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Gastric acid

Gastric acid, also known as stomach acid, is a specialized digestive fluid secreted by the parietal cells in the gastric glands of the stomach lining, primarily composed of hydrochloric acid (HCl) that creates a highly acidic environment with a pH typically ranging from 1.5 to 3.5.^[1]^[2] This secretion forms the core component of gastric juice, which also includes water, mucus, pepsin (a proteolytic enzyme), gastric lipase, and intrinsic factor, all contributing to the stomach's role in initial food breakdown.^[3]^[4] The primary physiological functions of gastric acid involve protein digestion, pathogen defense, and nutrient absorption. It denatures dietary proteins to make them more accessible to enzymatic cleavage, activates pepsinogen secreted by chief cells into active pepsin for hydrolyzing peptide bonds, and provides an optimal low-pH milieu (around 2.0) for pepsin activity.^[3]^[5] Additionally, the acidic conditions eradicate most ingested bacteria and parasites, preventing infections, while facilitating the release and absorption of minerals like iron and vitamins such as B12 through interactions with intrinsic factor.^[6]^[5] Gastric acid secretion is tightly regulated through neural and hormonal mechanisms across three phases: cephalic (triggered by sight/smell of food via vagus nerve releasing acetylcholine), gastric (stimulated by food in stomach via distension and peptides releasing gastrin from G cells), and intestinal (modulated by chyme entering duodenum).^[7] The key stimulants—gastrin from antral G cells, histamine from enterochromaffin-like cells, and acetylcholine from vagal nerves—act synergistically on parietal cells via receptors to activate the H+/K+-ATPase proton pump, which exchanges hydrogen ions for potassium to generate HCl.^[8]^[9] This dynamic control ensures acid production matches digestive needs, averaging 2-3 liters per day in adults under normal conditions.^[10]

Composition and Properties

Chemical Makeup

Gastric acid is primarily composed of hydrochloric acid (HCl), which constitutes the dominant component at concentrations typically ranging from 0.05 to 0.1 M in human gastric secretions, rendering it a strong acid capable of fully dissociating in solution.^[11] This HCl is the key acidic element, with the solution also containing water as the solvent, making up the bulk of the volume.^[9] The formation of HCl occurs within parietal cells of the gastric mucosa through a process involving the hydration of carbonic acid. Carbon dioxide (CO₂) and water (H₂O) react to form carbonic acid (H₂CO₃), catalyzed by the enzyme carbonic anhydrase, which then dissociates into hydrogen ions (H⁺) and bicarbonate ions (HCO₃⁻). The H⁺ ions are actively transported out of the cell into the gastric lumen via the H⁺/K⁺-ATPase proton pump, while chloride ions (Cl⁻) are secreted concurrently through chloride channels to combine with H⁺, forming HCl. This mechanism ensures the generation of a highly acidic environment.^[9] In addition to HCl, gastric acid includes minor ionic components such as potassium (K⁺) at around 15–17 mM, sodium (Na⁺) at about 3–7 mM, and Cl⁻ balancing the cations at approximately 170 mM, which maintain electrochemical balance but do not significantly contribute to acidity. Parietal cells also secrete intrinsic factor, a glycoprotein essential for vitamin B12 absorption, present in trace amounts within the gastric juice. These elements are secondary to HCl, which defines the acid's primary chemical identity.^[12]^[1] The overall production can be summarized by the key reaction:

\ce{CO2 + H2O ⇌ H2CO3 ⇌ H+ + HCO3-}

where the H⁺ is extruded by the H⁺/K⁺-ATPase, establishing the acidic milieu.^[9]

Physical Characteristics

Gastric acid is a colorless, watery fluid produced by the parietal cells of the stomach lining.^[13] Its appearance resembles a clear solution, with no inherent pigmentation, though it may take on hues from ingested materials or digestive processes in vivo. At body temperature (approximately 37°C), the density of gastric juice ranges from 1.004 to 1.010 g/cm³, making it slightly denser than pure water due to dissolved electrolytes and other solutes.^[14] The acidity of gastric acid is characterized by a pH typically ranging from 1.5 to 3.5 in the stomach lumen, reflecting its role as a highly acidic environment. In the fasted state, the median pH is around 1.7, while during digestion following a meal, the pH initially rises due to food buffering (reaching a median of about 4.6) before acid secretion intensifies, lowering it to approximately 2.1–2.8 over 1–2 hours.^[15] This variability underscores the dynamic nature of gastric acidity in response to physiological states. The low pH contributes to its corrosive properties, enabling it to denature proteins and damage unprotected tissues through protonation and hydrolysis, though the stomach mucosa is adapted to withstand such effects via protective barriers.^[1] Gastric acid exhibits high osmotic pressure, generally near iso-osmotic to plasma at 280–300 mOsm/L, arising from its electrolyte concentration, including chloride ions and other salts. This osmolarity enhances its corrosive potential by facilitating ion diffusion and tissue penetration in non-adapted environments. The specific heat capacity of gastric acid is similar to that of water, approximately 4.18 J/g·°C, reflecting its predominantly aqueous composition and allowing efficient heat transfer in the gastric environment.^[16]^[1]

Production and Secretion

Cellular Mechanisms

Gastric acid secretion primarily occurs in the parietal cells, which are specialized epithelial cells located in the gastric glands of the stomach's fundus and body regions. These cells are responsible for producing hydrochloric acid (HCl) through a series of coordinated intracellular and membrane transport processes that generate and release protons and chloride ions into the gastric lumen. The parietal cells feature a highly invaginated apical membrane forming canaliculi, which expand dramatically during active secretion to facilitate the extrusion of acid.^[17] The core mechanism of acid generation begins intracellularly with the enzyme carbonic anhydrase, which catalyzes the rapid conversion of carbon dioxide and water into carbonic acid (H₂CO₃), dissociating into bicarbonate (HCO₃⁻) and protons (H⁺). The protons are then actively transported across the apical membrane into the canaliculi via the H⁺/K⁺-ATPase proton pump, a P-type ATPase that exchanges intracellular H⁺ for extracellular K⁺ using ATP hydrolysis, creating a steep electrochemical gradient against which H⁺ is secreted. Simultaneously, chloride ions (Cl⁻) are released through apical chloride channels, such as the cystic fibrosis transmembrane conductance regulator (CFTR), allowing Cl⁻ to efflux into the canaliculi where it combines with H⁺ to form HCl. This process ensures electroneutral secretion of the acid.^[9]^[18]^[19] To sustain these transport activities, the basolateral membrane of parietal cells houses the Na⁺/K⁺-ATPase, which pumps sodium ions out and potassium ions in, maintaining low intracellular Na⁺ and high K⁺ concentrations essential for the ion gradients required by the apical pumps and channels. During stimulation, intracellular tubulovesicles containing H⁺/K⁺-ATPase and other components fuse with the apical membrane via exocytosis, vastly increasing the secretory surface area—up to 10-fold—and enabling high-volume acid release into the lumen. This dynamic membrane recycling is crucial for the cell's ability to switch between resting and secreting states.^[20]^[21]

Physiological Triggers

Gastric acid secretion is initiated through three overlapping physiological phases—cephalic, gastric, and intestinal—that collectively contribute to the stomach's daily output of approximately 2 to 3 liters of gastric juice, with secretion peaking in the hours following a meal.^[22] These phases respond to sensory and mechanical cues, coordinating the activation of parietal cells in the gastric mucosa to produce hydrochloric acid.^[23] The cephalic phase begins upon anticipation of food, triggered by the sight, smell, or even thought of eating, and accounts for about 30% of total meal-stimulated acid secretion. This phase is mediated primarily by vagal nerve stimulation, which releases acetylcholine (ACh) onto muscarinic receptors on parietal cells and enterochromaffin-like (ECL) cells, initiating acid production before food reaches the stomach.^[24]^[23] The gastric phase, representing roughly 60% of acid secretion, is activated once food enters the stomach, where mechanical distension of the gastric wall stimulates stretch receptors and chemical presence of peptides and amino acids excites mucosal chemoreceptors. These local stimuli trigger short neural reflexes via the enteric nervous system and promote the release of gastrin from G cells in the antrum, which further amplifies acid secretion through direct and indirect pathways.^[24]^[23] The intestinal phase provides a minor contribution of about 10% to overall acid secretion, occurring as partially digested chyme enters the duodenum and stimulates enteroendocrine cells to release various hormones, such as cholecystokinin (CCK), which contribute to sustaining gastric acid output alongside inhibitory signals like secretin. This phase includes both stimulatory and inhibitory components to fine-tune acid delivery to the duodenum, though its role diminishes rapidly to prevent excessive acidity.^[24]^[1] These phases are fine-tuned by local feedback mechanisms, such as somatostatin release from D cells in the gastric mucosa, which provides paracrine inhibition to modulate acid output in response to luminal pH changes.^[25]

Regulation of Secretion

Stimulatory Pathways

Gastric acid secretion by parietal cells in the stomach is primarily stimulated through three interconnected pathways involving histamine, gastrin, and acetylcholine, each activating specific receptors and second messenger systems to enhance the activity of the H⁺,K⁺-ATPase proton pump.^[26] These pathways are triggered by physiological stimuli such as food intake during the cephalic, gastric, and intestinal phases of digestion.^[27] Histamine, produced and released from enterochromaffin-like (ECL) cells in the oxyntic mucosa, binds to H₂ receptors on the basolateral membrane of parietal cells. This interaction couples to Gₛ proteins, activating adenylate cyclase and resulting in increased intracellular cyclic AMP (cAMP) levels. The elevated cAMP activates protein kinase A (PKA), which phosphorylates key proteins, including the H⁺,K⁺-ATPase, promoting its translocation from cytoplasmic tubulovesicles to the apical canalicular membrane and thereby stimulating acid extrusion into the gastric lumen.^[26]^[27] Gastrin, released from G cells in the gastric antrum, exerts its stimulatory effects both indirectly and directly. It binds to cholecystokinin-2 (CCK₂) receptors on ECL cells, prompting histamine release that amplifies the H₂-mediated pathway. Additionally, gastrin acts directly on CCK₂ receptors on parietal cells, coupling to G_q proteins to activate phospholipase C, which generates inositol trisphosphate (IP₃) and diacylglycerol, leading to an increase in cytosolic Ca²⁺ concentrations. This Ca²⁺ signaling mobilizes further intracellular stores and activates calmodulin-dependent kinases, enhancing proton pump function and acid secretion.^[27] Acetylcholine (ACh), released from postganglionic fibers of the vagus nerve, binds to M₃ muscarinic receptors on parietal cells. These G_q-coupled receptors stimulate phospholipase C, producing IP₃ and mobilizing Ca²⁺ from intracellular stores, which raises cytosolic Ca²⁺ levels and potentiates the activation of the apical proton pump.^[26] The histamine, gastrin, and ACh pathways operate synergistically, with their combined activation—known as the triple pathway—amplifying gastric acid secretion up to 10-fold compared to maximal stimulation by any single mediator, ensuring robust digestive response to meals.^[26] This amplification arises from cross-talk between cAMP and Ca²⁺ signaling, where, for instance, histamine's cAMP elevation sensitizes parietal cells to Ca²⁺-dependent effects from gastrin and ACh.^[27]

Inhibitory Mechanisms

Somatostatin, secreted by D cells in the gastric antrum and oxyntic mucosa, serves as the primary paracrine inhibitor of gastric acid secretion. It exerts its effects by binding to somatostatin receptor type 2 (SSTR2) on G cells and enterochromaffin-like (ECL) cells, thereby suppressing the release of gastrin and histamine, respectively. This inhibition prevents excessive stimulation of parietal cells, maintaining a balance against the stimulatory pathways involving acetylcholine, gastrin, and histamine. Additionally, somatostatin can directly inhibit parietal cell function by reducing cyclic AMP (cAMP) levels. Prostaglandins, particularly prostaglandin E2 (PGE2), provide another key inhibitory mechanism by acting directly on parietal cells. PGE2 binds to EP3 receptors on these cells, leading to a decrease in intracellular cAMP levels, which antagonizes the stimulatory effects of histamine at H2 receptors. This reduction in cAMP impairs the activation of protein kinase A and subsequent proton pump activity, effectively blocking acid secretion in response to histamine-driven stimuli. Non-steroidal anti-inflammatory drugs (NSAIDs) that inhibit prostaglandin synthesis can thus exacerbate acid production, highlighting the protective role of endogenous prostaglandins. During the intestinal phase of digestion, hormones released from the duodenum further modulate gastric acid secretion to prevent duodenal overload. Secretin, triggered by low duodenal pH, and cholecystokinin (CCK), stimulated by fats and proteins, both promote the release of somatostatin from D cells, indirectly inhibiting gastrin and histamine secretion. This mediated inhibition ensures that acid output decreases as chyme enters the small intestine, coordinating gastric emptying with duodenal processing capacity. A critical negative feedback loop operates within the stomach to autoregulate acid secretion based on luminal pH. When gastric pH falls below approximately 3, antral D cells increase somatostatin release, which potently suppresses further gastrin secretion from G cells and, to a lesser extent, histamine from ECL cells. This pH-dependent mechanism, involving both neural vagal reflexes and hormonal signals, rapidly shuts down parietal cell activity to avoid excessive acidity that could damage the mucosa. In response to chronic stimuli such as prolonged hypergastrinemia, the gastric mucosa undergoes adaptive changes to modulate acid secretion long-term. Sustained elevation of gastrin, often seen in conditions like chronic atrophic gastritis or long-term proton pump inhibitor use, induces parietal cell hyperplasia, increasing the number of acid-secreting cells. These adaptations help restore homeostasis by compensating for initial hypersecretion, though they can contribute to pathological states if dysregulated.

Physiological Functions

Digestive Processes

Gastric acid plays a central role in initiating protein digestion within the stomach by creating an acidic environment that activates pepsinogen, the inactive precursor secreted by chief cells, into the active enzyme pepsin. This autocatalytic process occurs at low pH levels, where hydrogen ions cleave the activation peptide from pepsinogen, enabling pepsin to hydrolyze dietary proteins into smaller peptides and polypeptides.^[3]^[28] Once activated, pepsin preferentially cleaves peptide bonds adjacent to aromatic amino acids, breaking down complex proteins into fragments that are more accessible for subsequent enzymatic action in the small intestine. In addition to enzyme activation, gastric acid denatures ingested proteins by disrupting their tertiary and quaternary structures through protonation of side chains and disruption of hydrogen bonds. This unfolding exposes internal peptide bonds that were previously shielded, making the proteins more susceptible to hydrolysis by pepsin and enhancing the overall efficiency of gastric proteolysis.^[29] Denaturation is particularly crucial for tough dietary proteins, such as those from meat or plant sources, ensuring partial breakdown before the mixture enters the duodenum.^[30] Gastric acid also facilitates the solubilization of essential minerals, converting insoluble forms of iron and calcium into bioavailable ions that can be absorbed in the small intestine. For instance, the acidic milieu reduces ferric iron (Fe³⁺) to ferrous iron (Fe²⁺) and dissolves calcium phosphates, preventing precipitation and promoting uptake via transporters like DMT1 for iron.^[30]^[31] This process is vital for maintaining mineral homeostasis, as deficiencies in gastric acid secretion, such as in hypochlorhydria, impair these absorptive steps.^[32] Beyond biochemical actions, gastric acid contributes to the physical processing of food by mixing with the bolus to form chyme, a semi-liquid paste that ensures uniform exposure to digestive enzymes. The acid's fluidity aids peristaltic contractions in liquefying solid food particles, typically reducing them to a consistency suitable for gradual release into the duodenum over 2–4 hours.^[1] Pepsin's proteolytic activity is optimized in the gastric environment at a pH of 1.5–2.5, where the enzyme's maximum velocity (Vmax) increases due to enhanced substrate binding and catalytic efficiency in the acidic milieu.^[28]^[33] At these conditions, the low pH stabilizes the active conformation of pepsin, allowing it to achieve peak hydrolysis rates before the mixture is neutralized downstream.^[3]

Protective Roles

Gastric acid serves a critical protective function through its bactericidal action, primarily due to the low pH environment it creates in the stomach, which effectively eliminates the majority of ingested pathogens. At a pH below 4.0, gastric acid kills approximately 99.9% of enteric bacteria, such as Escherichia coli and Salmonella species, within 30 minutes, acting as the stomach's primary innate defense mechanism against foodborne and waterborne microbes.^[34]^[35] By sterilizing the chyme in the stomach, gastric acid prevents bacterial overgrowth in the small intestine, where nutrient-rich conditions could otherwise promote excessive microbial proliferation and disrupt normal absorption processes. In individuals with reduced gastric acidity, such as those with achlorhydria, bacterial survival rates increase dramatically, leading to higher colonization in the distal gut.^[34]^[36] Gastric acid contributes to the overall integrity of the gastric mucosal barrier by synergizing with the protective mucus layer and peristaltic movements, which together limit pathogen adhesion, penetration, and potential damage to the epithelial lining. The mucus provides a physical diffusion barrier that traps microbes, while peristalsis mechanically clears them, and the acid's low pH ensures most are inactivated before they can compromise the mucosa.^[1]^[37] Additionally, gastric acid facilitates the release of vitamin B12 from food proteins through pepsin-mediated proteolysis in the low-pH environment. Intrinsic factor, a glycoprotein secreted by parietal cells and resistant to acid and pepsin, binds to the free vitamin B12, protecting it from degradation and enabling its absorption in the ileum via the cubam receptor. Hypochlorhydria impairs this process, as the higher pH reduces the dissociation of B12 from dietary complexes, underscoring acid's role in maintaining nutritional homeostasis.^[38]^[39] The low pH of gastric acid also inactivates microbial enzymes from surviving pathogens, denaturing their proteins and halting enzymatic activities that could otherwise facilitate tissue invasion or toxin production, thereby further reducing infection risk. This pH-dependent enzyme disruption complements the direct bactericidal effects, enhancing the stomach's barrier against opportunistic infections.^[40]^[41]

Neutralization and Homeostasis

Gastric Neutralization

Gastric neutralization refers to the processes within the stomach that buffer hydrochloric acid (HCl) to safeguard the gastric mucosa from self-digestion. Surface epithelial cells, including mucous cells, actively secrete bicarbonate ions (HCO₃⁻) into the overlying mucus gel layer, establishing a protective pH gradient that transitions from approximately pH 2 in the acidic lumen to near-neutral pH 7 at the epithelial surface.^[42] This secretion neutralizes hydrogen ions (H⁺) that diffuse into the mucus, preventing their penetration to the underlying cells.^[43] The mucus layer, produced by gastric mucous cells, forms a viscous, adherent barrier that traps these secreted bicarbonate ions, enhancing their neutralizing capacity and limiting acid back-diffusion. This gel-like structure, primarily composed of mucins such as MUC5AC, creates a stable diffusion barrier that maintains the integrity of the pH gradient even under high luminal acidity.^[44] Additionally, non-parietal secretions from chief and mucous cells, which include an alkaline bicarbonate component and constitute a significant portion of the total gastric fluid volume, further dilute and buffer the acidic environment.^[45] Tight junctions between epithelial cells play a crucial role in preventing the back-diffusion of H⁺ ions from the lumen into the intercellular spaces, thereby preserving mucosal integrity. Prostaglandins, such as PGE₂, enhance these protective mechanisms by stimulating both mucus production and bicarbonate secretion, amplifying the overall neutralizing capacity of the gastric mucosa.^[46] The fundamental chemical reaction underlying this neutralization is the interaction between luminal HCl and secreted HCO₃⁻:

\text{HCl} + \text{HCO}_3^- \rightarrow \text{H}_2\text{CO}_3 \rightarrow \text{CO}_2 + \text{H}_2\text{O}

This reaction rapidly converts acid into carbon dioxide and water, dissipating the threat to the epithelium without altering the overall gastric pH significantly.^[47]

Duodenal Protection

Upon entering the duodenum, the highly acidic chyme from the stomach, with a pH around 2, must be rapidly neutralized to prevent damage to the duodenal mucosa and to create an optimal environment for enzymatic digestion.^[48] The primary mechanism involves the secretion of bicarbonate-rich pancreatic juice, which can reach volumes of 1 to 2 liters per day, effectively raising the duodenal pH to 6–7.^[49] This alkaline fluid, produced by ductal epithelial cells in the pancreas, buffers the acid load and supports the activity of pancreatic enzymes like amylase and lipase.^[50] The process is hormonally regulated by enteroendocrine S cells in the duodenal mucosa, which detect low pH (below 4.5) and release secretin into the bloodstream.^[48] Secretin then stimulates the pancreas to increase bicarbonate secretion from acinar and ductal cells, while also enhancing bicarbonate output from Brunner's glands in the duodenal submucosa.^[51] These glands produce an alkaline mucus rich in HCO₃⁻, forming a protective layer that further neutralizes acid and shields the epithelium.^[52] Bile, secreted by the liver and stored in the gallbladder, contributes to this neutralization with its mildly alkaline pH (around 7–8), adding to the buffering capacity as it mixes with chyme to aid in fat emulsification.^[53] Collectively, these mechanisms maintain a critical pH gradient in the duodenum, preventing autodigestion of the intestinal lining; disruptions in this balance, such as impaired bicarbonate secretion, can lead to duodenal ulcers.^[54]

Clinical Significance

Associated Disorders

Gastroesophageal reflux disease (GERD) arises from excessive gastric acid refluxing into the esophagus, leading to mucosal erosion and inflammation known as reflux esophagitis. This condition affects approximately 20% of adults in Western populations, with symptoms including heartburn and regurgitation exacerbated by acid exposure.^[55]^[56] Peptic ulcers result from imbalances in gastric acid production that erode the protective mucosal lining, primarily due to Helicobacter pylori infection or nonsteroidal anti-inflammatory drug (NSAID) use. H. pylori is a major cause, accounting for 50–90% of duodenal ulcers and 40–80% of gastric ulcers, though rates have declined in regions with effective eradication programs by damaging the mucosa and promoting acid hypersecretion, while NSAIDs inhibit protective prostaglandin synthesis, increasing ulcer risk in 10-15% of chronic users in certain populations. The lifetime prevalence of peptic ulcer disease is estimated at 5-10% globally.^[57]^[58]^[57]^[59] Zollinger-Ellison syndrome is a rare disorder caused by gastrin-secreting tumors (gastrinomas), resulting in marked gastric acid hypersecretion and recurrent, refractory peptic ulcers often located in atypical sites such as the distal duodenum or jejunum. Excess gastrin stimulates parietal cells to produce up to 10 times normal acid levels, leading to severe ulceration in over 90% of cases.^[60]^[61] Achlorhydria, characterized by absent or severely reduced gastric acid secretion, can stem from autoimmune destruction of parietal cells (as in pernicious anemia) or drug-induced inhibition such as prolonged proton pump inhibitor use, increasing susceptibility to enteric infections and nutrient malabsorption. Hypoacidity impairs iron and vitamin B12 absorption, contributing to B12 deficiency anemia in up to 20% of affected individuals with autoimmune gastritis.^[62]^[63] Barrett's esophagus develops as a complication of chronic GERD, where prolonged acid and bile exposure induces metaplastic changes in the esophageal lining, replacing squamous epithelium with intestinal-type mucosa. This precancerous condition affects 10-15% of individuals with longstanding GERD symptoms.^[64]^[65]

Diagnostic and Therapeutic Approaches

Diagnostic approaches to gastric acid-related conditions primarily involve assessing acid secretion levels and evaluating mucosal integrity. The 24-hour ambulatory esophageal pH monitoring is considered the gold standard for diagnosing gastroesophageal reflux disease (GERD), as it quantifies the frequency and duration of acid exposure in the esophagus by detecting pH below 4, allowing correlation of symptoms with reflux events.^[66]^[67] Gastric acid output tests, such as the secretin stimulation test combined with fasting gastrin levels, measure basal and maximal acid secretion rates through blood sampling and gastric pH assessment, providing insight into hypersecretory states like Zollinger-Ellison syndrome.^[68]^[69] Upper endoscopy (esophagogastroduodenoscopy) is essential for visualizing mucosal damage, including erosive esophagitis, Barrett's esophagus, or peptic ulcers caused by excess acid, and can guide biopsy for complications like Helicobacter pylori infection.^[70]^[71] Therapeutic strategies aim to reduce acid production, neutralize existing acid, or address underlying causes to manage conditions such as peptic ulcers and GERD. Proton pump inhibitors (PPIs), exemplified by omeprazole, irreversibly inhibit the H+/K+-ATPase proton pump in parietal cells, suppressing gastric acid secretion by over 90% and promoting mucosal healing.^[72]^[73] H2-receptor antagonists like famotidine competitively block histamine at H2 receptors on parietal cells, reducing acid output by 50-70% and offering an alternative for milder cases or PPI intolerance.^[74]^[75] Antacids containing calcium carbonate (CaCO3) provide rapid, symptomatic relief by chemically neutralizing gastric acid, raising intragastric pH and alleviating heartburn within minutes, though their effect is short-lived.^[76]^[77] For acid-related disorders linked to H. pylori, such as duodenal ulcers, eradication therapy typically involves a combination of antibiotics (e.g., clarithromycin, amoxicillin, metronidazole) with a PPI for 10-14 days, achieving eradication rates of 80-90% and preventing recurrence. However, rising antibiotic resistance has reduced eradication rates in some regions, with guidelines now recommending bismuth-based quadruple therapy to achieve >90% success.^[78]^[79]^[80] Surgical interventions are reserved for refractory cases; vagotomy, by severing vagal nerves to diminish cholinergic stimulation of acid secretion, is used in hypersecretory syndromes to reduce basal and stimulated output.^[81] Fundoplication, particularly the laparoscopic Nissen procedure, reinforces the lower esophageal sphincter to prevent reflux in severe GERD, with long-term symptom control in over 80% of patients.^[82]^[83]

Historical Development

Early Discoveries

The concept of gastric acid traces its origins to ancient medical theories, particularly those of Hippocrates around 400 BCE, who described the stomach's role in digestion as involving the transformation of food through the body's four humors—blood, phlegm, yellow bile, and black bile—with yellow bile acting as a crucial gastric fluid that initiated the breakdown of ingested matter into vital essences.^[84] This humoral framework posited digestion as a qualitative process of heating and mixing rather than a specific chemical reaction, influencing Western medicine for centuries.^[84] In the 18th century, experimental approaches began to reveal the acidic nature of gastric secretions. René-Antoine Ferchault de Réaumur conducted pioneering studies in 1752 using a tame buzzard, feeding it small metal tubes containing meat; the recovered tubes held partially digested meat immersed in an acidic fluid, leading Réaumur to conclude that the stomach actively secreted a corrosive liquid essential for digestion, distinct from mere mechanical churning.^[85] This work shifted views from passive fermentation to active secretion, though the exact chemical composition remained unclear.^[85] A major breakthrough came in 1824 when English physician and chemist William Prout isolated hydrochloric acid (HCl) from human gastric juice obtained during cases of dyspepsia, using distillation and chemical assays to demonstrate its presence as free HCl rather than combined forms.^[86] Prout's analysis showed that gastric juice in its natural state contained this mineral acid, capable of dissolving proteins and resisting putrefaction, thus proving its inorganic chemical nature and refuting earlier notions that it resembled organic acids like vinegar or lactic acid derived from food fermentation.^[86] Prior to Prout, misconceptions persisted that the stomach's acidity arose from ingested sour substances, such as vinegar-like fluids, rather than an endogenous secretion.^[85] Building on these foundations, German physiologist Theodor Schwann discovered pepsin as the key enzyme in gastric juice in 1836, isolating it from stomach secretions and demonstrating its proteolytic activity in the presence of acid.^[85] French physiologist Claude Bernard advanced understanding in the 1850s through experiments on gastric digestion, elucidating how HCl facilitated the hydrolysis of proteins into peptides and amino acids.^[85] Bernard's work, detailed in studies using animal models like dogs with fistulas, emphasized the synergistic role of acid and enzyme in chemical digestion, solidifying the stomach's secretory mechanism as a cornerstone of physiology.

Key Scientific Advances

In the early 20th century, the physiological effects of histamine, including its stimulation of gastric acid secretion, were first elucidated by Henry Hallett Dale and P.P. Laidlaw through experiments demonstrating its vasoactive and secretory properties in animal models.^[87] This discovery laid the groundwork for understanding histamine as a key regulator of parietal cell function, though its specific receptor subtypes remained unidentified for decades. Building on this, the identification of histamine H2 receptors in the 1970s by James W. Black and colleagues revolutionized the field, as these receptors were shown to mediate histamine's stimulatory effect on gastric acid production via cyclic AMP signaling in parietal cells.^[88] The development of selective H2 receptor antagonists, such as cimetidine in 1973, provided the first targeted pharmacological inhibition of acid secretion, marking a shift from symptomatic treatments to mechanism-based therapies.^[89] A pivotal biochemical advance occurred in 1976 when George Sachs and collaborators isolated and characterized the gastric H+/K+ ATPase proton pump from hog gastric mucosa, confirming it as the terminal enzyme responsible for active hydrogen ion transport into the stomach lumen.^[90] This electroneutral ATP-driven exchanger exchanges intracellular H+ for extracellular K+, enabling the highly acidic environment of the stomach. The isolation paved the way for proton pump inhibitors (PPIs), with omeprazole emerging in 1984 as the first compound to irreversibly bind and inhibit the pump's catalytic subunit, achieving profound and sustained suppression of acid output in clinical trials.^[91] Omeprazole's introduction transformed peptic ulcer management by promoting rapid healing and reducing recurrence rates, with subsequent PPIs like lansoprazole and esomeprazole refining this class for broader gastrointestinal applications.^[72] In 1982, Barry J. Marshall and J. Robin Warren identified Helicobacter pylori as a primary etiological agent in gastritis and peptic ulcers, challenging the prevailing view that stress and diet were the main causes; their culture of the bacterium from gastric biopsies and self-experimentation by Marshall demonstrated its role in inducing inflammation and acid-related damage.^[92] This microbiological breakthrough, validated through Koch's postulates and large-scale eradication studies, earned them the 2005 Nobel Prize in Physiology or Medicine and shifted treatment paradigms toward antibiotic therapies combined with acid suppression.^[93] During the 2000s, genetic studies advanced the molecular understanding of parietal cell function, with knockout mouse models revealing the essential roles of ion channels such as KCNQ1 and ClC-2 in maintaining apical K+ conductance and Cl- recycling necessary for sustained acid secretion.^[94] For instance, ClC-2 ablation led to reduced parietal cell numbers and impaired H+/K+ ATPase activity, highlighting these channels' contributions to acid homeostasis. Concurrently, research established gastric acid's role in modulating the gastric microbiome, as its bactericidal properties limit pathogenic overgrowth while permitting a core commensal community dominated by genera like Streptococcus and Prevotella, thereby influencing downstream intestinal microbial composition and preventing dysbiosis.^[95] Post-2010 investigations have uncovered gastric acid's broader implications in systemic physiology, particularly its indirect influence on the gut-brain axis through microbiome regulation; alterations in acid secretion, often via PPI use, reshape microbial profiles that affect vagal signaling and neurotransmitter production, contributing to mood disorders and stress responses in preclinical models.^[96] Similarly, emerging links to immunotherapy highlight how acid-mediated microbial shifts can enhance or impair immune checkpoint inhibitor efficacy in gastric cancer, with studies showing that PPI-induced microbiome dysbiosis correlates with reduced T-cell infiltration and poorer responses to PD-1/PD-L1 blockade in clinical cohorts.^[97] These insights underscore acid's role in integrating gastrointestinal, neurological, and immunological networks.

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May 30, 2025 · Buoyancy (floating) property of ODDS in gastric juice The density of gastric juice ranges from 1.004 to 1.010 g/mL. If the density of an ODDS ...
[14]
Upper gastrointestinal (GI) pH in young, healthy men and women
In the fasted state, the median gastric pH was 1.7 and the median duodenal pH was 6.1.Missing: range | Show results with:range<|control11|><|separator|>
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Osmotic concentration of the gastric juice of dogs - PubMed
2. The osmolality of the blood that passes through the gastric mucosa increases during secretion of acid juice.3. The amount of water that should be removed ...Missing: pressure | Show results with:pressure<|separator|>
[16]
Histology, Parietal Cells - StatPearls - NCBI Bookshelf - NIH
Harbored in the gastric glands of the fundus and body, parietal cells are considered to be dynamic, as they undergo morphological transition during the resting ...Introduction · Function · Tissue Preparation · Microscopy, Electron
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Acid secretion and the H,K ATPase of stomach - PMC
It appears that gastrin and acetylcholine exert their effects on acid secretion mainly by stimulation of histamine release from the enterochromaffin-like (ECL) ...
[18]
In Pursuit of the Parietal Cell – An Evolution of Scientific ... - Frontiers
To maintain electroneutral acid secretion, chloride is also apically secreted along with hydrogen, generating HCl. On the apical side, the CFTR allows for ...
[19]
Role of potassium in acid secretion - Baishideng Publishing Group
Sep 14, 2005 · The H+,K+-ATPase located on the apical membrane of the parietal cell exchanges H+ for K+. K+ is recycled from the canaliculus into the cytoplasm ...
[20]
Gastric acid secretion from parietal cells is mediated by a ... - NIH
Gastric acid secretion by parietal cells requires trafficking and exocytosis of H-K-ATPaserich tubulovesicles (TVs) toward apical membranes in response to ...
[21]
Do We Need Gastric Acid? | Digestion - Karger Publishers
Jul 2, 2008 · Given the large volume of gastric acid secretions (1.5–2.5 liters/day), efficient feedback mechanisms are mandatory to ensure effective ...
[22]
Physiology, Gastrointestinal Nervous Control - StatPearls - NCBI - NIH
The first phase of gastric secretion is the cephalic phase. In this phase, a person sees, smells, or thinks about food, activating an area in the medulla ...
[23]
Stomach Acid Secretion - an overview | ScienceDirect Topics
The cephalic phase of gastric acid secretion results from olfactory, visual ... The intestinal phase accounts for up to 10% of gastric acid secretion ...
[24]
Entero-oxyntin: a stimulant of gastric acid secretion ... - PubMed
A peptide that further augments gastric acid secretion in cats, maximally stimulated by pentagastrin, was identified in porcine upper small intestine.
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Analysis of Somatostatin-Secreting Gastric Delta Cells according to ...
May 8, 2020 · D-cells produce somatostatin, the main paracrine inhibitor of acid secretion and GI motility [6]. Somatostatin influences gastric motility, ...
[26]
THE PHARMACOLOGY OF THE GASTRIC ACID PUMP: The H+,K+ ...
Histamine elevates cAMP and Ca2+ in the parietal cell, whereas acetylcholine and gastrin elevate only calcium in the parietal cell. Permissive interactions may ...
[27]
Differentiation of the Gastric Mucosa I. Role of histamine in control of ...
Gastric acid secretion is stimulated or inhibited by endocrine, paracrine, and neurocrine signals via at least three messenger pathways; gastrin-histamine, CCK- ...
[28]
Protein acidification and hydrolysis by pepsin ensure efficient trypsin ...
Apr 24, 2021 · Abstract. Enzyme-catalysed hydrolysis is important in protein digestion. Protein hydrolysis is initiated by pepsin at low pH in the stomach.
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Denaturation - an overview | ScienceDirect Topics
Indeed, stomach acid denatures dietary protein so that the digestive enzymes—pepsin, trypsin, and chymotrypsin—can hydrolyze dietary proteins to amino acids.Missing: gastric | Show results with:gastric
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Biochemistry, Iron Absorption - StatPearls - NCBI Bookshelf - NIH
Gastric acid production plays a key role in plasma iron homeostasis. When proton-pump inhibiting drugs such as omeprazole are used, iron absorption is ...
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Gastric Acid, Calcium Absorption, and Their Impact on Bone Health
This article reviews the physiology of gastric acid secretion, intestinal calcium absorption, and their respective neuroendocrine regulation
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Low gastric hydrochloric acid secretion and mineral bioavailability
It has been established that low hydrochloric acid secretion can lead to decreased absorption of ferric iron.
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Revisiting the enzymatic kinetics of pepsin using isothermal titration ...
Jun 4, 2018 · We found that pepsin has a higher catalytic rate at lower pH, while its affinity to substrate is lower. At the same pH, pepsin has lower ...
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Gastric Acid Barrier to Ingested Microorganisms in Man - PubMed
At pH less than 4.0, 99.9% of the bacteria were killed within 30 minutes. The presence of profuse bacterial flora, including coliforms, found in markedly acid- ...
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In Vitro Killing of Nosocomial Pathogens by Acid and Acidified Nitrite
Gastric acid may provide an important host defense by killing ingested pathogens (5). For example, normal gastric acidity kills more than 99.9% of several gram ...
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The role of gastric acid in preventing foodborne disease and how ...
The secretion of hydrochloric acid by the stomach plays an important role in protecting the body against pathogens ingested with food or water.Missing: article | Show results with:article
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Gastric mucosal defence mechanisms: a brief review - PubMed
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Physiology, Gastric Intrinsic Factor - StatPearls - NCBI Bookshelf
It plays a crucial role in the transportation and absorption of the vital micronutrient vitamin B12 (cobalamin, Cbl) by the terminal ileum. Insufficiency of ...Introduction · Cellular Level · Mechanism · Pathophysiology
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Vitamin B12 deficiency induced by the use of gastric acid inhibitors
Vitamin B12 malabsorption can occur from hypochlorhydria induced by the use of gastric acid inhibitors, specifically proton pump inhibitors (PPIs) and histamine ...
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Surviving the Acid Test: Responses of Gram-Positive Bacteria to ...
It has also been observed that neutralization of acid by food or bicarbonate decreases the infectious dose; for example, an increase in the pH of the stomach ...
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Coping with low pH: molecular strategies in neutralophilic bacteria
As part of their life cycle, neutralophilic bacteria are often exposed to varying environmental stresses, among which fluctuations in pH are the most frequent.
[42]
Role of mucus layers in gut infection and inflammation - PMC
The attached inner mucus layer maintains a pH gradient with a pH of 2 at the lumen and 7 at the epithelial surface [32]. Few bacteria have developed ...
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Gastroduodenal mucus bicarbonate barrier: protection against acid ...
The primary function of the mucosal bicarbonate secretion is to neutralize acid diffusing into the mucus gel layer and to be quantitatively sufficient to ...
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The gastrointestinal mucus system in health and disease - PMC
Like the colon, the stomach has a two-layered mucus system. The inner mucus layer, built around MUC5AC, acts as a diffusion barrier for hydrochloric acid. The ...
[45]
Gastric mucus and bicarbonate secretion in relation to mucosal ...
The magnitude of stimulated gastric bicarbonate secretion is 5 to 10% of maximal acid secretion for a given surface area of mucosa. Stimulants of gastric ...
[46]
Role of endogenous prostaglandins in gastric secretion ... - PubMed
Exogenous prostaglandins inhibit acid secretion, stimulate mucus and bicarbonate secretion, alter mucosal blood flow, and provide dramatic protection.
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Epithelial carbonic anhydrases facilitate PCO2 and pH regulation in ...
The duodenum is the site of mixing of massive amounts of gastric H+ with secreted HCO3−, generating CO2 and H2O accompanied by the neutralization of H+.Equilibrated High Co... · Results · Premixed SolutionMissing: H2CO3 H2O
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Physiology, Secretin - StatPearls - NCBI Bookshelf - NIH
May 1, 2023 · [12] Secretin increases bicarbonate secretion from duodenal Brunner's gland as well; this mechanism buffers the acidity from chyme and reduces ...
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Defective dietary fat processing in transgenic mice lacking ...
In humans, 1.5–2.0 liters of bicarbonate-rich fluid are secreted by the pancreas, and 0.5–1.0 liters of bile are secreted by the liver.
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Pancreatic Bicarbonate Secretion Involves Two Proton Pumps - PMC
Pancreas secretes fluid rich in digestive enzymes and bicarbonate. The alkaline secretion is important in buffering of acid chyme entering duodenum and for ...
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Pleiotropic Effects of Secretin: A Potential Drug Candidate in the ...
Secretin also neutralizes the acidic contents of the duodenal lumen by stimulating pancreatic acinar cells and duodenal Brunner's glands to produce bicarbonate ...
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Feb 18, 2025 · Brunner glands secrete bicarbonate into the duodenum to neutralize stomach acid before chyme reaches the jejunum. The duodenum and upper ...
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Physiology, Bile - StatPearls - NCBI Bookshelf
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Helicobacter pylori: the primary cause of duodenal ulceration ... - NIH
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Gastroesophageal reflux disease: Important considerations for the ...
It is highly prevalent worldwide with a prevalence of 10%-20% in the western world[1-4]. It is estimated that GERD affects 18.6 million people in the United ...<|control11|><|separator|>
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Peptic Ulcer Disease - StatPearls - NCBI Bookshelf - NIH
Helicobacter Pylori-Associated PUD This bacterium is responsible for 90% of duodenal ulcers and 70% to 90% of gastric ulcers. H. pylori infection is more ...
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Interaction between Helicobacter pylori infection, nonsteroidal anti ...
NSAIDs have emerged as one of the most important cause of peptic ulcer complications in many developed countries where the incidence of H. pylori-related ulcer ...
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Zollinger-Ellison syndrome - Symptoms and causes - Mayo Clinic
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Gastrinoma - StatPearls - NCBI Bookshelf - NIH
Feb 19, 2025 · Gastrinomas are rare neuroendocrine tumors that cause excess gastrin secretion, leading to ZES, characterized by severe peptic ulcers, ...
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Achlorhydria - StatPearls - NCBI Bookshelf - NIH
Achlorhydria is a condition in which the stomach does not produce hydrochloric acid, one of the components of gastric acid.
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Autoimmune Gastritis and Hypochlorhydria: Known Concepts from a ...
Jun 21, 2024 · Autoimmune atrophic gastritis is an immune-mediated disease resulting in autoimmune destruction of the specialized acid-producing gastric parietal cells.
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Barrett Esophagus - StatPearls - NCBI Bookshelf
May 26, 2025 · Most patients with Barrett esophagus will exhibit symptoms of GERD, such as heartburn (retrosternal burning), especially after eating. Acid ...
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Esophageal pH Monitoring - StatPearls - NCBI Bookshelf - NIH
Ambulatory esophageal pH testing is done with a wireless pH capsule or a traditional pH probe and is the gold standard test for GERD diagnosis.
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Advancements in the use of 24-hour impedance-pH monitoring for ...
24-h impedance-pH monitoring represents the best diagnostic tool to detect abnormal reflux and to correlate symptoms to reflux episodes.
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Continuous intravenous pentagastrin as a stimulant of maximal ...
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Pharmacology and clinical efficacy of ranitidine, a new H2-receptor ...
It is more potent than cimetidine in inhibiting gastric acid secretion and lacks cimetidine's anti-androgenic and hepatic microsomal enzyme inhibiting effects.
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Gastroesophageal reflux disease (GERD) - Diagnosis and treatment
If stomach acid washes back into the esophagus, it can cause discomfort and may lead to precancerous changes in the lining of the esophagus.
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Diagnosis and treatment of gastroesophageal reflux disease - PMC
The diagnosis of GERD is typically made by a combination of clinical symptoms, response to acid suppression, as well as objective testing with upper endoscopy ...Diagnosis · Treatment · Medical Therapy
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Omeprazole - StatPearls - NCBI Bookshelf - NIH
Omeprazole is a proton-pump inhibitor used to manage and treat several conditions, including uncomplicated heartburn, peptic ulcer disease, gastrointestinal ...Continuing Education Activity · Indications · Mechanism of Action · Administration
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Proton pump inhibitors: Review of reported risks and controversies
1 PPIs act on the gastric acid production by inhibition of the gastric H+/K+‐ATPase via covalent binding to cysteine residue of this proton pump, affecting the ...
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H2 Blockers - StatPearls - NCBI Bookshelf - NIH
Aug 11, 2024 · H2 receptor blockers, or histamine-2 receptor antagonists (H2RAs), are gastric acid-suppressing agents frequently used to treat various gastric conditions.
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Onset of acid-neutralizing action of a calcium/magnesium carbonate ...
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Antacids - StatPearls - NCBI Bookshelf - NIH
Aug 8, 2023 · The antacids act by neutralizing the acid in the stomach and by inhibiting pepsin, which is a proteolytic enzyme. Each of these cationic salts ...
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Helicobacter Pylori: A Review of Current Treatment Options in ...
Dec 6, 2022 · Though widely considered the most effective antimicrobial agent for treating and eradicating H. pylori, the use of clarithromycin is not without ...
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A New Era in Helicobacter pylori Treatment - NIH
Mar 12, 2023 · This review article provides an extensive overview of H. pylori antibiotic resistance and future treatment possibilities.
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Gastric Hypersecretory States: Investigation and Management - PMC
The gastric phase of gastric acid secretion occurs with the entry of nutrients into the gastrointestinal tract. Gastrin, released by antral G cells, is ...
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Nissen Fundoplication - StatPearls - NCBI Bookshelf - NIH
Anti-reflux surgery generally includes a fundoplication, which is a technique to recreate lower esophageal sphincter pressure by wrapping the fundus of the ...
[80]
Laparoscopic fundoplication for gastroesophageal reflux disease - NIH
Laparoscopic fundoplication is the standard surgical treatment for GERD. It is highly effective in curing GERD with a 80% success rate at 20-year follow-up.
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Ancient Theory of Elements and Humors
Hippocrates theorized that humors were set in motion inner air and innate heat. They traveled through the veins to different organs of the body. The blood ...
[82]
a journey through time in quest for the stomach's secretion - PMC - NIH
The first experiments René Antoine Ferchault de Réaumur (1683-1757), experimenting with a tame buzzard which he fed small hollow metal tubes containing a ...Missing: 1752 source
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III. On the nature of the acid and saline matters usually existing in the ...
This illustrious philosopher concluded, from his numerous experiments, that the gastric fluids, when in a perfectly natural state, are neither acid nor alkaline ...
[84]
None
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[85]
Histamine and gut mucosal immune regulation - Wiley Online Library
Nov 29, 2013 · Soon afterward in 1910, Dale and Laidlaw reported the first biological functions of histamine, whereby they recognized that histamine had the ...
[86]
Histamine and its receptors
This article reviews the development of our knowledge of the actions of histamine which have taken place during the course of the 20th century.
[87]
Characterization and development of cimetidine as a histamine H2 ...
The evidence suggests that cimetidine inhibits gastric acid secretion through blockade of histamine HZ-receptors in the gastric mucosa. Cimetidine has been ...
[88]
The gastric HK-ATPase: structure, function, and inhibition - PMC - NIH
In 1976, it was shown that gastric acid secretion was due to the action of an electroneutral ATP-dependent hydrogen–potassium exchanger [41]. The H,K-ATPase is ...
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The discovery and development of the proton pump inhibitor
... Omeprazole, the first proton pump inhibitor. Med Res Rev 10 ... (1984) Gastric acid secretion and duodenal ulcer healing during treatment with omeprazole.
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Press release: The Nobel Prize in Physiology or Medicine 2005
Oct 3, 2005 · In 1982, when this bacterium was discovered by Marshall and Warren, stress and lifestyle were considered the major causes of peptic ulcer ...
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Helicobacter pylori: A Nobel pursuit? - PMC - NIH
In 2005, Barry Marshall and Robin Warren were awarded the Nobel prize in Physiology for their pioneering work on Helicobacter pylori.
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Channel Disrupts Mouse Gastric Parietal Cell Acid Secretion
The present studies were designed to examine the effects of ClC-2 ablation on cellular morphology, parietal cell abundance, H/K ATPase expression, ...
[93]
The Evolution of Stomach Acidity and Its Relevance to the Human ...
Gastric acidity is likely a key factor shaping the diversity and composition of microbial communities found in the vertebrate gut.
[94]
The Microbiota-Gut-Brain Axis | Physiological Reviews
The importance of the gut-brain axis in maintaining homeostasis has long been appreciated. However, the past 15 yr have seen the emergence of the microbiota ...
[95]
Relationships among microbiota, gastric cancer, and immunotherapy
This paper reviewed the relationship between microorganisms and GC, potential links between microorganisms and immunotherapy and research of microorganisms ...Missing: post- | Show results with:post-