically near 1 to 2 in the fasting stomach, far below the neutral range found elsewhere in the body.

The same acidity drives the activation of digestive enzymes. Chief cells, concentrated in the base of the gastric glands, secrete pepsinogen, a proenzyme of about 42 kDa. Acid triggers the removal of a short segment from its N-terminus, converting it into the active enzyme pepsin of about 35 kDa. Pepsin then accelerates the conversion of further pepsinogen molecules, a self-activating pattern known as autocatalysis. Pepsin is an endopeptidase of the aspartic protease family, which cleaves peptide bonds within protein chains rather than only at the ends. It acts on most food proteins, though it does not attack keratins, mucoproteins or protamines. Its activity is lost irreversibly once the medium rises above about pH 7.2, which is why it works only in the acidic stomach. Acid also denatures ingested proteins, unfolding them so that pepsin can reach their cleavage sites. Pepsinogen release is driven mainly by rising intracellular calcium, and small peptides and amino acids produced by pepsin in turn stimulate G cells to release gastrin, which feeds back on acid secretion.

Gastric acid is also an antimicrobial barrier. It kills many bacteria and other microbes swallowed with food, so that far fewer organisms reach the small intestine. Pepsin contributes to this effect, and acidity also improves the absorption of certain minerals such as iron and calcium. This barrier is not absolute, and organisms such as Helicobacter pylori survive in the stomach and can damage the lining, a process linked to peptic ulcers.

Parietal cells also secrete intrinsic factor, a glycoprotein of about 55 kDa that is required for vitamin B12 absorption, since humans cannot synthesise this vitamin themselves. Acid and pepsin first release B12 from food proteins in the stomach. Free B12 binds haptocorrin, a salivary binding protein, which protects it through the stomach. In the duodenum, pancreatic enzymes degrade haptocorrin, and B12 transfers to intrinsic factor. The complex is carried to the terminal ileum, where it is taken up by receptor-mediated endocytosis. Because intrinsic factor depends on parietal cell function, loss of these cells, as in autoimmune gastritis, can lead to B12 deficiency and pernicious anemia. Long-term use of acid-suppressing drugs such as omeprazole has also been associated with reduced B12 release from food, because the acid and pepsin needed for that step are reduced.

Mucosal defence and regulation of secretion

The mucus–bicarbonate barrier

The gastric epithelium is protected first by a physical and chemical barrier. The surface cells secrete bicarbonate into an adherent layer of mucus gel. This creates a pH gradient: the lumen is strongly acidic, but the surface of the epithelium stays close to neutral (about pH 7). Bicarbonate neutralises acid that diffuses into the gel, while the gel itself slows the movement of acid and blocks pepsin from reaching the cells beneath. Pepsin is largely stopped by the mucus, whereas hydrogen ions can pass through it and are neutralised by bicarbonate. The mucus–bicarbonate layer is the only barrier that sits in front of the epithelium, so it is the first line of defence against gastric acid and pepsin in humans and other species.

The idea is old. In 1892 Schierbeck measured high carbon dioxide tensions in the dog stomach, and in 1898 Pavlov proposed that an alkaline mucus layer shields the gastric surface. About fifty years later Hollander proposed a two-component model, consisting of an alkaline mucus layer and a rapidly regenerating epithelium. Early experiments could not easily separate neutralisation in the mucus from the back-diffusion of acid into the epithelium, so the mechanism was refined only gradually. Modern work has shown that the surface pH gradient depends on the continuous secretion of bicarbonate and on the stability of the unstirred mucus layer.

Epithelial defence, blood flow and repair

When the mucus–bicarbonate barrier is overwhelmed or damaged, a second set of protections comes into play. The epithelial cells themselves limit acid injury. Their apical membranes and tight junctions restrict the back-diffusion of hydrogen ions, and intracellular buffering by negatively charged proteins and bicarbonate, together with ion exchangers such as the Na⁺/H⁺ exchanger, keeps the cytoplasmic pH stable. The surface cells are also replaced continuously, so that damaged cells are rapidly shed and new ones take their place. Because the gastric lining turns over quickly, small injuries can usually be repaired within hours to days.

The third defence is the mucosal blood flow. Adequate perfusion removes acid that has crossed the epithelium, delivers bicarbonate and nutrients for repair, and supports the cells' buffering capacity. The stomach's own prostaglandins help to maintain this flow and the secretion of mucus and bicarbonate. Disruption of any of these components, through infection, drugs such as aspirin and ibuprofen that suppress prostaglandin synthesis, ischaemia, or excessive acid and pepsin exposure, can lead to erosion and, if persistent, to ulceration. Thinning of the mucus layer is considered an early step in this process.

Phases of gastric secretion

Gastric secretion is conventionally divided into three overlapping phases, first described in detail by Pavlov in his studies of conditioned reflexes in dogs around 1900.

The cephalic phase begins before food reaches the stomach. The sight, smell, taste, chewing and even the thought of food activate the brain, and the vagus nerve carries signals to the stomach. Experiments with "sham feeding", in which food is chewed and swallowed but drains out of a fistula, demonstrated that this phase is real. The estimated share of acid output varies between sources, from about a fifth to a half of the response to a normal meal. Cephalic stimulation also prepares the pancreas and the gallbladder.

The gastric phase starts when food enters the stomach. Distension activates stretch receptors, and peptides and amino acids in the food stimulate chemoreceptors on the gastric mucosa. Local reflexes and gastrin release increase acid and pepsinogen secretion and motility, so that this phase accounts for the largest share of acid output, roughly half or somewhat more.

The intestinal phase begins when chyme enters the duodenum. It is mainly inhibitory. Fats, acid and certain peptides trigger hormones such as secretin and cholecystokinin, and nerve reflexes slow gastric secretion and emptying. This protects the small intestine from excessive acidity and keeps the stomach from emptying too quickly. The three phases can operate at the same time once secretion has started.

Hormonal and nervous control

Acid secretion by parietal cells is regulated by a network of signals. The vagus nerve releases acetylcholine, which acts directly on muscarinic M3 receptors on parietal cells and also stimulates histamine release from enterochromaffin-like (ECL) cells. The vagus also releases gastrin-releasing peptide, which stimulates the G cells of the antrum to secrete gastrin. The enteric nervous system, a network of neurons within the gut wall, adds local control and modulates the activity of G cells, D cells and ECL cells.

Gastrin is the main hormonal stimulant of acid secretion. G cells release it into the circulation, and food, particularly protein, promotes its release. Gastrin acts mainly through CCK2 receptors on ECL cells, which release histamine. Histamine then diffuses to nearby parietal cells, where it binds to H2 receptors, raises cyclic AMP and activates the H⁺/K⁺-ATPase proton pump. Gastrin also acts directly on parietal cells, but its effect through histamine is considered more important.

Somatostatin, released by D cells, is the principal inhibitor. It acts in a paracrine way on G cells, ECL cells and parietal cells, providing a tonic brake on secretion. Cholinergic activity during eating suppresses somatostatin release, which removes this restraint and allows acid output to increase. Histamine itself exerts a negative feedback effect on ECL cells, and other peptides, including vasoactive intestinal peptide, cholecystokinin and secretin, inhibit acid production. Together these pathways explain why secretion is tightly controlled through both positive regulators and negative feedback loops.

Absorption and interaction with other organs

Limited absorptive capacity

The stomach's lining is built mainly for secretion and protection, so it takes up only a small share of the nutrients in a meal. Most uptake of carbohydrates, proteins, fats, vitamins and minerals happens in the small intestine, whose folded surface and villi provide far more absorptive area. The stomach's role in absorption is therefore selective: it handles a few substances, mainly water, certain small lipid-soluble molecules, and ethanol.

Substances absorbed in the stomach

Ethanol is the best-documented case. In a study of seven healthy volunteers who were given alcohol with a homogenised meal, about 39% of the dose crossed the gastric wall during the first postprandial hour, while the segment of intestine beyond the duodenum contributed very little. A second study of five men found that the stomach absorbed roughly 30% of an alcohol dose taken with food, compared with about 10% when it was taken with water. Several factors change how quickly this happens. Food, especially carbohydrate, slows uptake markedly, and carbonated drinks speed it up. Concentration matters too: in an ultrasound study, ethanol solutions of 4%, 10% and 40% all lengthened the half-emptying time compared with water, and the caloric content of beer and wine appeared to strengthen that effect beyond their ethanol content alone.

Drugs follow a similar logic. Most orally taken drugs are absorbed faster from the small intestine than from the stomach, so their rate of entry into the blood depends on how quickly the stomach empties. Weakly acidic drugs, including aspirin, are partly absorbed across the gastric mucosa in the un-ionised form, which is a general pharmacological principle. A controlled crossover trial in ten men found that 75 mg of aspirin taken daily for a week delayed alcohol absorption, lowered peak blood ethanol levels and slowed the appearance of paracetamol in plasma, which the authors attributed to delayed gastric emptying. Paracetamol is used as a practical marker because it is absorbed rapidly from all parts of the gut, so the time it takes to appear in blood approximates gastric emptying.

Coordination with the pancreas, liver and small intestine

Gastric emptying is regulated by signals from the duodenum, including hormonal feedback, so the pace at which chyme enters the small intestine is adjusted to the digestive capacity of the pancreas and the intestine. Absorbed substances then travel to the liver through the portal vein, which is why the liver receives a higher concentration of alcohol than most other tissues. Among the incretins, GLP-1 delays gastric emptying, which slows the entry of glucose into the bloodstream after a meal.

Effects on blood glucose

Because nutrient absorption depends on delivery from the stomach, gastric emptying rate is a key determinant of the early postprandial rise in plasma glucose: the faster the stomach empties, the more rapid the rise. The relationship runs in both directions. In non-diabetic people, plasma glucose approaching the upper normal range slows emptying, a feedback that limits how much glucose reaches the blood at once, whereas hyperglycaemia slows emptying, and hypoglycaemia accelerates it. In people with diabetes, emptying can be either abnormally fast or abnormally slow, which complicates the matching of prandial insulin doses to meals. Among patients with well-controlled type 2 diabetes, the rise in blood glucose after a meal tracked the rate of gastric emptying regardless of whether metformin was used. In critically ill, mechanically ventilated patients, delayed emptying and reduced glucose absorption were both marked, although absorption remained impaired even in patients whose emptying was normal.

Effects on oral medicines

Because the stomach controls the timing of drug delivery to the intestine, altered emptying changes both the speed and the peak of drug levels in blood. Drugs given with food or delayed by slow emptying may reach peak concentrations later and at lower levels, as the aspirin–alcohol findings illustrate. Clinicians therefore consider emptying rate when they assess the timing of oral doses, particularly for drugs with a narrow therapeutic window.

Common disorders

Gastritis

Gastritis is inflammation of the gastric mucosa, and its causes differ in mechanism. The three most important causes of gastritis are H. pylori infection, NSAIDs (including aspirin) and autoimmunity. Helicobacter pylori is a bacterium that lives in the mucous layer that covers and protects tissues that line the stomach and small intestine, and in many carriers it causes swelling and irritation, called inflammation, of the stomach's inner layer. Gastritis caused by ibuprofen and related drugs, or by aspirin, is a different process. It is described as 'chemical gastritis' characterized by mucosal hyperplasia and oedema but minimal inflammatory cell infiltration. Autoimmune gastritis, in which the immune-system attacks the stomach lining, is virtually confined to the body of the stomach. Because it destroys acid-secreting parietal cells, it can also impair vitamin-b12 absorption and lead to anemia.

Peptic ulcer

A peptic ulcer is a defect in the upper gastrointestinal mucosa that extends through the muscularis mucosa into deeper layers of the gut wall. Smaller breaches are termed erosions, and small or shallow breaches <5 mm in size are termed 'erosions'; although often insignificant, these can precede frank ulceration. Worldwide, the two most common causes of peptic ulceration are Helicobacter pylori infection and use of non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin. In one estimate, approximately 1 in 5 peptic ulcers is associated with Helicobacter pylori infection, with most of the rest due to nonsteroidal anti-inflammatory drug (NSAID) use. The two factors can also combine: one review reports that co-exposure greatly increases the risk of bleeding ulcers.

The ulcer mechanism reflects an imbalance between aggressive factors (acid and pepsin) and the mucosal defences described elsewhere in this entry. NSAIDs act mainly by blocking the protective enzyme COX-1. Inhibition of COX-1 in the gastrointestinal tract leads to a reduction of prostaglandin secretion and its cytoprotective effects in gastric mucosa. H. pylori, by contrast, is thought to weaken the mucosa through chronic inflammation. Drug therapy therefore usually combines acid suppression, for example with a proton pump inhibitor such as omeprazole, and eradication of H. pylori with antibiotics. Because of rising clarithromycin resistance, bismuth quadruple therapy or concomitant therapy (nonbismuth quadruple therapy) is the preferred first-line treatment for eradication. Common ulcer symptoms include burning stomach pain, bloating, nausea, indigestion, and in severe cases, internal bleeding. Stress and spicy food are not considered causes, although they can make symptoms worse.

Gastro-oesophageal reflux disease

Gastro-oesophageal reflux disease (GERD) refers to reflux of gastric contents into the oesophagus leading to oesophagitis, reflux symptoms sufficient to impair quality of life, or long-term complications. The main mechanical barrier is the lower oesophageal sphincter at the cardia. Its resting tone varies among healthy individuals, from 10 to 30 mmHg, relative to intragastric pressure. Failure of this barrier is the central problem. Reflux can occur when the pressure barrier of the lower oesophageal sphincter (LOS) fails due to a low basal pressure (less than or equal to 6 mm Hg), sphincteric relaxations or a noncompensated increase in intragastric pressure. The most frequent trigger is transient lower oesophageal sphincter relaxations, which occur even in healthy people. A hiatal hernia can also weaken the barrier: the stomach is displaced upward into the chest when the diaphragm muscle is weak. Delayed gastric emptying adds to the problem, since delayed gastric emptying, resulting in gastric distension, can significantly increase the rate of transient lower oesophageal sphincter relaxations. Obesity and smoking are weakly associated with the disease and genetic factors might be important. Anti-reflux surgery, such as laparoscopic fundoplication, aims to increase the tightness of the sphincter.

Gastric cancer

Gastric cancer is one of the leading cancers worldwide. It is the fourth most common cancer and the second leading cause of cancer related death. Risk factors include family history, diet, alcohol consumption, smoking, Helicobacter pylori and Epstein–Barr virus (EBV) infections, and a family history of GC is also one of the most crucial risk factors. The infection's role is most clearly tied to one histological type: the intestinal subtype is associated with intestinal metaplasia of the gastric mucosa and the occurrence of H. pylori.

The most widely used classification is the Lauren classification, introduced in 1965. The Laurén classification separates gastric adenocarcinomas into two primary subtypes, intestinal and diffuse, and tumors exhibiting features of both the intestinal and diffuse types (>25% of either component) are designated as mixed-type adenocarcinoma. The intestinal type is characterized by the formation of glands exhibiting various degrees of differentiation either with or without extracellular mucin production, whereas the diffuse type is composed of poorly cohesive cells without gland formation. Relative frequencies in one series were approximately 54% for intestinal type, 32% for the diffuse type, and 15% for the indeterminate type. The two types differ in demographics and outcome. Although the intestinal-type is more frequent in men than in women (2:1), the proportion of the diffuse-type is similar between genders. Diffuse-type tumours are generally associated with poorer survival; in one large registry analysis, the diffuse type had a poorer cancer-specific survival (CSS) rate [hazard ratio (HR), 1.44; 95% confidence interval (CI), 1.38–1.50].

Motility disorders are a separate group. Gastroparesis is delayed emptying of the stomach without a mechanical obstruction, and diabetes is one of its best-known causes. Its symptoms can include nausea, early satiety and vomiting of undigested food.

Diagnosis and clinical management

Most gastric disease is investigated with upper gastrointestinal endoscopy, in which a flexible instrument carrying a camera passes through the mouth so the examiner can inspect the stomach lining directly The procedure involves an endoscope being inserted into the patient's stomach to examine the internal walls of the esophagus and stomach. Biopsies taken during the same examination are essential because the visual picture and the microscopic picture often disagree. Endoscopically normal stomachs may show severe histologic inflammation, whereas gastric erythema often corresponds to a normal biopsy. For this reason, a diagnosis of gastritis is formally made by a pathologist, who needs evidence of inflammation and mucosal damage in a biopsy specimen strictly speaking, gastritis is a formal medical term for a diagnosis made by a pathologist when evidence of inflammation and damage to the stomach lining is seen in a biopsy specimen.

Sampling strategy has changed over time. Because lesions are patchy, current guidance favours a standard set of about five specimens, taken from the antrum, the corpus or fundus, and the lesser curvature near the incisura angularis two each from the antrum and the corpus/fundus (one each from the greater and lesser curvature, respectively) and one from the lesser curvature at the incisura angularis. Some authors argue that unstructured random biopsies are poorly reproducible and can miss early changes, and they support targeted sampling guided by high-resolution imaging such as narrow band imaging, which can achieve a high degree of accuracy in the stomach for the diagnosis of these premalignant changes. Suspicious areas, such as possible intestinal metaplasia or an ulcer that may be malignant, are biopsied specifically.

Testing for Helicobacter pylori is a major part of the work-up. A biopsy can be tested rapidly for urease activity: the tissue is placed on a strip or gel containing urea and a pH indicator, and a colour change indicates the enzyme is present The sample is placed on a reaction strip or agar gel that contains urea, a pH indicator and a buffer. Non-invasive options include the urea breath test, stool antigen tests and serology. In a systematic review, urea breath tests were more accurate than blood and stool tests. The urea breath test is generally considered the most accurate option in patients who have not recently taken antibiotics or proton pump inhibitors the urea breath test has the highest diagnostic accuracy to identify H. pylori infection in patients without a history of gastrectomy or recent use of antibiotics or proton pump inhibitors. Accuracy depends on the test and the setting: in one cohort, the 13C breath test had a sensitivity of 94.1%, compared with 76.5% for the stool antigen test. Confirmation of eradication after treatment is also tested this way. Imaging plays a supporting role. Barium contrast studies outline the mucosal folds and any filling defects, while computed tomography (CT) is used mainly to stage gastric cancer and assess complications.

Acid-reducing drugs are the main pharmacological tools. Proton pump inhibitors, such as omeprazole, act by irreversibly inhibiting the stomach's H+/K+ ATPase proton pump, and the body must synthesize new pumps before acid production recovers. Histamine H2-receptor antagonists work differently: they reduce acid production through competitive blockade of H2 receptors, resulting in a less potent and shorter-lasting acid-suppressive effect. Potassium-competitive acid blockers have been marketed since the 2010s Potassium-competitive acid blockers (PCABs) have entered the market since the 2010s. Antacids neutralise acid directly, while mucosal protective agents, such as sucralfate and bismuth compounds, are intended to strengthen the epithelial barrier rather than suppress secretion. Eradication of H. pylori combines acid suppression with antibiotics; standard regimens achieve a 70% to 85% eradication rate, which is why antibiotic choice and resistance are part of treatment planning.

Surgery is used for complications such as bleeding ulcers, perforation, obstruction and cancer, and for obesity. Partial gastrectomy removes the distal part of the stomach, usually including the antrum, and is paired with reconstruction that restores continuity with the duodenum or jejunum. Total gastrectomy removes the whole organ, so the patient loses both the acid-secreting and the intrinsic-factor-producing mucosa; this often leads to vitamin B12 deficiency, which requires lifelong replacement, and to iron-deficiency anemia. Without a reservoir, food passes quickly into the small intestine, which can cause early satiety, weight loss and dumping syndrome. Bariatric operations such as sleeve gastrectomy, which removes most of the greater curvature to create a narrow tube, and gastric bypass, which reroutes food past much of the stomach and proximal small intestine, aim to reduce intake. They also alter absorption of iron, calcium and vitamins, and may change the timing of glucose entry into the bloodstream.

Development, evolution and research history

Embryological origin and rotation

The stomach begins as a dilation of the foregut, which enlarges into a lumen in the fourth week of development. Growth of the dorsal border outpaces the ventral border, and this imbalance establishes the greater curvature. The organ then turns twice. The first turn is about 90 degrees around its long axis, which moves the original left wall to the front and the original right wall to the back. A second, smaller turn follows, and it displaces the lower end toward the right side of the body, so that the pylorus lies higher and further right. Asymmetric wall growth begins around the fifth week, and the 90-degree rotation occurs during weeks seven and eight.

The mesenteries that originally suspended the gut tube are reshaped into adult structures. The dorsal mesogastrium gives rise to the greater omentum, while the ventral mesogastrium becomes the lesser omentum. The pyloric sphincter arises from smooth muscle that proliferates at the caudal end of the stomach.

Comparative anatomy

Among vertebrates, the single-chambered stomach is the common form in humans, dogs, pigs and many other mammals, where acid and enzymes are produced in one glandular cavity. Some fishes lack a distinct stomach altogether. Birds have a glandular proventriculus followed by a muscular gizzard. Ruminants such as cattle, sheep and deer have four compartments: the rumen, reticulum, omasum and abomasum. The first three are forestomachs in which microbial fermentation breaks down plant material, while only the abomasum is glandular and corresponds to the simple stomach of other mammals.

Early observations of gastric juice

Before the nineteenth century, gastric acid and pepsin were recognised as essential to digestion, and the glands that produce them were described in the mid-to-late 1800s. Hydrochloric acid was identified in the gastric juice of humans and other species by W. Prout in 1824.

The most important early experimental work came from William Beaumont, an army surgeon. In June 1822, a musket shot left a wound in the side of Alexis St. Martin, a fur trader on Mackinac Island, and the wound developed into a fistula connecting his stomach to the outside of his body. Beaumont used this opening to examine the stomach directly. His experiments ran from 1825 to 1831, and he sometimes had St. Martin carry vials of stomach contents in his armpits to study the effect of body heat on digestion. He published his account in 1833 as Experiments and Observations on the Gastric Juice, and the Physiology of Digestion. The work listed 51 conclusions about digestion. Among them, Beaumont found that digestion is aided by a churning motion within the stomach, and his data supported Prout's view that the lining of the stomach secretes hydrochloric acid into the gastric juice and he discovered gastric juice was secreted by the stomach lining.

Nervous and hormonal control

Ivan Pavlov's laboratory dominated the late nineteenth and early twentieth centuries with the doctrine of "nervism", the view that the nervous system controls digestive secretion. Pavlov's team built the gastric fistula preparations that allowed them to separate the effects of food from the effects of sensation and anticipation. The surgical setup was designed for sham feeding, in which swallowed food is diverted outside the body before it reaches the stomach. Pavlov received the first Nobel Prize awarded for work on neural reflex stimulation of gastric secretion, in 1904.

Hormonal control then emerged in parallel. Bayliss and Starling identified secretin in London in 1902, and in 1906 J. S. Edkins described gastrin as a gastric secretory hormone. Around the same time, a 1910 dictum attributed to K. Schwartz held that "no acid no ulcer", and he proposed gastrectomy as treatment for excessive acid secretion and peptic ulcer. Histamine was then shown to be a powerful stimulant: Popielski reported in 1916 that injected histamine produced copious gastric acid secretion in dogs with surgically prepared fistulas. Gastrin was isolated and synthesised in 1964. In 1972 James Black discovered that the effect of histamine on acid secretion was mediated by H2 receptors, which led to the development of selective H2 antagonists, and cimetidine was launched in 1976. Modern accounts describe a combined model in which gastrin stimulates acid secretion by acting directly on parietal cells and by releasing histamine from enterochromaffin-like cells, which then binds H2 receptors on parietal cells. The historian Konturek has noted that after a century of study, both neural and hormonal concepts have been proved to be right.

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