Mechanisms of increased acid secretion after eradication of Helicobacter pylori infection

Short abstract

Eradication of Helicobacter pylori infection leads to recovery of gastric acid secretion in some individuals but the mechanism is not fully understood. In the short term, there is an impressive increase in expression of H⁺/K⁺‐ATPase pumps without an increase in the number of parietal cells. Longer follow up studies are needed to see if the parietal cell mass eventually recovers

Gastric acid secretion represents an important non‐immunological first line of defence against ingested microbes. Almost all vertebrates produce acid in their upper gastrointestinal tracts, suggesting that this physiological process has a fundamental survival advantage. The ability to produce acid allowed vertebrates to ingest more complex diets, but more importantly, it protected them against microbes that gained access through the gastrointestinal tract. It seems that a pH of 4 or less is crucial in protecting the host against ingested bacteria and any therapy or disease that raises the intragastric pH above 4 will allow bacterial overgrowth to occur.¹ Perhaps the most important consequence of loss of gastric acid secretion is the increased risk of developing gastric cancer. This complication develops after decades of severe destructive inflammation, and usually in the context of Helicobacter pylori induced chronic gastritis. Understanding the mechanism by which inflammation, H pylori induced or otherwise, leads to loss of acid secretion is therefore crucial to understanding the pathogenesis of gastric neoplasia.

The effect of H pylori infection on gastric acid secretion depends on the severity and distribution of gastritis. Antral inflammation is associated with increased production of gastrin, which in turn increases the drive for acid secretion by parietal cells in the gastric corpus. If the corpus is affected by severe inflammation, the host's ability to respond to the increased gastrin is greatly attenuated. Thus subjects with severe corpus inflammation have reduced capacity to secrete acid, and this may initially be due to functional inhibition of parietal cells by either products of H pylori itself or more likely products of the inflammatory process.² In time and with sustained chronic inflammatory injury, the gastric glands atrophy and it is debatable whether loss of acid secretion in this context ever recovers. Permanent loss of parietal cells, resulting in achlorhydria, is a very strong risk factor for gastric cancer, especially if combined with sustained chronic inflammatory activity. This is no doubt related to the risk of bacterial overgrowth and colonisation of the gastric milieu by nitrosating bacteria that produce carcinogenic nitrosamines.³ In order to understand the effects of H pylori induced gastritis on acid secretion, it is important to consider its effects on parietal cells and the acid secretory machinery within these cells.

Effect of H pylori on parietal cells and acid secretion

Parietal cells are derived from anchored stem cells in the isthmus of the oxyntic pit‐gland units. They migrate bidirectionally along the pit‐gland axis so that in time they appear in the pit in an outward direction and also in the neck in an inward direction and continue until they reach the base of the gland.⁴ Interestingly, there seems to be functional heterogeneity in the parietal cell population along the pit‐gland axis such that younger cells in the isthmus and neck are more active than older cells in the pit and base regions.⁵ Preparietal cells develop from tissue derived stem cells and go through a number of stages during which they acquire an increase in the surface area of the apical plasma membrane forming numerous long microvilli. They then acquire a few cytoplasmic H⁺/K⁺‐ATPase containing tubules and vesicles and their apical membrane invaginates to form a canaliculus. Full maturation is heralded by expansion of the canaliculi and increase in cell size.⁴ Turnover time of parietal cells in humans is not certain but is thought to be approximately 54 days in mice,⁶ which clearly means that it is considerably longer in humans. There is surprisingly very little information on the life cycle of a human parietal cell. One report suggests the lifespan of a parietal cell is thought to be between 150 and 200 days, in contrast with the average surface epithelial cell (four days).⁷ This issue is important for understanding the potential for recovery of parietal cell function following removal of chronic inflammatory stimuli (for example, following H pylori eradication). It is patently evident however that it would take a considerable time for parietal cells to regenerate in humans, and this has to be reflected in the design of studies assessing recovery of parietal cell numbers or function.

H pylori can damage the gastric epithelial layer through direct and indirect mechanisms. The organism can directly induce apoptosis of gastric epithelial cells through production of numerous molecules, including cytotoxin (VacA), lipopolysaccharide, monochloramine, and nitric oxide.⁸ This proapoptotic effect is dependent on activation of nuclear factor κB.⁹H pylori organisms are capable of attaching to gastric epithelial cells and are responsible for triggering the production of proinflammatory cytokines such as interleukin (IL)‐8, IL‐1β, and tumour necrosis factor α (TNF‐α). The ensuing inflammatory activity can also damage epithelial cells, including parietal cells, and this could have an effect on acid secretion. However, the presence of these cytokines has a direct inhibitory effect on acid secretion per se. Indeed, IL‐1β is the most powerful acid inhibitor known and TNF‐α also has acid inhibitory properties, albeit weaker than IL‐1β.¹⁰,¹¹,¹²,¹³ The acid inhibitory effect of IL‐1β is thought to be mediated through IL‐1 receptors on parietal cells.¹⁴ IL‐1β also causes sustained functional impairment of ECL cells, which also express IL‐1 receptors.¹⁵

Effect of H pylori on the gastric H⁺/K⁺‐ATPase

The H⁺/K⁺‐ATPase is an ion motive ATPase that belongs to the P2 subfamily of ATPases and consists of alpha and beta subunits. It forms an integral part of the apical membranes of parietal cells. It transports its cations as a cycle of phosphorylation and dephosphorylation of the transport protein. When parietal cells are stimulated the pumps are translocated from the cytoplasmic tubulovesicles into the membrane of the secretory canaliculus, to form microvilli lining the canalicular space, and a KCl pathway is activated to allow K⁺ to access the external surface of the ATPase and secretion of Cl⁻.¹⁶,¹⁷ The H⁺/K⁺‐ATPase actually pumps hydronium ions (H₃O⁺) rather than H⁺ ions and is able to release H₃O⁺ at a concentration of 160 mM, which is equivalent to an external pH of 0.8 and a 4 million‐fold gradient across the surface of the parietal cell. The H⁺/K⁺‐ATPase pumps are involved in the final stages of gastric acid secretion and are stimulated to secrete acid by intracellular signals from H₂ receptors, muscarinic M₃ receptors, and gastrin receptors on parietal cells.¹⁷

There is evidence that H pylori infection exerts inhibitory effects on the human gastric H⁺/K⁺‐ATPase α subunit. Göõz et al showed that H pylori inhibits α subunit gene expression via intracellular pathways involving protein kinases A and C and protein tyrosine kinase.¹⁸

What is the effect of eradication of H pylori on gastric acid secretion?

The answer relies entirely on the extent to which the corpus mucosa is affected by inflammatory activity. Thus if the corpus is relatively healthy with an antral predominant pattern of gastritis, the net effect of eradication will be a reduction in the degree of hypergastrinaemia, which in turn may lead to a reduction in acid secretion. If on the other hand the corpus is severely inflamed, eradication will remove at least the functional inhibition of the parietal cells and this will be associated with an increase in acid secretion.¹⁹ We know that acid secretion recovers within a very short period after initiation of antibiotic therapy, which suggests that the inflammatory process exerts some functional inhibition on acid secretion that could easily be reversed by reducing the acute inflammatory component and associated array of acid inhibitory cytokines, such as IL‐1β and TNF‐α.²⁰ Acid recovery also continues well after successful eradication, suggesting perhaps recovery in parietal cell numbers also but it is generally accepted that the onset of gastric atrophy and intestinal metaplasia heralds a less reversible stage with very little recovery in acid secretion.

One of the major unanswered questions in this field has been the mechanism of recovery of acid secretion after eradication of H pylori. In this issue of Gut, Osawa and colleagues²¹ report on the effects of eradicating H pylori infection on expression of H⁺/K⁺‐ATPase mRNA, in addition to expression of other genes involved in acid secretion, including H₂ receptors, muscarinic M₃ receptors, and anion exchanger 2, which is involved in basolateral base exit during acid production (see page 152). They also assessed expression of IL‐1β expression, due to its role as a powerful proinflammatory cytokine and a potent inhibitor of acid secretion. The key question that Osawa et al asked was whether recovery of acid secretion after eradication of H pylori is due to recovery in expression of the proton pump or an increase in parietal cell numbers. The answer was unequivocally in favour of upregulation of H⁺/ K⁺‐ATPase mRNA. There was an impressive 250‐fold increase in expression of the pump mRNA but no significant change in the number of parietal cells, at least over the three month follow up period for this study. Interestingly, upregulation of expression of the pump mRNA was seen even in patients with severe atrophic gastritis. The change in H⁺/K⁺‐ATPase mRNA was accompanied by a significant reduction in IL‐1β levels but no major change in the other studied genes.

The findings of Osawa et al mirror those of Furuta et al, who found similar increases in H⁺/ K⁺‐ATPase mRNA expression one month following successful eradication of H pylori infection.²² Osawa et al extend the work by looking at the changes over a longer period (three months) and by showing that the increase was not due to any changes in parietal cell numbers. The work by Furuta et al however included the crucial demonstration of recovery in acid secretion in the same patients. Taken together, it is reasonable to conclude that the initial recovery in acid secretion is most likely due to release of inhibition on expression of the H⁺/K⁺‐ATPase. It remains an open question whether the parietal cell mass does recover with the passage of time. This issue needs to be addressed by much longer follow up studies that should last years rather than months.

What about future directions in this filed? There are many questions that have been asked over the past two decades; some have been answered while the majority remain the subject of much research. Is acid inhibition reversible? Is gastric atrophy reversible? Will eradication of H pylori infection lead to normalisation of acid secretion and recovery of parietal cell numbers? What is the exact mechanism of recovery of acid secretion? If acid secretion recovers fully or partially, will this reduce the risk of gastric cancer? Should we use eradication therapy as a strategy for reducing the risk of gastric cancer, and should this be carried out universally, or only in populations at risk? What is the optimal stage for intervention and does the recovery in acid secretion have any potential harmful effects?

Perhaps the most pertinent question is whether there is a point of no return in the multistage process of gastric carcinogenesis. These are very valid questions that have occupied workers in the field for a considerable time. However, it is immediately obvious that this is a very worthwhile scientific pursuit, for at stake here is the potential for eliminating the world's second commonest cause of cancer death, namely gastric cancer. Indeed, providing the full answers to these questions will not only help in eliminating gastric cancer, it will also provide a paradigm for understanding other cancers where there is a sustained chronic inflammatory insult. Cancers of the colon, oesophagus, pancreas, gall bladder, head and neck, prostate, urinary bladder, lung, and many others share a similar theme.

The most exciting news for us gastroenterologists came on 3 October 2005 with the announcement that Warren and Marshall have been awarded the Nobel Prize for physiology/medicine for their discovery of H pylori. The award was largely in recognition of the role of H pylori in peptic ulcer disease and the near total disappearance of this previous cause of major morbidity and mortality. However, in my humble opinion, H pylori's legacy will prove more in the field of cancer, and this will by no means be restricted to gastrointestinal malignancies. The next decade promises to be even more exciting than the last.