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Helicobacter pylori: A Bacterium Influencing and Causing Most of the Diseases in the Upper Gastrointestinal Tract. An Overview with Respect to Pathogenesis and Treatment Based on Basic Physiology

Written By

Helge L. Waldum

Submitted: 07 September 2022 Reviewed: 06 October 2022 Published: 05 December 2022

DOI: 10.5772/intechopen.108494

Helicobacter pylori Infection - An Up to Date on the Pathogenic Mechanisms, Diagnosis and Clinical Management IntechOpen
Helicobacter pylori Infection - An Up to Date on the Pathogenic M... Edited by Daniela Lazar

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Helicobacter pylori Infection - An Up to Date on the Pathogenic Mechanisms, Diagnosis and Clinical Management [Working Title]

Dr. Daniela Cornelia Lazar

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Abstract

The discovery that Helicobacter pylori was the dominating cause of gastritis is among the most important findings in the last century. It gave rise to the understanding and treatment of serious and common diseases, such as peptic ulcer disease and gastric cancer. The gastric hormone gastrin is involved in the pathogenesis of both duodenal ulcer and gastric cancer, whereas reduction in the defense mechanism (mucus and bicarbonate) by the inflammation itself predisposes to gastric ulcer. The search for carcinogenic H. pylori factors has been unsuccessful and based upon the fact that H. pylori predispose to gastric cancer only after having induced oxyntic atrophy is an important argument in favor of a central role of gastrin increase secondary to reduced acidity. The only cell with an undisputed gastrin receptor is the enterochromaffin-like cell where gastrin has a trophic effect leading to hyperplasia, neuroendocrine tumor (NET), and long-term carcinoma of diffuse type. H. pylori may be eradicated by a combination of antibiotics with a potent inhibitor of acid secretion. H. pylori is dependent on acid surrounding to thrive, and therefore anacidity due to complete oxyntic atrophy or profound inhibition of acid secretion by drugs will promote its disappearance.

Keywords

  • Helicobacter pylori
  • duodenal ulcer
  • gastric peptic ulcer
  • gastric cancer
  • gastrin
  • enterochromaffin-like cell

1. Introduction

Diseases of the upper gastrointestinal tract, such as peptic ulcer and gastric cancer, were previously very prevalent. Moreover, gastric cancer has high mortality, and peptic ulcer was an important disabling disease. With different types of surgical interventions on the regulation of acid secretion, such as removal of the gastrin-producing antrum or cutting of the vagal nerves, the prognosis of severe peptic ulcer disease improved but not seldom with serious postoperative complaints. With the description of the histamine 2(H2) receptor and the development of the first H2 receptor antagonist, cimetidine, by Black and coworkers [1], peptic ulcer disease became available for drug treatment. Later the more efficient inhibitor of acid secretion, omeprazole, was described and found to inhibit the final step in acid secretion, the proton pump (PPI) [2, 3]. Drugs inhibiting gastric acid secretion when dosed sufficiently made virtually every peptic ulcer heal but had to be continued indefinitely to prevent relapses. At the same time period, it was realized that peptic ulcer disease was associated with gastritis [4, 5].

Similarly, gastritis was recognized as a factor in gastric carcinogenesis [6, 7] in the 1950s, while a role of gastric hypoacidity was described the decade before [8, 9]. Gastritis was, thus, established as central in diseases of the upper gastrointestinal tract. The etiology of gastritis was unknown, but based upon distribution, two types of gastritis were described as type A only affecting the oxyntic mucosa and type B affecting the antral mucosa and gradually spreading to the oxyntic mucosa [10]. Thus, there was apparent that gastritis was very important in upper gastrointestinal pathology and that there existed two types of gastritis with presumed different etiology before Marshall and Warren made their description of H. pylori (H. pylori) [11], which subsequently has been shown to be the major cause of peptic ulcer [12], as well as gastric cancer [13].

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2. H. pylori

Around nineteen hundred “spirochete” resembling organisms were recognized in the gastric mucosa [14] in gastric tissue taken from stomachs with gastric cancer [15]. Similarly, epidemic gastritis with hypochlorhydria was reported in the fifties [16] and in the late seventies, the occurrence of gastritis leading to hypoacidity was described as to result of contaminated gastric tubes [17]. Likewise, a gastric urease had been described, which subsequently was shown to be of bacterial origin since tetracycline treatment changed gastric juice nitrogen from ammonium to urea [18]. The indications for an infectious agent causing gastritis accumulated during the nearly hundred years period ahead of the culture of the organism now known as H. pylori [11] are excellently summarized by Marshall himself [18]. H. pylori produces many factors that make the bacterium able to live in the gastric mucus, as well as to induce damage and inflammation in the epithelial cells. The urease is essential for its ability to survive in the highly acidic stomach, whereas the cytotoxin-associated gene A (Gag A) probably is most important in inducing inflammation, damage to the gastric mucosa, and diseases [19].

2.1 Urease

The high production of urease by H. pylori is a central trait for thriving in the gastric mucus [20] and is also the basis for the rapid urease test to diagnose gastric infection with H. pylori [21]. In the eradication cures of H. pylori, potent inhibition of acid secretion is combined with high doses of antibiotics, and it is probable that the reduction in acidity of the mucus contributes to the killing of the bacterium. Potassium-competitive acid blockers (P-CABs) are even more effective than proton pump inhibitors (PPIs) in inhibiting acid secretion. In combination with amoxicillin and clarithromycin, vonoprazan (a P-CAB) induced the same degree of H. pylori eradication after one-week therapy as with the same antibiotics at the same doses together with PPIs for 2 weeks [22].

2.2 Blood group antigen binding adhesin A (Bab A)

Urease activity of H. pylori is necessary for both establishing and persistence of infection [20]. The initial binding of H. pylori to the gastric mucosal cells depends on adhesins. Among them, Bab A has been considered particularly important, although the clinical implications of the different expressions seem marginal [23].

2.3 Cytotoxin-associated gene A (Cag A)

Among the virulence factors in H. pylori, Cag A is probably the most important. Cag A gene is part of the cytotoxin-associated gene pathogenicity island (cagPAI), which also contains the bacterial type IV secretion system (T4SS) whereby Cag A enters the gastric mucosal cells [24]. The presence of cagPAI seems to be associated with more severe gastric pathology, including gastric cancer [19], and some polymorphisms may also have a higher risk [25]. After having penetrated the epithelial cell membrane, Cag A is phosphorylated, and phosphorylated Cag A then interacts with different proteins causing damage to the infected cell [19]. However, any direct mechanism for the pathogenetic effect of Cag A or H. pylori itself is still missing.

2.4 Vacuolating cytotoxin A (Vac A)

Vac A is a pore-forming protein that binds to some receptors and enters the cell interior by endocytosis [26]. After having entered the cell, Vac A induces large vacuoles [27] and cell death possibly by affecting mitochondrial function [28].

The pathogenetic role of the different factors of H. pylori has been discussed in depth in different recent reviews [19, 29], but the exact mechanism for the carcinogenic effect has not been disclosed. Already, in 2000, Graham and Yamaoka wrote a review with the title: Disease-specific H. pylori virulence factors: the unfilled promise [30]. They concluded that only the cag pathogenicity island had passed the tests of biological plausibility with respect to increased inflammation. Subsequently, I will describe the course of H. pylori infection and afterward return to the question of the pathogenesis of gastric cancer due to H. pylori.

2.5 Course of H. pylori infection

The symptoms of acute H. pylori infection are probably best described by the two known voluntary infections [31, 32]. As early as 3 days after ingestion of H. pylori epigastric pains were noticed and mild symptoms persisted for 14 days. Normal gastric acidity before infection was changed to anacidity on day 8 after infection [32]. Interestingly, these two voluntary infections were successful only after giving an inhibitor of gastric acid secretion suggesting that gastric acidity protects to some degree against initial infection. In this context, it shall also be mentioned the outbreak of gastritis due to contamination of the equipment in a study of gastric secretion described in 1979 [17]. The healthy subjects were tested multiple times and developed epigastric symptoms, gastritis, and hypoacidity. In retrospect, this outbreak of hypo-acidic gastritis has been attributed to contamination with H. pylori. It should be noticed that also in these subjects H. pylori most probably was introduced into the stomach with hypoacidity since the gastric juice was continuously aspirated [33]. What about the role of gastric acidity in real-life initial steps of infection?

It is well-known that H. pylori infection occurs mainly in childhood both in developed and developing countries [34, 35]. Although gastric acidity is lower during the first year of life compared with healthy individuals later in life [36], a difference in gastric acidity cannot explain the different susceptibility for H. pylori infection in childhood. The habit of small children putting so many things into their mouths may perhaps contribute. The present prevalent use of profound inhibitors of acid secretion in adults seen during the last decades has not resulted in any increased tendency to new H. pylori infections in grown-ups, indicating that hypoacidity is not as important for establishing H. pylori infection as the two voluntary studies [31, 32] suggested. On the other hand, in those studies acid secretion was inhibited by a histamine blocker, thus only moderate reduction in gastric acidity compared with PPIs. It is possible that profound acid inhibition could reduce the susceptibility for H. pylori infection due to a reduction in acidity in gastric mucous. In contrast, PPI treatment has been reported to increase the proximal spread of H. pylori gastritis [37] possibly by reducing mucous acidity reflecting that H. pylori require some acidity, but not too high acidity as patients with gastrinoma generally have a low frequency of H. pylori infection [38].

The mechanism for the initial inhibition of acid secretion is not completely elucidated, but hypoacidity may persist for weeks or even months [17]. After ingestion, H. pylori first infects the antral mucosa but after days spreads to the oxyntic mucosa as well [31, 32]. Properties both by H. pylori itself, and the inflammation provoked have been implicated [33, 39]. For some reason or the other, the transition from acute to chronic gastritis is accompanied by resolution of the inflammation in the oxyntic mucosa, whereas it persists in the antral mucosa. Concomitant with the healing of the oxyntic mucosa, gastric acidity is normalized [17, 32]. The general belief is that when first infected, H. pylori infection will persist until eventual eradication or reaching complete anacidity secondary to atrophic oxyntic atrophy. In some patients, H. pylori gastritis remain confined to the antral mucosa for years, whereas in others H. pylori and accompanying gastritis early spread in the oral direction. The reason for this difference is not known, but the fact that inhibition of gastric acid secretion promotes the distribution of gastritis orally [40] and may suggest that acidity plays a role [33].

The development of the H. pylori gastritis has a dual effect on gastric acid secretion. When the infection is confined to the antral mucosa, gastric acid secretion is increased due to elevated gastrin release [41], whereas gastric acid secretion is impaired when oxyntic gastritis with damage to the parietal cells has occurred. It is probable that the increase in gastrin release, in relation to gastric acidity (inappropriate gastrin release), is due to an effect on gastrin release by NH3 produced by H. pylori urease. Studies to examine whether NH3 could be the causative factor for this effect on gastrin release have been ambivalent, but in a careful evaluation of the data related to this question, we concluded that H. pylori-induced NH3 was the cause of inappropriate gastrin release and thus hypersecretion of acid [33].

Subsequently, the inflammation in most patients spreads to the oxyntic mucosa. Why some patients are more resistant to oxyntic affection is not known. Similarly, the reason why the oxyntic mucosa is apparently less susceptible to H. pylori gastritis than the antral mucosa is also unknown. However, it is thought that higher acidity could play a role. Nevertheless, the oxyntic glands empty their contents into the lumen through transient openings and not by diffusion through the mucous layer. Anyhow, the luminal acidity is slightly higher in the oxyntic area, and this could play a role in the relative resistance. The oxyntic H. pylori gastritis starts as superficial gastritis, which gradually affects the deeper layers of the mucosa including the glands finally destroying them and leading to reduced acid production by the disappearance of the parietal cells and other specialized cells, such as the chief cells. All the specialized cells of the oxyntic mucosa are killed during this process except the target cell of gastrin, the enterochromaffin-like (ECL) cell [42]. With time, all the oxyntic mucosa is destroyed leading to anacidity and disappearance of the H. pylori infection [43] since the bacterium depends on some acidity in the surroundings to neutralize the NH3 production caused by the urease. The complete atrophy of the oxyntic mucosa naturally leads to hypergastrinemia [44].

2.6 Consequences of H. pylori infection

2.6.1 Gastritis

The acute infection causes acute gastritis, which subsides within a week or two. Chronic uncomplicated phase of gastritis does not cause any symptoms, which is exemplified by the previous belief that gastritis could be regarded as a normal phenomenon of older age. However, chronic H. pylori gastritis is complicated with many serious upper gastrointestinal diseases; in fact, most of the diseases in the upper gastrointestinal tract are influenced or caused by this infection.

2.6.2 Peptic ulcer disease

Peptic ulcer disease consists of two subgroups: duodenal and gastric ulcers. At both locations, the ulcer is caused by the digestion of the mucosa by the acidic and proteolytic gastric juice. In duodenal ulcer, the aggressive forces are increased as shown by the increased acid secretion [45], whereas in gastric ulcers, a reduction in defense (bicarbonate and mucous production by superficial cells) is probably the mechanism. H. pylori gastritis has been shown to inhibit mucin synthesis [46]. Generally, the more oral a gastric ulcer is localized, the lower is the capacity to produce acid [45]. Also, reflux oesophagitis is ultimately due to the erosive activity of gastric juice. The roles of acid versus pepsin in tissue damage in all these conditions are difficult to differentiate since the regulations of pepsinogen, and acid secretions in many ways are similar. Furthermore, acid is required for the autocatalytic activation of pepsinogen into the active form pepsin [47]. The most important factor in the pathogenesis of reflux oesophagitis is insufficiency of the functional gastro-esophageal valve, whereas H. pylori is the dominating cause of both duodenal and gastric ulcers. H. pylori gastritis influences the risk and severity of gastro-esophageal reflux through the reduction of gastric acid secretion due to oxyntic atrophy [33].

2.6.3 Duodenal ulcer

Duodenal ulcer has for long been known to be associated with increased gastric acid secretion [45]. Concomitant with the description that H. pylori was the dominating cause of gastritis, it was also shown that most patients with peptic ulcer, being duodenal or gastric, also were infected [11]. Initially, it was thought that duodenal ulcers occurred at islands of gastric metaplasia in the duodenum. This has not been substantiated [48, 49], and the focus has been directed toward the elevation of gastric acid secretion. It was detected that patients with antral gastritis had a slight elevation of gastrin in the blood causing an increase in gastric acid secretion [33, 41]. The pathogenesis of duodenal ulcer is, thus, most likely the increase in gastric acid secretion due to H. pylori infection of the antrum. An increase in gastric acid secretion is alone sufficient to induce peptic ulcer as shown in non-infected patients with gastrinoma [38]. Moreover, the lower frequency of H. pylori in gastrinoma patients compared with age-matched controls suggests that high acidity can eradicate H. pylori since infection with H. pylori most often occurs in childhood, and gastrinoma seldom manifests itself before adulthood [33]. H. pylori eradication reduces gastrin and gastric acid secretion and prevents new ulcers, in other words, cures duodenal ulcer disease [41, 50].

2.6.4 Gastric peptic ulcer

In gastric peptic ulcers, it is the defense mechanisms (bicarbonate and mucous) that are reduced and not an increase in aggressive factors that cause the ulcers. The decline in the defense factors is caused by H. pylori gastritis [46] in most instances but may also be due to other factors with intake of nonsteroidal anti-inflammatory drugs (NSAIDs) as the most important one. The effect of NSAIDs on the gastric mucosa is related to their ability to inhibit prostaglandin synthesis [51]. Prostaglandin treatment may prevent development or heal gastric ulcers [52]. The distribution between H. pylori and NSAIDs use as the cause of peptic gastric ulcer depends on the time for the study, the age of the patients, as well as their country, because the prevalence of H. pylori in many populations is rapidly declining and shows great variability between countries. Of course, whenever H. pylori is found in a patient with upper gastrointestinal disease, it should be eradicated. The treatment of NSAID- induced gastric ulcers is termination of NSAID use when possible, or otherwise add an inhibitor of gastric acid secretion or possibly a prostaglandin analog.

2.6.5 Gastro-esophageal reflux disease

Patients with duodenal ulcer have increased gastric acid secretion, which can induce reflux symptoms as exemplified in patients with gastrinoma [53]. Such symptoms may occur in patients with duodenal ulcer, but the increase in gastric acid secretion due to antral H. pylori gastritis seldom leads to reflux oesophagitis, possibly due to maintained regulation of gastrin release, and thus only a marginal increase in gastrin. On the other hand, H. pylori gastritis leading to oxyntic atrophy may reduce the occurrence of gastrointestinal reflux due to impaired gastric acid secretion [54]. Thus, H. pylori may induce gastro-esophageal symptoms or at another phase of gastritis reduce such symptoms. Generally, it may be stated that H. pylori does not play any central role in gastro-esophageal reflux disease.

2.6.6 Gastric cancer

An old slogan was “no acid, no peptic ulcer.” Similarly, with some limitations, it may be said: “no gastritis, no gastric cancer” [6]. After the recognition that H. pylori was the major cause of gastritis [11], it was logical that H. pylori also was an important contributor to gastric cancer [13]. This induced a search for the carcinogenic factor in H. pylori, the first bacterium to be accepted to be carcinogenic. Despite intense work by many groups for many years, the mechanism has not been disclosed leading to the paper containing: “unfulfilled promise” in the title [30]. However, major progress was done by the recognition that H. pylori did not cause gastric cancer before having induced oxyntic atrophy [55]. Moreover, even after the disappearance of H. pylori either due to eradication therapy or complete oxyntic atrophy leading to anacidity, patients having been infected for years have an increased risk for gastric cancer for decades after the loss of the bacterium [56]. Also, when the infection was confined to the antral mucosa, the patients were not predisposed to gastric cancer. On the contrary, patients with a duodenal ulcer, which has mainly antral gastritis, have lower cancer risk than controls [57]. Altogether, these data do not support a direct carcinogen effect of H. pylori. In any way, carcinogenesis is connected to induced gastritis in the oxyntic mucosa. Among the H. pylori factors, Cag A seems to be the most important in the pathogenesis of gastritis, although its direct role in gastric carcinogenesis beyond driving the inflammation is still not disclosed [19]. The H. pylori infection goes through stages from superficial to atrophic gastritis, and the latter may be complicated by intestinal metaplasia [58]. Intestinal metaplasia has been regarded as a very important step and according to Correa [59], being a precursor to gastric cancer of the intestinal type (Lauren [60]). However, the importance of intestinal metaplasia in carcinogenesis has been questioned [61, 62], and intestinal metaplasia may only be a marker of long-standing oxyntic atrophy [63]. It, thus, seems that atrophic gastritis is central in gastric carcinogenesis, a condition that leads to reduced killing of swallowed micro-organisms, as well as hypergastrinemia. If changes in microbiological milieu secondary to impaired gastric acid secretion are the mechanism, it is peculiar that patients with autoimmune gastritis do develop cancers only in the oxyntic mucosa, and not the whole stomach [64]. Therefore, hypergastrinemia may be the factor mediating the cancers induced by H. pylori [63]. This concept is compatible with no increase or lower incidence of gastric cancers in patients with duodenal ulcers [57], as well as the continuous predisposition decades after eradication of the bacterium [56]. This view has implications for the treatment with H. pylori eradication in those still being infected, and the use of a gastrin analog such as netazepide [65] in those having oxyntic atrophy and hypergastrinemia but having lost the bacterium.

H. pylori gastritis also predisposes to gastric lymphoma so-called mucosa-associated lymphoid tumor (MALT). In contrast to gastric carcinomas, these tumors develop because of the continuous and chronic inflammation itself and are independent of gastric atrophy [66]. Many of the gastric MALT-lymphomas associated with H. pylori may be cured by H. pylori eradication [67].

2.6.7 H. pylori eradication: When and how

H. pylori is an important cause of serious diseases. The eradication of H. pylori in peptic ulcer diseases cures the diseases, which previously were rather frequent and could have grave consequences. Gastric cancer was among the most common cancers and had and still has a high mortality. During the last fifty years, there has been a remarkable decline in occurrence of gastric cancer [68], most probably due to a decline in infection with H. pylori, especially in the Western world. However, still, a proportion of the population is infected, and in non-Western countries, the percentage infected is even today high [69]. The spontaneous reduction in infection rate seen during the last decades is attributed to improved hygienic conditions. Most of the infections occur in childhood and even above the age of five years, reinfection is seldom [70]. After infection, chronic gastritis develops spreading slowly to include the oxyntic mucosa and gradually destroying the specialized cells leading to atrophy. Atrophy usually precedes development of intestinal metaplasia [71]. Uemura and coworkers showed that H. pylori infection predisposed to gastric cancer first after having induced oxyntic atrophy [55], and a separate role of intestinal metaplasia in gastric carcinogenesis as suggested by Correa [59] is not ambiguously accepted [61, 62]. Alternatively, intestinal metaplasia could just be a consequence of long-standing atrophy [63]. Anyhow, to prevent common and serious diseases, such as peptic ulcer disease and gastric cancer, H. pylori should be eradicated before irreversible atrophic gastritis has developed. Since H. pylori infection occurs in childhood and the actual diseases, as well as atrophic gastritis seldom, occurs in young people, the natural conclusion is that all should be tested for H. pylori infection around the age of twenty years, and those positive should have H. pylori eradicated at that age. Eradication of H. pylori has traditionally been achieved by a combination of two or more antibiotics and rather early together with an inhibitor of acid secretion. Bismuth salts were among the first to show efficacy in H. pylori eradication [72]. Antibiotic resistance has been a problem in the eradication of H. pylori [73]. The initial argument for adding an inhibitor of acid secretion was to prevent destruction of the antibiotics in the stomach, thus prolonging their local effect. To achieve acceptable H. pylori eradication, cures of two weeks duration were most often required. Recently, the potassium-competitive acid blocker (P-CAB) vonoprazan in combination with amoxicillin, and clarithromycin for 1 week was as efficient in eradicating H. pylori compared to the same antibiotics in combination with PPIs for 2 weeks [22], indicating that even more complete acid inhibition further improved the efficacy of the treatment cure. In other words, the more efficient inhibition of gastric acid secretion, the more likely H. pylori will not survive reflecting the self-toxicity by NH3 produced by its urease. It is conceivable that high doses of P-CABs will totally remove gastric acidity, and thus be suitable for H. pylori eradication alone. The reported bactericide effect on H. pylori by high doses of PPIs most probably is caused by the dependence of some acidity in the surrounding of H. pylori [74]. Of course, such treatment will naturally induce marked hypergastrinemia, which could make harm even during a short period but could be prevented by a gastrin antagonist. Marked oxyntic atrophy after H. pylori eradication and termination of inflammation nevertheless predisposes to gastric cancer, which probably is caused by the corresponding hypergastrinemia. Thus, such patients will most likely also profit from treatment with a gastrin antagonist [75].

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3. Conclusion

The description of H. pylori as the main cause of gastritis leading to peptic ulcer disease, and gastric cancer is among the most important achievement in medicine in the last century. This allows prevention of such important diseases and opens up for an understanding of new mechanisms in diseases, including cancer. Together with the hormone gastrin, H. pylori may explain most aspects of diseases of the upper gastrointestinal tract. It is probable that a similar cause/mechanism also is found in other organs, but it is not surprising that it is first disclosed in the stomach, an organ ideal for studying biological mechanisms.

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Conflict of interest

The authors declare no conflict of interest.

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Written By

Helge L. Waldum

Submitted: 07 September 2022 Reviewed: 06 October 2022 Published: 05 December 2022

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