Helicobacter pylori
Electron micrograph of H. pylori possessing multiple flagella (negative staining)
Scientific classification Edit this classification
Domain: Bacteria
Phylum: Campylobacterota
Class: "Campylobacteria"
Order: Campylobacterales
Family: Helicobacteraceae
Genus: Helicobacter
Species:
H. pylori
Binomial name
Helicobacter pylori
(Marshall et al. 1985) Goodwin et al., 1989
Synonyms
  • Campylobacter pylori Marshall et al. 1985

Helicobacter pylori, previously known as Campylobacter pylori, is a gram-negative, flagellated, helical bacterium. Mutants can have a rod or curved rod shape, and these are less effective.[1][2] Its helical body (from which the genus name, Helicobacter, derives) is thought to have evolved in order to penetrate the mucous lining of the stomach, helped by its flagella, and thereby establish infection.[3][4] The bacterium was first identified as the causal agent of gastric ulcers in 1983 by the Australian doctors Barry Marshall and Robin Warren.[5][6]

Infection of the stomach with H. pylori is not the cause of illness itself; most H. pylori positive cases are asymptomatic.[7][8] But persistent colonization can induce a number of gastric and extragastric disorders.[9] Gastric disorders due to infection begin with gastritis, inflammation of the stomach.[10] When infection is persistent the prolonged inflammation will become chronic gastritis. Initially this will be non-atrophic gastritis, but damage caused to the stomach lining can bring about the change to atrophic gastritis, and the development of ulcers both within the stomach itself or in the duodenum, the nearest part of the intestine.[10] At this stage the risk of developing cancer is high.[11] However, the development of a duodenal ulcer has a lower risk of cancer.[12]Helicobacter pylori is a class I carcinogen, and potential cancers include gastric mucosa-associated lymphoid tissue (MALT) lymphomas and gastric cancer.[10][11] Infection with H. pylori is responsible for around 89 per cent of all gastric cancers, and is linked to the development of 5.5 per cent of all cases of cancer worldwide.[13][14] H. pylori is the only bacterium linked to any cancer.[15]

Many investigators have suggested that H. pylori causes or prevents a wide range of other diseases, but many of these relationships remain controversial.[16][17][18]

Some studies suggest that H. pylori plays an important role in the natural stomach ecology, e.g. by influencing the type of bacteria that colonize the gastrointestinal tract.[19][17] Other studies suggest that non-pathogenic strains of H. pylori may beneficially normalize stomach acid secretion, and regulate appetite.[20]

In 2023, it was estimated that about two-third's of the world's population had H. pylori infection, with its being more common in developing countries.[21] The prevalence has declined in many countries due to eradication treatments with antibiotics, and proton-pump inhibitors[22][23] and with increased standards of living.[24]

Microbiology

Helicobacter pylori is a species of gram-negative bacteria in the Helicobacter genus.[25] About half the world's population is infected with H. pylori but only a few strains are pathogenic.

H. pylori can be demonstrated in tissue by Gram stain, Giemsa stain, H&E stain, Warthin-Starry silver stain, acridine orange stain, and phase-contrast microscopy. It is capable of forming biofilms.[26]

Morphology

Helicobacter pylori is a helical bacterium having a helical shape, about 2–4 μm long with a diameter of about 0.5–1 μm.[27] H. pylori can convert from a helical to an inactive coccoid form, that may possibly become viable, known as viable but nonculturable (VBNC).[28] It is of debate whether this form is a type of dormant state or has metabolic activity.[29]

Its helical shape is better suited for progressing through the viscous mucosa lining of the stomach, and is maintained by a number of enzymes in the cell wall's peptidoglycan.[1] The bacteria reach the less acidic mucosa by use of their flagella.

Helicobacter pylori has from two to seven flagella at the same location which gives it a high motility. The characteristic sheathed flagellar filaments are about 3 μm long, and composed of two copolymerized flagellins, FlaA and FlaB, coded by the genes flaA, and flaB.[29][30]

Physiology

Helicobacter pylori is microaerophilic – that is, it requires oxygen, but at lower concentration than in the atmosphere. It contains a hydrogenase that can produce energy by oxidizing molecular hydrogen (H2) made by intestinal bacteria.[31] It produces oxidase, catalase, and urease.

H. pylori possesses five major outer membrane protein families.[27] The largest family includes known and putative adhesins. The other four families are porins, iron transporters, flagellum-associated proteins, and proteins of unknown function. Like other typical gram-negative bacteria, the outer membrane of H. pylori consists of phospholipids and lipopolysaccharide (LPS). The O-antigen of LPS may be fucosylated and mimic Lewis blood group antigens found on the gastric epithelium.[27] The outer membrane also contains cholesterol glucosides, which are present in few other bacteria.[27]

Genome

Helicobacter pylori consists of a large diversity of strains, and hundreds of genomes have been completely sequenced.[32][33][34] The genome of the strain 26695 consists of about 1.7 million base pairs, with some 1,576 genes.[35][36] The pan-genome, that is the combined set of 30 sequenced strains, encodes 2,239 protein families (orthologous groups OGs).[37] Among them, 1,248 OGs are conserved in all the 30 strains, and represent the universal core. The remaining 991 OGs correspond to the accessory genome in which 277 OGs are unique to one strain.[38]

There is an unusually high number of restriction modification systems in the genome of H. pylori.[39]

Transcriptome

In 2010, Sharma et al. presented a comprehensive analysis of transcription at single-nucleotide resolution by differential RNA-seq that confirmed the known acid induction of major virulence loci, such as the urease (ure) operon or the cag pathogenicity island (see below).[40] More importantly, this study identified a total of 1,907 transcription start sites 337 primary operons, and 126 additional suboperons, and 66 monocistrons. Until 2010, only about 55 transcription start sites (TSSs) were known in this species. Notably, 27% of the primary TSSs are also antisense TSSs, indicating that – similar to E. coli – antisense transcription occurs across the entire H. pylori genome. At least one antisense TSS is associated with about 46% of all open reading frames, including many housekeeping genes.[40] Most (about 50%) of the 5′ UTRs are 20–40 nucleotides (nt) in length and support the AAGGag motif located about 6 nt (median distance) upstream of start codons as the consensus Shine–Dalgarno sequence in H. pylori.[40]

Proteome

The proteins of H. pylori have been systematically analyzed by multiple studies. As a consequence, more than 70% of its proteome have been detected by mass spectrometry and other biochemical methods. In fact, about 50% of the proteome have been quantified, that is, we know how many copies of each protein are present in a typical cell.[41] Furthermore, the interactome of H. pylori has been systematically studied and more than 3000 protein-protein interactions have been identified. The latter provide information of how proteins interact with each other, e.g. in stable protein complexes or in more dynamic, transient interactions. This in turn helps researchers to find out what the function of uncharacterized proteins is, e.g. when an uncharacterized protein interacts with several proteins of the ribosome (that is, it is likely also involved in ribosome function). Nevertheless, about a third of all ~1,500 proteins in H. pylori remain uncharacterized and their function is largely unknown.[42]

H. pylori infection

Micrograph of H. pylori colonizing the stomach lining

Helicobacter pylori harms the stomach and duodenal linings by several mechanisms. The ammonia produced to regulate pH is toxic to epithelial cells, as are biochemicals produced by H. pylori such as proteases, vacuolating cytotoxin A (VacA) (this damages epithelial cells, disrupts tight junctions and causes apoptosis), and certain phospholipases.[43] Cytotoxin associated gene CagA can also cause inflammation and is potentially a carcinogen.[44]

Colonization of the stomach by H. pylori can result in chronic gastritis, an inflammation of the stomach lining, at the site of infection. Helicobacter cysteine-rich proteins (Hcp), particularly HcpA (hp0211), are known to trigger an immune response, causing inflammation.[45] H. pylori has been shown to increase the levels of COX2 in H. pylori positive gastritis.[46] Chronic gastritis is likely to underlie H. pylori-related diseases.[47]

Peptic ulcers in the stomach and duodenum are a consequence of inflammation that allows stomach acid and the digestive enzyme pepsin to overwhelm the protective mechanisms of the stomach and duodenal mucous membranes. The location of colonization of H. pylori, which affects the location of the ulcer, depends on the acidity of the stomach.[48] In people producing large amounts of acid, H. pylori colonizes near the pyloric antrum (exit to the duodenum) to avoid the acid-secreting parietal cells at the fundus (near the entrance to the stomach).[27] G cells express relatively high levels of PD-L1 that protects these cells from H. pylori-induced immune destruction.[49] In people producing normal or reduced amounts of acid, H. pylori can also colonize the rest of the stomach.

The inflammatory response caused by bacteria colonizing near the pyloric antrum induces G cells in the antrum to secrete the hormone gastrin, which travels through the bloodstream to parietal cells in the fundus.[50] Gastrin stimulates the parietal cells to secrete more acid into the stomach lumen, and over time increases the number of parietal cells, as well.[51] The increased acid load damages the duodenum, which may eventually result in ulcers forming in the duodenum.

When H. pylori colonizes other areas of the stomach, the inflammatory response can result in atrophy of the stomach lining and eventually ulcers in the stomach. This also may increase the risk of stomach cancer.[52] Individuals with chronic H. pylori infection have an increased risk of acquiring a cancer that is directly related to this infection.[53][54][27] These cancers are stomach adenocarcinoma, gastric MALT lymphoma, and less commonly diffuse large B-cell lymphoma of the stomach.[55][56][57] A modest association of H. pylori has been made with the development of colorectal cancers but as of 2020 causality has yet to be proved.[58][59]

Signs and symptoms

Most people infected with H. pylori never experience symptoms or complications.[8] However, individuals infected with H. pylori have a 10% to 20% risk of developing peptic ulcers, and 0.5% to 2% risk of developing stomach cancer.[60] Acute infection may appear as an acute gastritis with upper abdominal pain (stomach ache) or nausea.[61] Where this develops into chronic gastritis, the symptoms, if present, are often those of indigestion, stomach pains, nausea, bloating, belching, and sometimes vomiting.[62][63] Pain typically occurs when the stomach is empty, between meals, and in the early morning hours, but it can also occur at other times. Symptoms of an ulcer may include nausea, vomiting, and loss of appetite.

Bleeding in the stomach can also occur as evidenced by the passage of black stools; prolonged bleeding may cause anemia leading to weakness and fatigue. If bleeding is heavy, hematemesis, hematochezia, or melena may occur. Inflammation of the pyloric antrum, which connects the stomach to the duodenum, is more likely to lead to duodenal ulcers, while inflammation of the corpus (i.e. body of the stomach) is more likely to lead to gastric ulcers.[52][64] Individuals infected with H. pylori may also develop colorectal[65] or gastric[66] polyps, i.e. non-cancerous growths of tissue projecting from the mucous membranes of these organs. Usually, these polyps are asymptomatic but gastric polyps may be the cause of dyspepsia, heartburn, bleeding from the upper gastrointestinal tract, and, rarely, gastric outlet obstruction[66] while colorectal polyps may be the cause of rectal bleeding, anemia, constipation, diarrhea, weight loss, and abdominal pain.[67]

Cancer

H. pylori is a major source of worldwide cancer mortality.[68] Although the data varies between different countries, overall about 1% to 3% of people infected with Helicobacter pylori develop gastric cancer in their lifetime compared to 0.13% of individuals who have had no H. pylori infection.[69][27] H. pylori infection is very prevalent. As evaluated in 2002, it is present in the gastric tissues of 74% of middle-aged adults in developing countries and 58% in developed countries.[70] Since 1% to 3% of infected individuals are likely to develop gastric cancer,[71] H. pylori-induced gastric cancer is the third highest cause of worldwide cancer mortality as of 2018.[68]

Infection by H. pylori causes no symptoms in about 80% of those infected.[72] About 75% of individuals infected with H. pylori develop gastritis.[73] Thus, the usual consequence of H. pylori infection is chronic asymptomatic gastritis.[74] Because of the usual lack of symptoms, when gastric cancer is finally diagnosed it is often fairly advanced. More than half of gastric cancer patients have lymph node metastasis when they are initially diagnosed.[75]

The gastritis caused by H. pylori is accompanied by inflammation, characterized by infiltration of neutrophils and macrophages to the gastric epithelium, which favors the accumulation of pro-inflammatory cytokines and reactive oxygen species/reactive nitrogen species (ROS/RNS).[76] The substantial presence of ROS/RNS causes DNA damage including 8-oxo-2'-deoxyguanosine (8-OHdG).[76] If the infecting H. pylori carry the cytotoxic cagA gene (present in about 60% of Western isolates and a higher percentage of Asian isolates), they can increase the level of 8-OHdG in gastric cells by 8-fold, while if the H. pylori do not carry the cagA gene, the increase in 8-OHdG is about 4-fold.[77] In addition to the oxidative DNA damage 8-OHdG, H. pylori infection causes other characteristic DNA damages including DNA double-strand breaks.[78]

H. pylori also causes many epigenetic alterations linked to cancer development.[79][80] These epigenetic alterations are due to H. pylori-induced methylation of CpG sites in promoters of genes[79] and H. pylori-induced altered expression of multiple microRNAs.[80]

As reviewed by Santos and Ribeiro[81] H. pylori infection is associated with epigenetically reduced efficiency of the DNA repair machinery, which favors the accumulation of mutations and genomic instability as well as gastric carcinogenesis. In particular, Raza et al.[82] showed that expression of two DNA repair proteins, ERCC1 and PMS2, was severely reduced once H. pylori infection had progressed to cause dyspepsia. Dyspepsia occurs in about 20% of infected individuals.[83] In addition, as reviewed by Raza et al.,[82] human gastric infection with H. pylori causes epigenetically reduced protein expression of DNA repair proteins MLH1, MGMT and MRE11. Reduced DNA repair in the presence of increased DNA damage increases carcinogenic mutations and is likely a significant cause of H. pylori carcinogenesis.

Two related mechanisms by which H. pylori could promote cancer are under investigation. One mechanism involves the enhanced production of free radicals near H. pylori and an increased rate of host cell mutation. The other proposed mechanism has been called a "perigenetic pathway",[84] and involves enhancement of the transformed host cell phenotype by means of alterations in cell proteins, such as adhesion proteins. H. pylori has been proposed to induce inflammation and locally high levels of TNF-α and/or interleukin 6 (IL-6). According to the proposed perigenetic mechanism, inflammation-associated signaling molecules, such as TNF-α, can alter gastric epithelial cell adhesion and lead to the dispersion and migration of mutated epithelial cells without the need for additional mutations in tumor suppressor genes, such as genes that code for cell adhesion proteins.[85]

The strain of H. pylori a person is exposed to may influence the risk of developing gastric cancer. Strains of H. pylori that produce high levels of two proteins, vacuolating toxin A (VacA) and the cytotoxin-associated gene A (CagA), appear to cause greater tissue damage than those that produce lower levels or that lack those genes completely.[86] These proteins are directly toxic to cells lining the stomach and signal strongly to the immune system that an invasion is under way. As a result of the bacterial presence, neutrophils and macrophages set up residence in the tissue to fight the bacteria assault.[87]

Pathophysiology

Adaptation to the stomach

Diagram showing how H. pylori reaches the epithelium of the stomach

H. pylori is able to sense the less acidic pH gradient in the mucus, and using its flagella can move towards it. Once there it can burrow through into the underlying epithelial cell layer.[88] H. pylori is found in the mucus, on the inner surface of the epithelium, and occasionally inside the epithelial cells themselves.[89] H. pylori adheres to the epithelial cells by producing adhesins, known virulence factors, which bind to lipids and carbohydrates in the epithelial cell membrane. This keeps the bacteria from being swept away with the constant movement of the mucus from the lining to its dissolution into the stomach lumen.[90]

H. pylori urease enzyme diagram

One such adhesin, BabA, binds to the Lewis b antigen displayed on the surface of stomach epithelial cells.[91] H. pylori adherence via BabA is acid sensitive and can be fully reversed by a decreased pH. It has been proposed that BabA's acid responsiveness enables adherence while also allowing an effective escape from unfavorable environment at pH that is harmful to the organism.[92] Another such adhesin, SabA, binds to increased levels of sialyl-Lewis X (sLeX) antigen expressed on gastric mucosa.[93]

In addition to using chemotaxis to avoid areas of low pH (high acidity), H. pylori also neutralizes the acid in its environment by producing large amounts of urease, an enzyme which breaks down the urea present in the stomach to carbon dioxide and ammonia. These react with the strong acids in the environment to produce a neutralized area around H. pylori.[94] Urease expression is not only required for establishing initial colonization but is essential for maintaining chronic infection.[60] Another enzyme Helicobacter pylori arginase is crucial for establishing infection in the stomach. Arginase is a bimetallic metalloenzyme that also provides acid resistance. Arginase also helps the pathogen evade the host’s immune system by competing with the host’s production of nitric oxide normally a major component of the innate immune system.[95]

Survival

In the stomach H. pylori has to not only survive the harsh gastric acidity but also the constant sweeping of mucus by continuous peristalsis, and phagocytic attack accompanied by the release of reactive oxygen species.[96] This oxidative stress can induce potentially lethal mutagenic DNA adducts in its genome. Surviving this DNA damage is supported by transformation-mediated recombinational repair, that contributes to successful colonization.[97][98]

Transformation (the transfer of DNA from one bacterial cell to another through the intervening medium) appears to be part of an adaptation for DNA repair. H. pylori is naturally competent for transformation. While many organisms are competent only under certain environmental conditions, such as starvation, H. pylori is competent throughout logarithmic growth.[99] All organisms encode genetic programs for response to stressful conditions including those that cause DNA damage.[99] In H. pylori, homologous recombination is required for repairing DNA double-strand breaks (DSBs). The AddAB helicase-nuclease complex resects DSBs and loads RecA onto single-strand DNA (ssDNA), which then mediates strand exchange, leading to homologous recombination and repair. The requirement of RecA plus AddAB for efficient gastric colonization suggests, in the stomach, H. pylori is either exposed to double-strand DNA damage that must be repaired or requires some other recombination-mediated event. In particular, natural transformation is increased by DNA damage in H. pylori, and a connection exists between the DNA damage response and DNA uptake in H. pylori,[99] suggesting natural competence contributes to persistence of H. pylori in its human host and explains the retention of competence in most clinical isolates.

RuvC protein is essential to the process of recombinational repair, since it resolves intermediates in this process termed Holliday junctions. H. pylori mutants that are defective in RuvC have increased sensitivity to DNA-damaging agents and to oxidative stress, exhibit reduced survival within macrophages, and are unable to establish successful infection in a mouse model.[100] Similarly, RecN protein plays an important role in DSB repair in H. pylori.[101] An H. pylori recN mutant displays an attenuated ability to colonize mouse stomachs, highlighting the importance of recombinational DNA repair in survival of H. pylori within its host.[101]

Virulence factors

Diagram of H. pylori and associated virulence factors

CagA (cytotoxin-associated gene A) codes for the major H. pylori virulence protein. Bacterial strains with the cagA gene are associated with the ability to cause ulcers, MALT lymphomas, and gastric cancer.[102][103] The cagA gene codes for a relatively long (1186-amino acid) protein. The cag pathogenicity island (PAI) has about 30 genes, part of which code for a complex type IV secretion system. The low GC-content of the cag PAI relative to the rest of the Helicobacter genome suggests the island was acquired by horizontal transfer from another bacterial species.[36] The serine protease HtrA also plays a major role in the pathogenesis of H. pylori. The HtrA protein enables the bacterium to transmigrate across the host cells' epithelium, and is also needed for the translocation of CagA.[104]

The vacA (Q48245) gene codes for another major H. pylori virulence protein. There are four main subtypes of vacA: s1/m1, s1/m2, s2/m1, and s2/m2. s1/m1 and s1/m2 subtypes are known to cause increased risk of gastric cancer.[105] This has been linked to the ability for toxigenic vacA to promote the generation of intracellular reservoirs of H. pylori via disruption of calcium channel TRPML1.[106]

The virulence of H. pylori may be increased by genes of the cag pathogenicity island; about 50–70% of H. pylori strains in Western countries carry it.[107] Western people infected with strains carrying the cag PAI have a stronger inflammatory response in the stomach and are at a greater risk of developing peptic ulcers or stomach cancer than those infected with strains lacking the island.[27] Following attachment of H. pylori to stomach epithelial cells, the type IV secretion system expressed by the cag PAI "injects" the inflammation-inducing agent, peptidoglycan, from their own cell walls into the epithelial cells. The injected peptidoglycan is recognized by the cytoplasmic pattern recognition receptor (immune sensor) Nod1, which then stimulates expression of cytokines that promote inflammation.[108]

The type-IV secretion apparatus also injects the cag PAI-encoded protein CagA into the stomach's epithelial cells, where it disrupts the cytoskeleton, adherence to adjacent cells, intracellular signaling, cell polarity, and other cellular activities.[109] Once inside the cell, the CagA protein is phosphorylated on tyrosine residues by a host cell membrane-associated tyrosine kinase (TK). CagA then allosterically activates protein tyrosine phosphatase/protooncogene Shp2.[110] Pathogenic strains of H. pylori have been shown to activate the epidermal growth factor receptor (EGFR), a membrane protein with a TK domain. Activation of the EGFR by H. pylori is associated with altered signal transduction and gene expression in host epithelial cells that may contribute to pathogenesis. A C-terminal region of the CagA protein (amino acids 873–1002) has also been suggested to be able to regulate host cell gene transcription, independent of protein tyrosine phosphorylation.[103] A great deal of diversity exists between strains of H. pylori, and the strain that infects a person can predict the outcome.

Diagnosis

H. pylori colonized on the surface of regenerative epithelium (Warthin-Starry silver stain)

Colonization with H. pylori is not a disease in itself, but a condition associated with a number of stomach diseases.[27] Testing is recommended in cases of peptic ulcer disease or low-grade gastric MALT lymphoma; after endoscopic resection of early gastric cancer; for first-degree relatives with gastric cancer, and in certain cases of indigestion. Other indications that prompt testing for H. pylori include long term aspirin or other non-steroidal anti-inflammatory use, unexplained iron deficiency anemia, or in cases of immune thrombocytopenic purpura.[111] Several methods of testing exist, both invasive and non-invasive.

Non-invasive tests for H. pylori infection include serological tests for antibodies, stool tests, and urea breath tests. Carbon urea breath tests include the use of carbon-13, or a radioactive carbon-14 producing a labelled carbon dioxide that can be detected in the breath.[112] Carbon urea breath tests have a high sensitivity and specificity for the diagnosis of H. pylori.[112]

Proton-pump inhibitors and antibiotics should be discontinued for at least 30 days prior to testing for H. pylori infection or eradication, as both agents inhibit H. pylori growth and may lead to false negative results.[111] Testing to confirm eradication is recommended 30 days or more after completion of treatment for H. pylori infection. H. pylori breath testing or stool antigen testing are both reasonable tests to confirm eradication.[111] H. pylori serologic testing, including IgG antibodies, are not recommended as a test of eradication as they may remain elevated for years after successful treatment of infection.[111]

An endoscopic biopsy is an invasive means to test for H. pylori infection. Low-level infections can be missed by biopsy, so multiple samples are recommended. The most accurate method for detecting H. pylori infection is with a histological examination from two sites after endoscopic biopsy, combined with either a rapid urease test or microbial culture.[113] Generally, repeating endoscopy is not recommended to confirm H. pylori eradication, unless there are specific indications to repeat the procedure.[111]

Transmission

Helicobacter pylori is contagious, and transmission is through either the oral–oral route or the fecal–oral route.[8] Consistent with these transmission routes, the bacteria have been isolated from feces, saliva, and dental plaque. Findings suggest H. pylori is more easily transmitted by gastric mucus than saliva.[4] H. pylori may also be transmitted orally by means of fecal matter through the ingestion of waste-tainted water.[4] Transmission occurs mainly within families in developed nations, yet can also be acquired from the community in developing countries.[114]

Prevention

Due to H. pylori's role as a major cause of certain diseases (particularly cancers) and its consistently increasing antibiotic resistance, there is a clear need for new therapeutic strategies to prevent or remove the bacterium from colonizing humans.[115] Much work has been done on developing viable vaccines aimed at providing an alternative strategy to control H. pylori infection and related diseases.[116] Researchers are studying different adjuvants, antigens, and routes of immunization to ascertain the most appropriate system of immune protection.[117] An economic evaluation of the use of a potential H. pylori vaccine in babies found its introduction could, at least in the Netherlands, prove cost-effective for the prevention of peptic ulcer and stomach adenocarcinoma.[118] A similar approach has also been studied for the United States.[119] Notwithstanding this proof-of-concept (i.e. vaccination protects children from acquisition of infection with H. pylori), as of late 2019 there have been no advanced vaccine candidates and only one vaccine in a Phase I clinical trial. Furthermore, development of a vaccine against H. pylori has not been a current priority of major pharmaceutical companies.[120] A key target for potential therapy is the proton-gated urea channel, since the secretion of urease enables the survival of the bacterium.[121]

Many investigations have attempted to prevent the development of Helicobacter pylori-related diseases by eradicating the bacterium during the early stages of infection using antibiotic-based drug regimens. Studies find that such treatments, when effectively eradicating H. pylori from the stomach, reduce the inflammation and some of the histopathological abnormalities associated with the infection. However studies disagree on the ability of these treatments to alleviate the more serious histopathological abnormalities in H. pylori infections, e.g. gastric atrophy and metaplasia, both of which are precursors to gastric adenocarcinoma.[122] There is similar disagreement on the ability of antibiotic-based regiments to prevent gastric adenocarcinoma. A meta-analysis (i.e. a statistical analysis that combines the results of multiple randomized controlled trials) published in 2014 found that these regimens did not appear to prevent development of this adenocarcinoma.[123] However, two subsequent prospective cohort studies conducted on high-risk individuals in China and Taiwan found that eradication of the bacterium produced a significant decrease in the number of individuals developing the disease. These results agreed with a retrospective cohort study done in Japan and published in 2016,[124] as well as a meta-analysis, also published in 2016, of 24 studies conducted on individuals with varying levels of risk for developing the disease.[125] These later studies suggest that the eradication of H. pylori infection reduces the incidence of H. pylori-related gastric adenocarcinoma in individuals at all levels of baseline risk.[125] Further studies will be required to clarify this issue. In all events, studies agree that antibiotic-based regimens effectively reduce the occurrence of metachronous H. pylori-associated gastric adenocarcinoma.[122] (Metachronous cancers are cancers that reoccur 6 months or later after resection of the original cancer.) It is suggested that antibiotic-based drug regimens be used after resecting H. pylori-associated gastric adenocarcinoma in order to reduce its metachronus reoccurrence.[126]

Treatment

Gastritis

Following Maastricht Consensus Reports, H. pylori gastritis, has been included in ICD11, and listed as Helicobacter pylori induced gastritis.[127][128][129] Initially the infection tends to be superficial, localised to the upper mucosal layers of the stomach.[130] The intensity of chronic inflammation is related to the cytotoxicity of the H. pylori strain. A greater cytotoxicity will result in the change from a non-atrophic gastritis to an atrophic gastritis with the loss of mucous glands. This condition is a prequel to the development of peptic ulcers and gastric adenocarcinoma.[130]

Various antibiotic plus proton-pump inhibitor drug regimens are used to eradicate the infection and thereby successfully treat the disorder[123] with triple-drug therapy consisting of clarithromycin, amoxicillin, and a proton-pump inhibitor given for 14–21 days often being considered first line treatment.[130]

Peptic ulcers

Once H. pylori is detected in a person with a peptic ulcer, the normal procedure is to eradicate it and allow the ulcer to heal. The standard first-line therapy is a 14-day "triple therapy" consisting of acid-suppressive therapy, most commonly proton-pump inhibitors, such as omeprazole, or less commonly potassium-competitive acid blockers, such as vonoprazan, combined with the antibiotics clarithromycin and amoxicillin.[131][132] (The actions of proton pump inhibitors against H. pylori may reflect their direct bacteriostatic effect due to inhibition of the bacterium's P-type ATPase or urease.[23]) Variations of the triple therapy have been developed over the years, such as using a different proton pump inhibitor, as with pantoprazole or rabeprazole, or replacing amoxicillin with metronidazole for people who are allergic to penicillin.[133] In areas with higher rates of clarithromycin resistance, other options are recommended.[134] Such a therapy has revolutionized the treatment of peptic ulcers and has made a cure to the disease possible. Previously, the only option was symptom control using antacids, H2-antagonists or proton pump inhibitors alone.[135][136] Eradication of H. pylori is associated with a subsequent decreased risk of duodenal or gastric ulcer recurrence.[111]

Antibiotic resistance

An increase in antibiotic resistance is shown to be the cause of initial treatment failure. Additional rounds of antibiotics may be used or other therapies.[137][138][139] In patients with any previous macrolide exposure or who are allergic to penicillin, a quadruple therapy that consisting of a proton pump inhibitor, bismuth, tetracycline, and a nitroimidazole for 10–14 days is a recommended first-line treatment option.[140] For the treatment of clarithromycin-resistant strains of H. pylori, the use of levofloxacin as part of the therapy has been suggested.[141][142] Next generation sequencing is looked to for providing initial specific antibiotic resistances that will help in targeting more effective treatment.[143]

Probiotic yogurts containing lactic acid bacteria, Bifidobacteria and Lactobacillus exerts a suppressive effect on H. pylori infection, and their use has been shown to improve the rates of eradication of H. pylori.[144] Symbiotic butyrate-producing bacteria which are normally present in the intestine are sometimes used as probiotics to help suppress H. pylori infections as an adjunct to antibiotic therapy.[145] Butyrate itself is an antimicrobial which destroys the cell envelope of H. pylori by inducing regulatory T cell expression (specifically, FOXP3) and synthesis of an antimicrobial peptide called LL-37, which arises through its action as a histone deacetylase inhibitor.[lower-alpha 1][147][148][149]

The increasing antibiotic resistance encountered has spurred interest in developing alternative therapies using a number of plant compounds.[150][151][152] Compounds that have been shown to have antibiotic effects against H. pylori include sulfur-containing plants, coumarins, and terpines.[150]

Periodontal therapy or scaling and root planing has also been suggested as an additional treatment.[153]

Cancers

MALT lymphomas

MALT lymphomas are lymphomas of mucosa-associated lymphoid tissue, and are generally accepted to be malignant. Recommended treatment of H. pylori-positive gastric MALT lymphoma, when localized (i.e. Ann Arbor stages I and II), employs one of the antibiotic-proton pump inhibitor regimens listed in the H. pylori eradication protocols. If the initial regimen fails to eradicate the pathogen, an alternate protocol is used. Eradication of the pathogen is successful in 70–95% of cases.[14] Some 50–80% of patients who experience eradication of the pathogen develop within 3–28 months a remission and long-term clinical control of their lymphoma. Radiation therapy to the stomach and surrounding (i.e. peri-gastric) lymph nodes has also been used to successfully treat these localized cases. Patients with non-localized (i.e. systemic Ann Arbor stage III and IV) disease who are free of symptoms have been treated with watchful waiting or, if symptomatic, with the immunotherapy drug, rituximab, (given for 4 weeks) combined with the chemotherapy drug, chlorambucil, for 6–12 months; 58% of these patients attain a 58% progression-free survival rate at 5 years. Frail stage III/IV patients have been successfully treated with rituximab or the chemotherapy drug, cyclophosphamide, alone.[154] Antibiotic-proton pump inhibitor eradication therapy and localized radiation therapy have been used successfully to treat H. pylori-positive MALT lymphomas of the rectum; however radiation therapy has given slightly better results and therefore been suggested to be the disease' preferred treatment.[155] However, the generally recognized treatment of choice for patients with systemic involvement uses various chemotherapy drugs often combined with rituximab.

Diffuse large B-cell lymphoma

Diffuse large B-cell lymphoma is a far more aggressive cancer than extranodal marginal zone B-cell lymphoma. Cases of this malignancy that are H. pylori-positive may be derived from the latter lymphoma[156] and are less aggressive as well as more susceptible to treatment than H. pylori negative cases.[157][158] Several recent studies strongly suggest that localized, early-stage diffuse Helicobacter pylori positive diffuse large B-cell lymphoma, when limited to the stomach, can be successfully treated with antibiotic-proton pump inhibitor regimens.[55][157][159][158] However, these studies also agree that, given the aggressiveness of diffuse large B-cell lymphoma, patients treated with one of these H. pylori eradication regimes need to be carefully followed. If found unresponsive to or clinically worsening on these regimens, these patients should be switched to more conventional therapy such as chemotherapy (e.g. CHOP or a CHOP-like regimen), immunotherapy (e.g. rituximab), surgery, and/or local radiotherapy.[157] H. pylori positive diffuse large B-cell lymphoma has been successfully treated with one or a combination of these methods.[158]

Stomach adenocarcinoma

Helicobacter pylori is linked to the majority of gastric adenocarcinoma cases, and to the majority of non-cardia adenocarcinomas located at the gastroesophageal junction.[124] The treatment for this cancer is highly aggressive with even localized disease being treated sequentially with chemotherapy and radiotherapy before surgical resection.[160] Since this cancer, once developed, is independent of H. pylori infection, antibiotic-proton pump inhibitor regimens are not used in its treatment.[124]

Prognosis

Helicobacter pylori colonizes the stomach and induces chronic gastritis, a long-lasting inflammation of the stomach. The bacterium persists in the stomach for decades in most people. Most individuals infected by H. pylori never experience clinical symptoms, despite having chronic gastritis. About 10–20% of those colonized by H. pylori ultimately develop gastric and duodenal ulcers.[27] H. pylori infection is also associated with a 1–2% lifetime risk of gastric cancer and a less than 1% risk of gastric MALT lymphoma.[27] A diet high in salt worsens the infection and increases the risk of developing gastric cancer.[161][162]

In the absence of treatment, H. pylori infection – once established in its gastric niche – is widely believed to persist for life.[4] In the elderly, however, infection likely can disappear as the stomach's mucosa becomes increasingly atrophic and inhospitable to colonization. The proportion of acute infections that persist is not known, but several studies that followed the natural history in populations have reported apparent spontaneous elimination.[163][164]

It is possible for H. pylori to re-establish in a person after eradication. This recurrence can be caused by the original strain (recrudescence), or be caused by a different strain (reinfection). According to a 2017 meta-analysis by Hu et al., the global per-person annual rates of recurrence, reinfection, and recrudescence is 4.3%, 3.1%, and 2.2% respectively. It is unclear what the main risk factors are.[165]

Mounting evidence suggests H. pylori has an important role in protection from some diseases.[166] The incidence of acid reflux disease, Barrett's esophagus, and esophageal cancer have been rising dramatically at the same time as H. pylori's presence decreases.[167] In 1996, Martin J. Blaser advanced the hypothesis that H. pylori has a beneficial effect by regulating the acidity of the stomach contents.[50][167] The hypothesis is not universally accepted as several randomized controlled trials failed to demonstrate worsening of acid reflux disease symptoms following eradication of H. pylori.[168][169] Nevertheless, Blaser has reasserted his view that H. pylori is a member of the normal flora of the stomach.[19] He postulates that the changes in gastric physiology caused by the loss of H. pylori account for the recent increase in incidence of several diseases, including type 2 diabetes, obesity, and asthma.[19][170] His group has recently shown that H. pylori colonization is associated with a lower incidence of childhood asthma.[171]

Epidemiology

As of 1995 at least half the world's population was infected with H. pylori, making it the most widespread infection in the world.[172] H. pylori infection is more prevalent in South America, Sub-Saharan Africa, and the Middle East.[123] The global prevalence declined markedly in the decade following 2010, with a particular reduction in Africa.[22]

The age when someone acquires this bacterium seems to influence the pathologic outcome of the infection. People infected at an early age are likely to develop more intense inflammation that may be followed by atrophic gastritis with a higher subsequent risk of gastric ulcer, gastric cancer, or both. Acquisition at an older age brings different gastric changes more likely to lead to duodenal ulcer.[4] Infections are usually acquired in early childhood in all countries.[27] However, the infection rate of children in developing nations is higher than in industrialized nations, probably due to poor sanitary conditions, perhaps combined with lower antibiotics usage for unrelated pathologies. In developed nations, it is currently uncommon to find infected children, but the percentage of infected people increases with age, with about 50% infected for those over the age of 60 compared with around 10% between 18 and 30 years.[172] The higher prevalence among the elderly reflects higher infection rates in the past when the individuals were children rather than more recent infection at a later age of the individual.[27] In the United States, prevalence appears higher in African-American and Hispanic populations, most likely due to socioeconomic factors.[173][174] The lower rate of infection in the West is largely attributed to higher hygiene standards and widespread use of antibiotics. Despite high rates of infection in certain areas of the world, the overall frequency of H. pylori infection is declining.[175] However, antibiotic resistance is appearing in H. pylori; many metronidazole- and clarithromycin-resistant strains are found in most parts of the world.[176]

History

Helicobacter pylori migrated out of Africa along with its human host circa 60,000 years ago.[177] Recent research states that genetic diversity in H. pylori, like that of its host, decreases with geographic distance from East Africa. Using the genetic diversity data, researchers have created simulations that indicate the bacteria seem to have spread from East Africa around 58,000 years ago. Their results indicate modern humans were already infected by H. pylori before their migrations out of Africa, and it has remained associated with human hosts since that time.[178]

H. pylori was first discovered in the stomachs of patients with gastritis and ulcers in 1982 by Barry Marshall and Robin Warren of Perth, Western Australia. At the time, the conventional thinking was that no bacterium could live in the acid environment of the human stomach. In recognition of their discovery, Marshall and Warren were awarded the 2005 Nobel Prize in Physiology or Medicine.[179]

Before the research of Marshall and Warren, German scientists found spiral-shaped bacteria in the lining of the human stomach in 1875, but they were unable to culture them, and the results were eventually forgotten.[167] The Italian researcher Giulio Bizzozero described similarly shaped bacteria living in the acidic environment of the stomach of dogs in 1893.[180] Professor Walery Jaworski of the Jagiellonian University in Kraków investigated sediments of gastric washings obtained by lavage from humans in 1899. Among some rod-like bacteria, he also found bacteria with a characteristic spiral shape, which he called Vibrio rugula. He was the first to suggest a possible role of this organism in the pathogenesis of gastric diseases. His work was included in the Handbook of Gastric Diseases, but it had little impact, as it was written in Polish.[181] Several small studies conducted in the early 20th century demonstrated the presence of curved rods in the stomachs of many people with peptic ulcers and stomach cancers.[182] Interest in the bacteria waned, however, when an American study published in 1954 failed to observe the bacteria in 1180 stomach biopsies.[183]

Interest in understanding the role of bacteria in stomach diseases was rekindled in the 1970s, with the visualization of bacteria in the stomachs of people with gastric ulcers.[184] The bacteria had also been observed in 1979, by Robin Warren, who researched it further with Barry Marshall from 1981. After unsuccessful attempts at culturing the bacteria from the stomach, they finally succeeded in visualizing colonies in 1982, when they unintentionally left their Petri dishes incubating for five days over the Easter weekend. In their original paper, Warren and Marshall contended that most stomach ulcers and gastritis were caused by bacterial infection and not by stress or spicy food, as had been assumed before.[185]

Some skepticism was expressed initially, but within a few years multiple research groups had verified the association of H. pylori with gastritis and, to a lesser extent, ulcers.[186] To demonstrate H. pylori caused gastritis and was not merely a bystander, Marshall drank a beaker of H. pylori culture. He became ill with nausea and vomiting several days later. An endoscopy 10 days after inoculation revealed signs of gastritis and the presence of H. pylori. These results suggested H. pylori was the causative agent. Marshall and Warren went on to demonstrate antibiotics are effective in the treatment of many cases of gastritis. In 1994, the National Institutes of Health stated most recurrent duodenal and gastric ulcers were caused by H. pylori, and recommended antibiotics be included in the treatment regimen.[187]

The bacterium was initially named Campylobacter pyloridis, then renamed C. pylori in 1987 (pylori being the genitive of pylorus, the circular opening leading from the stomach into the duodenum, from the Ancient Greek word πυλωρός, which means gatekeeper[188]).[189] When 16S ribosomal RNA gene sequencing and other research showed in 1989 that the bacterium did not belong in the genus Campylobacter, it was placed in its own genus, Helicobacter from the Ancient Greek έλιξ (hělix) "spiral" or "coil".[188][190]

In October 1987, a group of experts met in Copenhagen to found the European Helicobacter Study Group (EHSG), an international multidisciplinary research group and the only institution focused on H. pylori.[191] The Group is involved with the Annual International Workshop on Helicobacter and Related Bacteria,[192] (renamed as the European Helicobacter and Microbiota Study Group[193]), the Maastricht Consensus Reports (European Consensus on the management of H. pylori),[131][133][194][195] and other educational and research projects, including two international long-term projects:

  • European Registry on H. pylori Management (Hp-EuReg) – a database systematically registering the routine clinical practice of European gastroenterologists.[196]
  • Optimal H. pylori management in primary care (OptiCare) – a long-term educational project aiming to disseminate the evidence based recommendations of the Maastricht IV Consensus to primary care physicians in Europe, funded by an educational grant from United European Gastroenterology.[197][198]

Research

Results from in vitro studies suggest that fatty acids, mainly polyunsaturated fatty acids, have a bactericidal effect against H. pylori, but their in vivo effects have not been proven.[199]

A suitable vaccine for H.pylori, either prophylactic or therapeutic, is an ongoing research aim.[8] The Murdoch Children's Research Institute is working at developing a vaccine that instead of specifically targeting the bacteria, aims to inhibit the inflammation caused that leads to the associated diseases.[120]

See also

Explanatory footnotes

  1. ↑ The establishment of a link between light therapy, vitamin D and human cathelicidin LL-37 expression provides a completely different way for infection treatment. Instead of treating patients with traditional antibiotics, doctors may be able to use light or vitamin D. Indeed using narrow-band UV B light, the level of vitamin D was increased in psoriasis patients (psoriasis is a common autoimmune disease on skin). In addition, other small molecules such as butyrate can induce LL-37 expression. Components from Traditional Chinese Medicine may regulate the AMP expression as well. These factors may induce the expression of a single peptide or multiple AMPs. It is also possible that certain factors can work together to induce AMP expression. While cyclic AMP and butyrate synergistically stimulate the expression of chicken β-defensin 9, 4-phenylbutyrate (PBA) and 1,25-dihydroxyvitamin D3 (or lactose) can induce AMP gene expression synergistically. It appears that stimulation of LL-37 expression by histone deacetylase (HDAC) inhibitors is cell dependent. Trichostatin and sodium butyrate increased the peptide expression in human NCI-H292 airway epithelial cells but not in the primary cultures of normal nasal epithelial cells. However, the induction of the human LL-37 expression may not be a general approach for bacterial clearance. During Salmonella enterica infection of human monocyte-derived macrophages, LL-37 is neither induced nor required for bacterial clearance.[146]
    Table 3:[146] Select human antimicrobial peptides and their proposed targets.
    Table 4:[146] Some known factors that induce antimicrobial peptide expression.

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