HISTAMINE

Histamine, produced in ECL cells by decarboxylation of l-histidine by histidine decarboxylase (HDC), stimulates the parietal cell directly by binding to H₂ receptors coupled to activation of adenylate cyclase and generation of cAMP (see Fig. 49-9).⁴³ Histamine also stimulates acid secretion indirectly by binding to H₃ receptors coupled to inhibition of somatostatin release from oxyntic D cells, thus resulting in stimulation of histamine release and acid secretion (see Fig. 49-10).^44,45 Gastrin, PACAP, VIP, and ghrelin stimulate, whereas somatostatin, CGRP, prostaglandins, peptide YY (PYY), and galanin inhibit histamine secretion.^46,47 As discussed following, gastrin also exerts a direct proliferative effect on ECL cells. ACh has no direct effect on histamine secretion.^48–50

GASTRIN

Gastrin, the main stimulant of acid secretion during meal ingestion, is produced in G cells of the gastric antrum and, in much lower and variable amounts, in the proximal small intestine, colon, and pancreas. Gastrin is synthesized as a large precursor molecule of 101 amino acids, which is converted to progastrin (80 amino acids) by cleavage of the N-terminal signal peptide. Progastrin is further processed to yield peptides with C-terminal glycine, that is, G34gly and G17gly. The final processing step involves amidation to yield G34amide and G17amide. The plasma half-life of G34amide is 30 minutes and that of G17amide is three to seven minutes; they are metabolized primarily by the kidney and, in addition, by the intestine and liver.^51,52 Consequently, most gastrin in the circulation during fasting is G34, whereas after a meal it is G17. In patients with renal insuffiency as well as massive small bowel resection, fasting blood levels of G17 and G34 are elevated.^53,54 It should be noted that the commercially available test substance pentagastrin is not a naturally occurring peptide but rather is a manufactured analog that contains the biologically active C-terminus sequence Trp-Met-Asp-Phe-NH₂.

Gastrin and cholecystokinin (CCK) belong to the same family of peptides and possess an identical carboxyl-terminal pentapeptide sequence (-Gly-Trp-Met-Asp-Phe-NH₂). Two main classes of gastrin/CCK receptors have been characterized: CCK₁ (formerly CCK-A) and CCK-2 (formerly CCK_B or CCK_B/gastrin). CCK₁ receptors are specific for CCK, whereas CCK-2 receptors recognize both CCK and gastrin with high affinity. Gastrin, acting via CCK-2 receptors that activate phospholipase C to induce release of intracellular calcium, stimulates the parietal cell directly and, more importantly, indirectly by releasing histamine from ECL cells (see Figs. 49-9 and 49-10).^55,56 Gastrin regulates the secretion and synthesis of histamine in a biphasic manner. The first phase involves release of stored histamine. The second phase relates to the replenishment of histamine stores and involves an increase in HDC activity followed by an increase in HDC gene transcription.⁵⁷ H₂ receptor, HDC, and CCK-2 receptor knockout mice manifest decreased acid secretion, especially in response to gastrin.^58–60

Although amidated gastrins had been thought to be the only forms with biological activity, glycine-extended gastrins may regulate the capacity of the parietal cell to respond to secretagogues, release histamine from ECL cells, and stimulate proliferation of colonic mucosa and colorectal cancers.^61,62 ACh, GRP, secretin, β2/β3-adrenergic agonists, calcium, protein, and alcoholic beverages produced by fermentation stimulate, whereas somatostatin, galanin, and adenosine inhibit gastrin secretion. In addition, at least two negative-feedback pathways, mediated via release of somatostatin, regulate gastrin secretion. The first is activated by luminal acidity and involves sensory CGRP neurons (see Fig. 49-10). Low intragastric pH (high intragastric acidity) activates CGRP neurons that, via an axon reflex, stimulate somatostatin and thus inhibit gastrin secretion.^63–65 Conversely, when intragastric pH rises (low intragastric acidity), for example, by administering antisecretory medications such as proton pump inhibitors (PPIs) or by developing gastric atrophy, somatostatin secretion is inhibited and patients develop hypergastrinemia. There is some evidence that bacterial overgrowth induced by hypochlorhydria may also contribute to hypergastrinemia.⁶⁶ The second negative-feedback pathway involves a paracrine action whereby gastrin directly stimulates somatostatin and thus attenuates its own secretion (see Fig. 49-10).⁶⁷

Gastrin also functions as a trophic hormone to stimulate mucosal proliferation. CCK-2 receptors have been localized to the progenitor zone in oxyntic glands, and chronic hypergastrinemia induces proliferation of ECL and parietal cells directly as well as indirectly via the autocrine or paracrine action of growth factors such as heparin-binding epidermal growth factor, amphiregulin, transforming growth factor-α, metalloproteinases, and regenerating islet-derived 1.^68,69 Rats rendered hypergastrinemic by a PPI demonstrate a five-fold increase in the number of ECL cells and a 1.5-fold increase in the number of parietal cells.⁷⁰ Gastrin acts directly on ECL cells to induce hyperplasia, dysplasia, and eventually neoplasia (carcinoids).⁷¹ In contrast to rodents, humans rarely develop carcinoid tumors in response to hypergastrinemia unless other factors are present such as chronic active gastritis or gastrinoma associated with multiple endocrine neoplasia type 1 (see Chapter 31).⁷² Because ECL cells contain somatostatin subtype 2 receptors (SSTR2), somatostatin scintigraphy with ¹¹¹indium-diethylenetriamine pentaacetic acid [¹¹¹In-DTPA]octreotide is the preferred imaging method to detect carcinoid tumors (see Chapter 31).^73,74

ACETYLCHOLINE

ACh, released from postganglionic neurons whose cell bodies are located primarily in the submucosal (Meissner’s) plexus, stimulates the parietal cell directly as well as indirectly by inhibiting somatostatin secretion (see Fig. 49-10). The parietal cell muscarinic receptor is of the M₃ subtype.^75,76 Like CCK-2 receptors, M₃ receptors are coupled to activation of phospholipase C with generation of inositol trisphosphate and release of intracellular calcium (see Fig. 49-9).⁷⁷ Alcoholic beverages produced by fermentation stimulate gastric acid secretion and the effect may be mediated via activation of M₃ receptors.⁷⁸ ACh also stimulates acid secretion indirectly by activating M₂ and M₄ receptors on D cells coupled to inhibition of somatostatin secretion, thus removing the tonic restraint exerted by this peptide on gastrin, ECL, and parietal cells (see Fig. 49-10).

SOMATOSTATIN

The main inhibitor of acid secretion is somatostatin. Somatostatin is synthesized from a 92-amino acid preprosomatostatin precursor molecule that is processed to yield somatostatin-14 and somatostatin-28. Somatostatin-14 is predominantly found in stomach, pancreatic islets, and enteric neurons, whereas somatostatin-28 is the major form in small intestine. The half-life of somatostatin-14 is 1 to 3 minutes, whereas the half-life of somatostatin-28 is about 15 minutes.

In the stomach, somatostatin cells are closely coupled to their target cells (gastrin cells in the antrum, or parietal and ECL cells in the fundus/body) either directly via cytoplasmic processes or indirectly via the local circulation.^28,79 The functional correlate of this anatomic coupling is a tonic restraint exerted by somatostatin on acid secretion from the parietal cell, histamine secretion from the ECL cell, and gastrin secretion from the G cell (see Figs. 49-5 and 49-10).^{30,31,34,80,81} Removing this restraint (i.e., disinhibition or elimination of the influence of an inhibitor), by activation of cholinergic neurons, is an important physiologic mechanism for stimulating acid secretion (see Fig. 49-10). In the stomach, the actions of somatostatin are mediated primarily via the somatostatin subtype 2 receptor (SSTR2).^82–84 Gastrin, GRP, VIP, PACAP, β2/β3-adrenergic agonists, secretin, ANP, adrenomedullin, amylin, adenosine, and CGRP stimulate, whereas ACh and interferon-γ inhibit somatostatin secretion. As mentioned, an increase in luminal acidity acts to attenuate acid secretion via a pathway involving release of somatostatin in the antrum and the fundus. The change in gastric somatostatin secretion can be demonstrated over a range of pH 3 to pH 5, which is within the range observed after ingestion of a meal (Fig. 49-11).⁸⁵

Figure 49-11. Relationship between luminal pH and gastric somatostatin secretion. In isolated mouse stomach, addition of bicarbonate (HCO₃⁻) to neutralize basal acid secretion or HCl to augment luminal acidity causes a corresponding change in somatostatin secretion.

(From Schubert ML, Edwards NF, Makhlouf GM. Regulation of gastric somatostatin secretion in the mouse by luminal acid: A local feedback mechanism. Gastroenterology 1988; 94:317-22).

MISCELLANEOUS PEPTIDES

Ghrelin, the natural ligand for the growth hormone secretagogue receptor, is present in greatest concentrations in gastric oxyntic mucosa and is localized to A-like (or Gr) cells.^86,87 Lesser amounts are present in the antrum, small intestine, and colon (see Chapter 1). Plasma ghrelin concentrations increase before meals and decrease postprandially.⁸⁸ It is postulated that ghrelin triggers premeal hunger and promotes feeding. Its suppression after Roux-en-Y gastric bypass may, in part, contribute to weight loss.⁸⁹ Most studies report that exogenously administered ghrelin stimulates acid secretion.^90,91 The stimulatory effect appears to involve the vagus nerve and histamine release because it is abolished by vagotomy and is associated with an increase in HDC messenger ribonucleic acid (mRNA).^92,93

Orexin-A, derived from propro-orexin by post-translational processing, is co-localized with gastrin in human pyloric mucosa.^91,94 Intracerebroventricular and peripherally administered orexin-A stimulate gastric acid secretion.⁹⁵ In rats equipped with gastric fistulas, an orexin receptor 1 antagonist inhibits basal and pentagastrin-stimulated acid secretion, implying that endogenous orexin-A stimulates acid secretion.^94,95

ANP, CCK, secretin, neurotensin, glucagon-like peptide 1 (GLP-1), glicentin, oxyntomodulin, peptide YY, adrenomedullin, amylin, glucose-dependent insulinotropic polypeptide (GIP), leptin, epidermal growth factor, and interleukin-1β (IL-1β) inhibit acid secretion. The effect of each, except perhaps for IL-1β, is mediated via release of somatostatin.^24–2696 The term enterogastrone has been used to describe the intestinal factor or factors responsible for inhibiting acid secretion in response to nutrients in the intestine. Prime candidates include CCK, secretin, neurotensin, GLP-1, glicentin, and oxyntomodulin because they are present in intestinal mucosa, released into the circulation in response to luminal nutrients, and capable of inhibiting acid secretion at “physiologic” concentrations.^97–101 Although it is likely that enterogastrone activity represents the combined influence of several of these peptides, the strongest evidence favors CCK. CCK, produced in I cells in the proximal small intestine, is released by luminal protein and fat. The acid-inhibitory response to intraduodenal fat is abolished by pretreatment with a CCK-1 receptor antagonist in dogs, and the response is blocked in CCK-1 receptor knockout mice as well.^102–105

PARIETAL CELL INTRACELLULAR PATHWAYS

In parietal cells, acid secretion is increased by activation of intracellular cAMP- and calcium-dependent signaling pathways that activate downstream protein kinases, ultimately leading to fusion and activation of H⁺,K⁺-ATPase (the proton pump) with concomitant activation of luminal membrane conductances for K⁺ and Cl⁻ (see Fig. 49-9; Fig. 49-12). The H⁺,K⁺-ATPase actively pumps out H⁺ against a tremendous concentration gradient (cell interior pH 7.4 or 40 nM; acid secreted at pH 0.8 or 160 million nM) in exchange for luminal K⁺. The energy required comes from adenosine triphosphate (ATP) produced by the parietal cell’s extensive mitochondrial network. H⁺,K⁺-ATPase consists of an α–subunit that carries out the catalytic and transport function of the enzyme and contains sequences responsible for apical membrane localization¹⁰⁶ as well as a β-subunit, which is heavily glycosylated, and protects the enzyme from degradation and is necessary for trafficking to and from the luminal membrane.¹⁰⁷

Figure 49-12. Model illustrating ion transport in the parietal cell. Acid secretion requires a functional H⁺,K⁺-ATPase as well as apical K⁺ and Cl⁻ channels and basolateral transporters and/or channels for K⁺, Cl⁻, and HCO₃⁻. Acid is produced from the hydration of CO₂ to form H⁺ and HCO₃⁻, a reaction catalyzed by cytoplasmic carbonic anhydrase (CA). In the presence of luminal K⁺, H⁺,K⁺-ATPase pumps H⁺ into the lumen in exchange for K⁺. Luminal K⁺ channels (KCNE2/KCNQ1 and ROMK [not shown]) recycle K⁺ across the luminal membrane. The source of intracellular K⁺ is the basolateral Na⁺,K⁺-ATPase and the sodium-2 chloride potassium-cotransporter-1 (NKCC1). For each H⁺ secreted, a HCO₃⁻ exits the cell across the basolateral membrane via the anion exchanger (AE2, or Slc4a2). Concurrently with H⁺, Cl⁻ is extruded across the luminal membrane via an apical chloride channel. The sources of intracellular Cl⁻ are AE2, NKCCl, and the SLC26A7 channel.

In the resting unstimulated state, H⁺,K⁺-ATPase activity is sequestered within cytoplasmic tubulovesicles. On stimulation, there is a dramatic morphologic transformation as these vesicles fuse with the apical plasma membrane, resulting in a 6- to 10-fold increase in the membrane and the formation of the canalicular system (Fig. 49-13). Translocation of the H⁺,K⁺-ATPase into the canalicular membrane together with the presence of luminal K⁺ activates the enzyme.¹⁰⁸ On cessation of secretion, the H⁺,K⁺-ATPase is retrieved from the apical membrane and the tubulovesicular compartment is reestablished. The precise mechanisms regulating trafficking are not known, but data suggest that it involves actin-based microfilaments, small GTPases, docking/fusion proteins, ezrin, and clathrin.^109–111

Figure 49-13. Model illustrating translocation and activation of H⁺,K⁺-ATPase. In the resting state, H⁺,K⁺-ATPase is sequestered within cytoplasmic tubulovesicles and is inactive. On stimulation, the tubulovesicles move to and fuse with the apical membrane, forming an extensive canalicular system. Translocation of H⁺,K⁺-ATPase into the canalicular membrane together with the presence of luminal K⁺ activates the enzyme.

Acid secretion requires not only a functional H⁺,K⁺-ATPase but also apical K⁺ and Cl⁻ channels and basolateral HCO₃⁻ and Cl⁻ exchangers. Acid is produced from the hydration of CO₂ to form H⁺ and HCO₃⁻, a reaction catalyzed by cytoplasmic carbonic anhydrase (see Fig. 49-12). Because the H⁺,K⁺-ATPase is unable to pump H⁺ into the lumen without a parallel uptake of K⁺, sufficient quantities of K⁺ must be delivered to the lumen. This K⁺ recycling is accomplished by luminal KCNE2/KCNQ1 and ROMK (KCNJ1) potassium channels. KCNQ1 is a voltage-activated K⁺ channel, which, when modified by the small regulatory subunit, KCNE2, becomes voltage insensitive, constitutively open, and acid activated.^108,112,113 ROMK may be regulated by the cystic fibrosis transmembrane conductance regulator (CFTR).^{108,112–114} The concentration of K⁺ in gastric juice (8 to 12 mM) exceeds plasma K⁺ by two- to four-fold.

For each H⁺ secreted, an HCO₃⁻ ion exits the cell across the basolateral membrane via the anion exchanger 2 (AE2), Slc4a2 (see Fig. 49-12).¹¹⁵ As a result of this HCO₃⁻/Cl⁻ exchange, the pH within the parietal cell remains only slightly alkaline during acid secretion.¹¹⁶ Rapid entry of HCO₃⁻ from parietal cells into blood has been referred to as the alkaline tide. Some of this HCO₃⁻ may be taken up and secreted by surface epithelial cells.

Concurrently with H⁺, Cl⁻ is extruded across the luminal membrane via an apical chloride channel, the precise identity of which is not known. The sources of intracellular Cl⁻ are the basolateral anion exchanger 2 (AE2), sodium-2 chloride potassium-cotransporter-1 (NKCC1), and the SLC26A7 channel (see Fig. 49-12).^117,118

PROTON PUMP INHIBITORS

Current PPIs (e.g., omeprazole, lansoprazole, rabeprazole, pantoprazole, and esomeprazole) consist of two heterocyclic moieties, a pyridine and a benzimidazole ring, connected by a methylsulphinyl group (Fig. 49-14). They are weak bases (pKa 4 or 5) that concentrate in acidic spaces within the body that have a pH less than 4. The pKa of a molecule refers to the degree of willingness of the compound to accept or donate a proton and is based on a logarithmic scale such that a compound with a pKa of 5 is 10-fold more basic than a compound with a pKa of 4. When a compound is in an environment with a pH equal to its pKa, half the molecules will be protonated and half will be non-protonated. If a compound with a pKa of 4 is placed in an environment with a pH less than 1, more than 99.9% of the molecules will be protonated. PPIs are membrane permeable in the nonprotonated form and relatively impermeable in the protonated form. In blood (pH 7.4), PPIs are predominantly nonprotonated and thus pass readily into cells (time to reach peak plasma concentration, ≈2 hours; elimination half-life, ≈1 hour), diffuse through the cytoplasm, and then become protonated and trapped, probably as sulfenamides or sulfenic acid, in the acid environment of the secretory canaliculus (Fig. 49-15).¹¹⁹ As a consequence of the basic pKa of PPIs and “ion trapping,” the concentration of PPIs in the secretory canaliculus is 100,000- to 1,000,000-fold higher than in the blood. The sulfenamide rapidly reacts with cysteines on the luminally exposed α-subunit of the H⁺,K⁺-ATPase to form a covalent (electrochemical) disulfide bond (see Fig. 49-15).¹²⁰ Whereas all PPIs bind to cysteine 813, omeprazole also binds to cysteine 892, lansoprazole to cysteine 321, and pantoprazole to cysteine 822. Because only the apical-membrane inserted H⁺,K⁺-ATPase is susceptible to blockade by PPIs and an acid environment (pH < 4) is necessary for trapping and converting the PPI to its reactive species, the potency of PPIs is decreased when administered during the basal (fasting) state or when acid secretion is inhibited.^121,122 Because most pumps are inserted with breakfast, it is recommended that PPIs be taken 30 minutes to 1 hour before the first meal. If greater inhibition is needed, an additional dose should be taken before dinner. Recovery from inhibition of acid secretion occurs by de novo synthesis of pump protein (54 hours in rat). It has been postulated that reduction of the cysteine disulfide bonds by reducing agents such as glutathione (15 hours in rat) could also play a role.¹²³

Figure 49-14. Structure of proton pump inhibitors (PPIs). PPIs consist of two heterocyclic moieties, a benzimidazole ring, and a pyridine, connected by a methylsulphinyl bridge. PPIs are weak bases (pKa 4-5) that accumulate and activate in acidic spaces within the body that have a pH less than 4. Once activated within the parietal cell canaliculus, the PPI binds covalently with certain cysteine residues within the α-subunit of the inserted H⁺,K⁺-ATPase.

Figure 49-15. Model illustrating the mechanism of action of proton pump inhibitors (PPIs). PPIs reach the parietal cell from the bloodstream, diffuse through the cytoplasm, and accumulate in the acid environment of the secretory canaliculus. In the canaliculus, the PPI becomes protonated and trapped as a sulfenic acid followed by dehydration to a sulfenamide. The sulfenamide binds covalently by disulfide bonds to one or more cysteines of the H⁺,K⁺-ATPase to inhibit the enzyme. Whereas all PPIs bind to cysteine 813, omeprazole also binds to cysteine 892, lansoprazole to cysteine 321, and pantoprazole to cysteine 822.

INTEGRATED RESPONSE TO A MEAL: INTERPLAY OF NEURAL, PARACRINE, AND HORMONAL PATHWAYS

Stimuli originating inside and outside the stomach converge on gastric intramural efferent neurons that are the primary regulators of acid secretion. The effector neurons comprise cholinergic and peptidergic (i.e., GRP and VIP) neurons. Although nitric oxide and PACAP neurons are present in gastric mucosa their precise physiologic roles as regulators of acid secretion are not known. The effector neurons act on target cells directly as well as indirectly by regulating secretion of gastrin, somatostatin, and possibly histamine (see Figs. 49-8 and 49-10).

During the basal state, acid secretion is maintained at an economically low level by the continuous inhibitory restraint exerted by somatostatin on the ECL cell (histamine) and parietal cell (acid) in the fundus/body and on the G cell (gastrin) in the antrum (see Figs. 49-5, 49-9, and 49-10). During ingestion of a meal, maximal secretion may be achieved by removing the inhibitory influence of somatostatin while at the same time directly stimulating acid and gastrin secretion. This is accomplished, in large part, by activation of intramural cholinergic neurons (see Fig. 49-10). The thought, sight, smell, and taste of food contributes up to 50% of total postprandial acid secretion.^124,125 Anticipation of a meal activates central neurons whose input is relayed via the vagus nerve to gastric intramural cholinergic neurons in oxyntic as well as pyloric mucosa. The components of the central nervous system include the dorsal motor nucleus of the vagus, the nucleus tractus solitarius, and the hypothalamus. In the fundus/body, ACh, released from cholinergic neurons, stimulates the parietal cell directly, as well as indirectly, by eliminating the inhibitory paracrine influence of somatostatin on parietal and ECL cells.^44,126 The resultant increase in histamine stimulates acid secretion directly via H₂ receptors on the parietal cell and indirectly via H₃ receptors that mediate suppression of somatostatin secretion (see Fig. 49-10).^44,127 Thus, histamine, acting via H₃ receptors, amplifies the ability of secretagogues to stimulate acid secretion by suppressing somatostatin secretion. The net effect of cholinergic neurons is suppression of all paracrine inhibitory influence (i.e., somatostatin) and enhancement of paracrine stimulatory influences (i.e., histamine acting via H₂ receptors) on parietal cells. There is some evidence that PACAP, a member of the glucagon/VIP superfamily of regulatory peptides, may participate in the regulation of acid secretion, but its precise physiologic role is not known.^26,128,129 PACAP is present in gastric mucosal nerves and capable of releasing histamine from ECL cells and somatostatin from D cells. The net effect of exogenous PACAP on acid secretion has been reported to be either stimulation or inhibition, depending on the relative contributions of released histamine and somatostatin in each preparation.^128,130,131

In the antrum, cholinergic neurons activated by anticipation of the meal stimulate gastrin secretion directly as well as indirectly by suppressing somatostatin secretion (see Fig. 49-10).^{30,31,34,132–144} In physiologic concentrations, gastrin stimulates parietal cells directly and, more importantly, indirectly by enhancing the secretion of histamine.^145,146

As the meal enters the stomach, the same cholinergic neurons are further activated mechanically by high distention and chemically by protein components of the food.^{141,142,147,148} Initially, the ingested meal acts as a buffer of secreted acid. The decrease in acidity (i.e., increase in pH) further inhibits somatostatin secretion and thus increases gastrin secretion. Luminal protein activates GRP neurons that directly stimulate gastrin secretion (see Fig. 49-10).^79,142 It should be noted that suppression of somatostatin secretion permits an optimal gastrin response.

As the meal empties the stomach, a number of paracrine and neural pathways are activated to restore the inhibitory influence of somatostatin in the fundus/body and antrum and hence restrain acid secretion (see Fig. 49-10). First, a stimulatory paracrine pathway linking gastrin to antral somatostatin cells is activated that acts to restore antral somatostatin secretion after release of gastrin.⁶⁷ Second, there is less activation of cholinergic neurons by anticipation of the meal as well as by protein and distention. Third, as distention decreases, VIP neurons are preferentially activated that stimulate somatostatin secretion.¹⁴¹ Fourth, as the buffering capacity of the meal is lost, antral and fundic somatostatin cells (via sensory CGRP neurons) are exposed to the full stimulatory effect of luminal acid. Fifth, enterogastrones released from the small intestine, such as CCK, stimulate somatostatin secretion. The resultant increase in antral and fundic somatostatin secretion attenuates gastrin and acid secretion and restores the basal interdigestive state. This state is marked by the continuous restraint exerted on G (gastrin), ECL (histamine), and parietal (acid) cells by contiguous somatostatin cells (see Figs. 49-9 and 49-10). A decrease in this restraint is sufficient to again initiate acid secretion.

HELICOBACTER PYLORI–INDUCED PERTURBATIONS IN ACID SECRETION (see also Chapter 50)

Acute infection with H. pylori (HP) results in hypochlorhydria,^149–152 whereas chronic infection results in either hypo- or hyperchlorhydria (Fig. 49-16). Appreciation of the pathways discussed earlier provides some insight into the mechanisms whereby HP colonizes the stomach and may lead to ulceration.

Figure 49-16. Model illustrating the consequences of Helicobacter pylori (HP) infection on gastric acid secretion. Acute HP infection is associated with an increase in somatostatin (SST) and thus a decrease in gastrin and acid secretion. Chronic infection may be associated with either decreased or increased acid secretion depending on the severity and distribution of gastritis. Most patients chronically infected with HP manifest a pan-gastritis and exhibit decreased acid secretion. A minority of chronically infected patients manifest an antral-predominant gastritis; these patients, who are predisposed to duodenal ulcer, produce increased amounts of acid as a result of reduced antral SST secretion and a subsequent reciprocal increase in gastrin secretion.

(From Schubert ML, Peura DA. Control of gastric acid secretion in health and disease. Gastroenterology 2008; 134:1842-60.)

The decrease in acid secretion during acute HP infection is thought to facilitate survival of the organism and its colonization of the stomach.¹⁵³ The mechanism whereby HP inhibits acid secretion is multifactorial and includes (1) direct inhibition of the parietal cell (and perhaps ECL cell) by a constituent of the bacterium (e.g., vacuolating cytotoxin, lipopolysaccharide, or acid-inhibitory factor) and (2) indirect inhibition of parietal cell function as a result of changes in cytokines as well as hormonal, paracrine, and neural regulatory mechanisms.^154–157 HP itself inhibits human H⁺,K⁺-ATPase α-subunit gene expression.¹⁵⁸

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