Infection of the stomach withH. pylori does not necessarily cause illness: over half of the global population is infected, but most individuals are asymptomatic.[7][8] Persistentcolonization with more virulent strains can induce a number of gastric and non-gastric disorders.[9] Gastric disorders due to infection begin withgastritis, or inflammation of the stomach lining.[10] When infection is persistent, the prolonged inflammation will becomechronic gastritis. Initially, this will be non-atrophic gastritis, but the damage caused to the stomach lining can bring about the development ofatrophic gastritis and ulcers within the stomach itself or theduodenum (the nearest part of the intestine).[10] At this stage, the risk of developinggastric cancer is high.[11] However, the development of aduodenal ulcer confers a comparatively lower risk of cancer.[12]Helicobacter pylori areclass 1 carcinogenic bacteria, and potential cancers include gastricMALT lymphoma andgastric cancer.[10][11] Infection withH. pylori is responsible for an estimated 89% of all gastric cancers and is linked to the development of 5.5% of all cases cancers worldwide.[13][14]H. pylori is the only bacterium known to cause cancer.[15]
Some studies suggest thatH. pylori plays an important role in the natural stomach ecology by influencing the type of bacteria that colonize the gastrointestinal tract.[17][18] Other studies suggest that non-pathogenic strains ofH. pylori may beneficially normalize stomach acid secretion, and regulate appetite.[19]
Helicobacter pylori is a species ofgram-negative bacteria in theHelicobacter genus.[23]About half the world's population is infected withH. pylori but only a few strains arepathogenic.H pylori is ahelical bacterium having a predominantlyhelical shape, also often described as having a spiral orS shape.[24][25] Its helical shape is better suited for progressing through the viscousmucosa lining of the stomach, and is maintained by a number ofenzymes in thecell wall'speptidoglycan.[1] The bacteria reach the less acidic mucosa by use of theirflagella.[26] Three strains studied showed a variation in length from 2.8 to 3.3 μm but a fairly constant diameter of 0.55–0.58 μm.[24]H. pylori can convert from a helical to an inactivecoccoid form that can evade the immune system, and that may possibly become viable, known asviable but nonculturable (VBNC).[27][28]
To successfully colonize its host,H. pylori uses many differentvirulence factors includingoxidase,catalase, andurease.[32] Urease is the most abundant protein, its expression representing about 10% of the total protein weight.[33]
Helicobacter pylori consists of a large diversity of strains, and hundreds ofgenomes have been completelysequenced.[34][35][36] The genome of the strain26695 consists of about 1.7 millionbase pairs, with some 1,576 genes.[37][38] Thepan-genome, that is the combined set of 30 sequenced strains, encodes 2,239 protein families (orthologous groups OGs).[39] Among them, 1,248 OGs are conserved in all the 30 strains, and represent theuniversal core. The remaining 991 OGs correspond to theaccessory genome in which 277 OGs are unique to one strain.[40]
Single-cell transcriptomics usingsingle-cell RNA-Seq gave the completetranscriptome ofH. pylori which was published in 2010. This analysis of itstranscription confirmed the known acid induction of majorvirulence loci, including the urease (ure) operon and the Cagpathogenicity island (PAI).[41] A total of 1,907 transcription start sites 337 primaryoperons, and 126 additional suboperons, and 66 monocistrons were identified. Until 2010, only about 55 transcription start sites (TSSs) were known in this species. 27% of the primary TSSs are also antisense TSSs, indicating that – similar toE. coli –antisense transcription occurs across the entireH. pylori genome. At least one antisense TSS is associated with about 46% of allopen reading frames, including manyhousekeeping genes.[41] About 50% of the5′ UTRs (leader sequences) are 20–40 nucleotides (nt) in length and support the AAGGag motif located about 6 nt (median distance) upstream of start codons as the consensusShine–Dalgarno sequence inH. pylori.[41]
Theproteome ofH. pylori has been systematically analyzed and more than 70% of itsproteins have been detected bymass spectrometry, and other methods. About 50% of the proteome has been quantified, informing of the number of protein copies in a typical cell.[42]
Studies of theinteractome have identified more than 3000protein-protein interactions. This has provided information of how proteins interact with each other, either in stableprotein complexes or in more dynamic, transient interactions, which can help to identify the functions of the protein. 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 theribosome (that is, it is likely also involved in ribosome function). About a third of all ~1,500 proteins inH. pylori remain uncharacterized and their function is largely unknown.[43]
An infection withHelicobacter pylori can either have no symptoms even when lasting a lifetime, or can harm the stomach and duodenallinings byinflammatory responses induced by several mechanisms associated with a number ofvirulence factors.Colonization can initially causeH. pylori induced gastritis, aninflammation of the stomach lining that became a listed disease inICD11.[44][45][46] This will progress tochronic gastritis if left untreated. Chronic gastritis may lead toatrophy of the stomach lining, and the development ofpeptic ulcers (gastric or duodenal). These changes may be seen as stages in the development ofgastric cancer, known asCorrea's cascade.[47][48] Extragastric complications that have been linked toH. pylori includeanemia due either to iron-deficiency or vitamin B12 deficiency, diabetes mellitus, cardiovascular, and certain neurological disorders.[16]
Peptic ulcers are a consequence of inflammation that allows stomach acid and the digestive enzymepepsin to overwhelm the protective mechanisms of themucous membranes. The location of colonization ofH. pylori, which affects the location of the ulcer, depends on the acidity of the stomach.[49] In people producing large amounts of acid,H. pylori colonizes near thepyloric antrum (exit to the duodenum) to avoid the acid-secretingparietal cells at thefundus (near the entrance to the stomach).[32]G cells express relatively high levels ofPD-L1 that protects these cells fromH. pylori-induced immune destruction.[50] In people producing normal or reduced amounts of acid,H. pylori can also colonize the rest of the stomach.
Diagram showing parts of the stomach
The inflammatory response caused by bacteria colonizing near the pyloric antrum induces G cells in the antrum to secrete the hormonegastrin, which travels through the bloodstream to parietal cells in the fundus.[51] Gastrin stimulates the parietal cells to secrete more acid into the stomach lumen, and over time increases the number of parietal cells, as well.[52] The increased acid load damages the duodenum, which may eventually lead to the formation of ulcers.
Helicobacter pylori is a class Icarcinogen, and potential cancers include gastricmucosa-associated lymphoid tissue (MALT)lymphomas andgastric cancer.[10][11][53] Less commonly,diffuse large B-cell lymphoma of the stomach is a risk.[54] Infection withH. 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] Although the data varies between different countries, overall about 1% to 3% of people infected withHelicobacter pylori develop gastric cancer in their lifetime compared to 0.13% of individuals who have had noH. pylori infection.[55][32]H. pylori-induced gastric cancer is the third highest cause of worldwide cancer mortality as of 2018.[56] 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.[57]
Smallgastric andcolorectal polyps areadenomas that are more commonly found in association with the mucosal damage induced byH. pylori gastritis.[61][62] Larger polyps can in time become cancerous.[63][61] A modest association ofH. pylori has been made with the development ofcolorectal cancers, but as of 2020 causality had yet to be proved.[64][63]
Most people infected withH. pylori never experience any symptoms or complications, but will have a 10% to 20% risk of developingpeptic ulcers or a 0.5% to 2% risk of stomach cancer.[8][65]H. pylori induced gastritis may present as acute gastritis withstomach ache,nausea, and ongoingdyspepsia (indigestion) that is sometimes accompanied by depression and anxiety.[8][66] Where the gastritis develops into chronic gastritis, or an ulcer, the symptoms are the same and can includeindigestion, stomach or abdominal pains, nausea,bloating,belching, feeling hunger in the morning, feeling full too soon, and sometimesvomiting, heartburn, bad breath, and weight loss.[67][68]
Complications of an ulcer can cause severe signs and symptoms such as black or tarry stool indicative ofbleeding into the stomach or duodenum; blood - either red or coffee-ground colored in vomit; persistent sharp or severe abdominal pain; dizziness, and a fast heartbeat.[67][68] Bleeding is the most common complication. In cases caused byH. pylori there was a greater need forhemostasis often requiring gastric resection.[69] Prolonged bleeding may cause anemia leading to weakness and fatigue. Inflammation of the pyloric antrum, which connects the stomach to the duodenum, is more likely to lead to duodenal ulcers, while inflammation of thecorpus may lead to a gastric ulcer.
Stomach cancer can cause nausea, vomiting, diarrhoea, constipation, and unexplained weight loss.[70]Gastric polyps areadenomas that are usually asymptomatic and benign, but may be the cause of dyspepsia, heartburn, bleeding from the stomach, and, rarely, gastric outlet obstruction.[61][71] Larger polyps may havebecome cancerous.[61]Colorectal polyps may be the cause of rectal bleeding, anemia, constipation, diarrhea, weight loss, and abdominal pain.[72]
Virulence factors help a pathogen to evade the immune response of the host, and to successfullycolonize. The many virulence factors ofH. pylori include its flagella, the production of urease, adhesins,serine proteaseHtrA (high temperature requirement A), and the majorexotoxinsCagA andVacA.[30][73] The presence of VacA and CagA are associated with moreadvanced outcomes.[74] CagA is an oncoprotein associated with the development of gastric cancer.[7]
Diagram ofH. pylori and associatedvirulence factorsDiagram showing howH. pylori reaches the epithelium of the stomach
H. pylori infection is associated withepigenetically reduced efficiency of theDNA repair machinery, which favors the accumulation of mutations and genomic instability as well as gastric carcinogenesis.[75] It has been shown that expression of two DNA repair proteins,ERCC1 andPMS2, was severely reduced onceH. pylori infection had progressed to causedyspepsia.[76] Dyspepsia occurs in about 20% of infected individuals.[77] Epigenetically reduced protein expression of DNA repair proteinsMLH1,MGMT andMRE11 are also evident. Reduced DNA repair in the presence of increased DNA damage increases carcinogenic mutations and is likely a significant cause of gastric carcinogenesis.[59][78][79] Theseepigenetic alterations are due toH. pylori-inducedmethylation of CpG sites in promoters of genes[78] andH. pylori-induced altered expression of multiplemicroRNAs.[79]
Two related mechanisms by whichH. pylori could promote cancer have been proposed. One mechanism involves the enhanced production offree radicals nearH. pylori and an increased rate of host cellmutation. The other proposed mechanism has been called a "perigenetic pathway",[80] and involves enhancement of the transformed host cell phenotype by means of alterations in cell proteins, such asadhesion proteins.H. pylori has been proposed to induce inflammation and locally high levels oftumor necrosis factor (TNF), also known as tumor necrosis factor alpha (TNFα)), and/orinterleukin 6 (IL-6).[81] According to the proposed perigenetic mechanism, inflammation-associated signaling molecules, such as TNF, can alter gastric epithelial cell adhesion and lead to the dispersion and migration of mutated epithelial cells without the need for additional mutations intumor suppressor genes, such as genes that code for cell adhesion proteins.[82]
The first virulence factor ofHelicobacter pylori that enables colonization is itsflagellum.[83]H. pylori has from two to seven flagella atthe same polar location which gives it a high motility. The flagellar filaments are about 3 μm long, and composed of two copolymerizedflagellins, FlaA and FlaB, coded by the genesflaA, andflaB.[26][73] The minor flagellin FlaB is located in the proximal region and the major flagellin FlaA makes up the rest of the flagellum.[84] The flagella are sheathed in a continuation of the bacterial outer membrane which gives protection against the gastric acidity. The sheath is also the location of the origin of the outer membrane vesicles that gives protection to the bacterium from bacteriophages.[84]
Flagella motility is provided by theproton motive force provided by urease-driven hydrolysis allowingchemotactic movements towards the less acidicpH gradient in the mucosa.[30] The mucus layer is about 300μm thick, and the helical shape ofH. pylori aided by its flagella helps it to burrow through this layer where it colonises a narrow region of about 25 μm closest to the epithelial cell layer, where the pH is near to neutral. They further colonise thegastric pits and live in thegastric glands.[1][84][85] Occasionally the bacteria are found inside the epithelial cells themselves.[86] The use ofquorum sensing by the bacteria enables the formation of a biofilm which furthers persistent colonisation. In the layers of the biofilm,H. pylori can escape from the actions of antibiotics, and also be protected from host-immune responses.[87][88] In the biofilm,H. pylori can change the flagella to become adhesive structures.[89]
In addition to usingchemotaxis to avoid areas of high acidity (low pH),H. pylori also produces large amounts ofurease, anenzyme which breaks down theurea present in the stomach to produceammonia andbicarbonate, which are released into the bacterial cytosol and the surrounding environment, creating a neutral area.[90] The decreased acidity (higher pH) changes the mucus layer from a gel-like state to a more viscous state that makes it easier for the flagella to move the bacteria through the mucosa and attach to the gastric epithelial cells.[90]Helicobacter pylori is one of the few known types of bacterium that has aurea cycle which is uniquely configured in the bacterium.[91] 10% of the cell is ofnitrogen, a balance that needs to be maintained. Any excess is stored in urea excreted in the urea cycle.[91]
A final stage enzyme in the urea cycle isarginase, an enzyme that is crucial to the pathogenesis ofH. pylori. Arginase producesornithine and urea, which the enzyme urease breaks down into carbonic acid and ammonia. Urease is the bacterium's most abundant protein, accounting for 10–15% of the bacterium's total protein content. Its expression is not only required for establishing initial colonization in the breakdown of urea to carbonic acid and ammonia, but is also essential for maintaining chronic infection.[92][65] Ammonia reduces stomach acidity, allowing the bacteria to become locally established. Arginase promotes the persistence of infection by consuming arginine; arginine is used by macrophages to produce nitric oxide, which has a strong antimicrobial effect.[91][93] The ammonia produced to regulatepH is toxic to epithelial cells.[94]
H. pylori must make attachment with the epithelial cells to prevent its being swept away with the constant movement and renewal of the mucus. To give them this adhesion,bacterial outer membrane proteins as virulence factors calledadhesins are produced.[95] BabA (blood group antigen binding adhesin) is most important during initial colonization, and SabA (sialic acid binding adhesin) is important in persistence. BabA attaches to glycans and mucins in the epithelium.[95] BabA (coded for by thebabA2 gene) also binds to theLewis b antigen displayed on the surface of the epithelial cells.[96] 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 an unfavorable environment such as a low pH that is harmful to the organism.[97] SabA (coded for by thesabA gene) binds to increased levels ofsialyl-LewisX antigen expressed on gastric mucosa.[98]
The outer membrane containscholesterol glucoside, a sterol glucoside thatH. pyloriglycosylates from thecholesterol in the gastric gland cells, and inserts it into its outer membrane.[99] This cholesterol glucoside is important for membrane stability, morphology and immune evasion, and is rarely found in other bacteria.[100][101]
The enzyme responsible for this ischolesteryl α-glucosyltransferase (αCgT or Cgt), encoded by theHP0421 gene.[102] A major effect of the depletion of host cholesterol by Cgt is to disrupt cholesterol-richlipid rafts in the epithelial cells. Lipid rafts are involved in cell signalling and their disruption causes a reduction in the immune inflammatory response, particularly by reducinginterferon gamma.[103] Cgt is also secreted by the type IV secretion system, and is secreted in a selective way so that gastric niches where the pathogen can thrive are created.[102] Its lack has been shown to give vulnerability from environmental stress to bacteria, and also to disrupt CagA-mediated interactions.[99]
Colonization induces an intense anti-inflammatory response as a first-line immune system defence. Phagocytic leukocytes and monocytes infiltrate the site of infection, and antibodies are produced.[104]H. pylori is able to adhere to the surface of the phagocytes and impede their action. This is responded to by the phagocyte in the generation and release of oxygen metabolites into the surrounding space.H. pylori can survive this response by the activity ofcatalase at its attachment to the phagocytic cell surface. Catalase decomposes hydrogen peroxide into water and oxygen, protecting the bacteria from toxicity. Catalase has been shown to almost completely inhibit the phagocytic oxidative response.[104] It is coded for by the genekatA.[105]
TNF-inducing protein alpha (Tipα) is a carcinogenic protein encoded byHP0596 unique toH. pylori that induces the expression oftumor necrosis factor.[82][106] Tipα enters gastric cancer cells where it binds to cell surfacenucleolin, and induces the expression ofvimentin. Vimentin is important in theepithelial–mesenchymal transition associated with the progression of tumors.[107]
CagA (cytotoxin-associated antigen A) is a majorvirulence factor forH. pylori, anoncoprotein that is encoded by thecagA gene. Bacterial strains with thecagA gene are associated with the ability to cause ulcers, MALT lymphomas, and gastric cancer.[108][109] ThecagA gene codes for a relatively long (1186-amino acid) protein. Thecagpathogenicity island (PAI) has about 30 genes, part of which code for a complextype IV secretion system (T4SS or TFSS). The lowGC-content of thecag PAI relative to the rest of theHelicobacter genome suggests the island was acquired byhorizontal transfer from another bacterial species.[38] Theserine proteaseHtrA also plays a major role in the pathogenesis ofH. pylori. The HtrA protein enables the bacterium to transmigrate across the host cells' epithelium, and is also needed for the translocation of CagA.[110]
The virulence ofH. pylori may be increased by genes of thecag pathogenicity island; about 50–70% ofH. pylori strains in Western countries carry it.[111] Western people infected with strains carrying thecag 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.[32] Following attachment ofH. pylori to stomach epithelial cells, the type IV secretion system expressed by thecag PAI "injects" theinflammation-inducing agent, peptidoglycan, from their owncell walls into the epithelial cells. The injected peptidoglycan is recognized by the cytoplasmicpattern recognition receptor (immune sensor) Nod1, which then stimulates expression ofcytokines that promote inflammation.[112]
The type-IVsecretion apparatus also injects thecag PAI-encoded protein CagA into the stomach's epithelial cells, where it disrupts thecytoskeleton, adherence to adjacent cells, intracellular signaling,cell polarity, and other cellular activities.[113] Once inside the cell, the CagA protein isphosphorylated ontyrosine residues by a host cell membrane-associatedtyrosine kinase (TK). CagA then allosterically activatesprotein tyrosine phosphatase/protooncogeneShp2.[114]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.[115] Pathogenic strains ofH. pylori have been shown to activate theepidermal growth factor receptor (EGFR), amembrane protein with a TKdomain. Activation of the EGFR byH. pylori is associated with alteredsignal transduction andgene expression in host epithelial cells that may contribute to pathogenesis. AC-terminal region of the CagA protein (amino acids 873–1002) has also been suggested to be able to regulate host cellgene transcription, independent of protein tyrosine phosphorylation.[109] A great deal of diversity exists between strains ofH. pylori, and the strain that infects a person can predict the outcome.
VacA (vacuolating cytotoxin autotransporter) is another major virulence factor encoded by thevacA gene.[116] All strains ofH. pylori carry this gene but there is much diversity, and only 50% produce the encoded cytotoxin.[92][33] The four main subtypes ofvacA ares1/m1, s1/m2, s2/m1, ands2/m2.s1/m1 ands1/m2 are known to cause an increased risk of gastric cancer.[117] VacA is an oligomeric protein complex that causes a progressive vacuolation in the epithelial cells leading to their death.[118] The vacuolation has also been associated with promoting intracellular reservoirs ofH. pylori by disrupting the calcium channel cell membraneTRPML1.[119] VacA has been shown to increase the levels ofCOX2, an up-regulation that increases the production of aprostaglandin indicating a strong host cell inflammatory response.[118][120]
H. pylori forms blebs from the outer membrane that pinch off asouter membrane vesicles to provide an alternative delivery system for virulence factors including CagA.[99]
AHelicobactercysteine-rich protein HcpA is known to trigger an immune response, causing inflammation.[122] AHelicobacter pylori virulence factorDupA is associated with the development of duodenal ulcers.[123]
The need for survival has led to the development of different mechanisms of tolerance that enable the persistence ofH. pylori.[124] These mechanisms can also help to overcome the effects of antibiotics.[124]H. pylori has to not only survive the harsh gastric acidity but also the sweeping of mucus by continuousperistalsis, andphagocytic attack accompanied by the release ofreactive oxygen species.[125] All organisms encode genetic programs for response to stressful conditions including those that cause DNA damage.[126] Stress conditions activate bacterial response mechanisms that are regulated by proteins expressed byregulator genes.[124] Theoxidative stress can induce potentially lethal mutagenicDNA adducts in its genome. Surviving thisDNA damage is supported bytransformation-mediatedrecombinational repair, that contributes to successful colonization.[127][128]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.[126]
Transformation (the transfer of DNA from one bacterial cell to another through the intervening medium) appears to be part of an adaptation forDNA repair.[126]Homologous recombination is required for repairingdouble-strand breaks (DSBs). The AddAB helicase-nuclease complex resects DSBs and loadsRecA 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 thatH. 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 inH. pylori, and a connection exists between the DNA damage response and DNA uptake inH. pylori.[126] This natural competence contributes to the persistence ofH. pylori.H. pylori has much greater rates of recombination and mutation than other bacteria.[3] Genetically different strains can be found in the same host, and also in different regions of the stomach.[129] An overall response to multiple stressors can result from an interaction of the mechanisms.[124]
RuvABC proteins are essential to the process of recombinational repair, since they resolve intermediates in this process termedHolliday 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.[130] Similarly, RecN protein plays an important role in DSB repair.[131] AnH. pylori recN mutant displays an attenuated ability to colonize mouse stomachs, highlighting the importance of recombinational DNA repair in survival ofH. pylori within its host.[131]
An effective sustained colonization response is the formation of abiofilm.Having first adhered to cellular surfaces, the bacteria produce and secreteextracellular polymeric substance (EPS). EPS consists largely ofbiopolymers and provides the framework for the biofilm structure.[90]H. pylori helps the biofilm formation by altering its flagella into adhesive structures that provide adhesion between the cells.[89] Layers of aggregated bacteria as microcolonies accumulate to thicken the biofilm.
The matrix of EPS prevents the entry of antibiotics and immune cells, and provides protection from heat and competition from other microorganisms.[90] Channels form between the cells in the biofilm matrix allowing the transport of nutrients, enzymes, metabolites, and waste.[90] Cells in the deep layers may be nutritionally deprived and enter into the coccoid dormant-like state.[132][133] By changing the shape of the bacterium to a coccoid form, the exposure ofLPS (targeted by antibiotics) becomes limited, and so evades detection by the immune system.[134] It has also been shown that thecag pathogenicity island remains intact in the coccoid form.[134] Some of these antibiotic resistant cells may remain in the host aspersister cells. Following eradication, the persister cells can cause a recurrence of the infection.[132][133] Bacteria can detach from the biofilm to relocate and colonize elsewhere in the stomach to form other biofilms.[90]
Proton-pump inhibitors and antibiotics should be discontinued for at least 30 days prior to testing forH. pylori infection or eradication, as both agents inhibitH. pylori growth and may lead to false negative results.[135] Testing to confirm eradication is recommended 30 days or more after completion of treatment forH. pylori infection.H. pylori breath testing or stool antigen testing are both reasonable tests to confirm eradication.[135]H. pylori serologic testing, includingIgG antibodies, are not recommended as a test of eradication as they may remain elevated for years after successful treatment of infection.[135]
An endoscopic biopsy is an invasive means to test forH. pylori infection. Low-level infections can be missed by biopsy, so multiple samples are recommended. The most accurate method for detectingH. pylori infection is with ahistological examination from two sites after endoscopicbiopsy, combined with either arapid urease test or microbial culture.[137] Generally, repeating endoscopy is not recommended to confirmH. pylori eradication, unless there are specific indications to repeat the procedure.[135]
Helicobacter pylori is contagious, and istransmitted through direct contact either withsaliva (oral-oral) orfeces (fecal–oral route), but mainly through the oral–oral route.[8] Consistent with these transmission routes, the bacteria have been isolated fromfeces,saliva, anddental plaque.[138]H. pylori may also be transmitted by consuming contaminated food or water.[139] Transmission occurs mainly within families in developed nations, but also from the broader community in developing countries.[140]
To prevent the development ofH. pylori-related diseases when infection is suspected, antibiotic-based therapy regimens are recommended toeradicate the bacteria.[46] When successful the disease progression is halted. First line therapy is recommended if low-grade gastric MALT lymphoma is diagnosed, regardless of evidence ofH. pylori. However, if a severe condition of atrophic gastritis with gastric lesions is reached antibiotic-based treatment regimens are not advised since such lesions are often not reversible and will progress to gastric cancer.[46] If the cancer is managed to be treated it is advised that an eradication program be followed to prevent a recurrence of infection, or reduce a recurrence of the cancer, known as metachronous.[46][141][142]
Due toH. pylori's role as a major cause of certain diseases (particularly cancers) and its consistently increasingresistance to antibiotic therapy, there is an obvious need for alternative treatments.[143] A vaccine targeted towards the development of gastric cancer, including MALT lymphoma, would also prevent the development of gastric ulcers.[5] A vaccine that would be prophylactic for use in children, and one that would be therapeutic later are the main goals. Challenges to this are the extreme genomic diversity shown byH. pylori and complex host-immune responses.[143][144]
Previous studies in the Netherlands and in the US have shown that such a prophylactic vaccine programme would be ultimately cost-effective.[145][146] However, 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 againstH. pylori has not been a priority of major pharmaceutical companies.[147] A key target for potential therapy is theproton-gated urea channel, since the secretion of urease enables the survival of the bacterium.[148]
The 2022 Maastricht Consensus Report recognisedH. pylori gastritis asHelicobacter pylori induced gastritis, and has been included inICD11.[44][45][46] Initially the infection tends to be superficial, localised to the upper mucosal layers of the stomach.[149] The intensity of chronic inflammation is related to the cytotoxicity of theH. pylori strain. A greater cytotoxicity will result in the change from a non-atrophic gastritis to an atrophic gastritis, with the loss ofmucous glands. This condition is a prequel to the development of peptic ulcers and gastric adenocarcinoma.[149]
Eradication ofH. pylori is recommended to treat the infection, including when advanced topeptic ulcer disease. The recommendations for first-line treatment is a quadruple therapy consisting of aproton-pump inhibitor,amoxicillin,clarithromycin, andmetronidazole. Prior to treatment, testing is recommended to identify any pre-existing antibiotic resistances. A high rate of resistance to metronidazole has been observed. In areas of known clarithromycin resistance, the first-line therapy is changed to abismuth based regimen includingtetracycline and metronidazole for 14 days. If one of these courses of treatment fails, it is suggested to use the alternative.[44]
Treatment failure may typically be attributed to antibiotic resistance, or inadequate acid suppression from proton-pump inhibitors.[150] Following clinical trials, the use of thepotassium-competitive acid blockervonoprazan, which has a greater acid suppressive action, was approved for use in the US in 2022.[151][150] Its recommended use is in combination with amoxicillin, with or without clarithromycin. It has been shown to have a faster action and can be used with or without food.[150] Successful eradication regimens have revolutionised the treatment of peptic ulcers.[152][153] Eradication ofH. pylori is also associated with a subsequent decreased risk of duodenal or gastric ulcer recurrence.[135]
Plant extracts andprobiotic foods are being increasingly used asadd-ons to usual treatments. Probiotic yogurts containinglactic acid bacteriaBifidobacteria andLactobacillus exert a suppressive effect onH. pylori infection, and their use has been shown to improve the rates of eradication.[14] Some commensal intestinal bacteria as part of thegut microbiota producebutyrate that acts as aprebiotic and enhances the mucosal immune barrier. Their use as probiotics may help balance the gut dysbiosis that accompanies antibiotic use.[154] Some probiotic strains have been shown to have bactericidal and bacteriostatic activity againstH. pylori, and also help to balance the gut dysbiosis.[155][134] Antibiotics have a negative impact on gastrointestinal microbiota and cause nausea, diarrhea, andsickness for which probiotics can alleviate.[134]
Increasingantibiotic resistance is the main cause of initial treatment failure. Factors linked to resistance include mutations,efflux pumps, and the formation ofbiofilms.[156][157] One of the mainantibiotics used in eradication therapies isclarithromycin, but clarithromycin-resistant strains have become well-established and the use of alternative antibiotics needs to be considered. Fortunately, non-invasive stool tests for clarithromycin have become available that allow selection of patients that are likely to respond to the therapy.[158] Multidrug resistance has also increased.[157] Additional rounds of antibiotics or other therapies may be used.[159][160][161]Next generation sequencing is looked to for identifying initial specific antibiotic resistances that will help in targeting more effective treatment.[162]
In 2018, theWHO listedH. pylori as a high priority pathogen for the research anddiscovery of new drugs and treatments.[163] The increasing antibiotic resistance encountered has spurred interest in developing alternative therapies using a number of plant compounds.[164][165] Plant compounds have fewer side effects than synthetic drugs. Most plant extracts contain a complex mix of components that may not act on their own as antimicrobials but can work together with antibiotics to enhance treatment and work towards overcoming resistance.[164] Plant compounds have a different mechanism of action that has proved useful in fighting antimicrobial resistance. For example, various compounds can act by inhibiting enzymes such as urease, and weakening adhesions to the mucous membrane.[166] Sulfur-containing compounds from plants with high concentrations of polysulfides,coumarins, andterpenes have all been shown to be effective againstH. pylori.[164]
H. pylori is found in saliva anddental plaque. Its transmission is known to include oral-oral, suggesting that the dental plaque biofilm may act as a reservoir for the bacteria. Periodontal therapy orscaling and root planing has therefore been suggested as an additional treatment to enhance eradication rates, but more research is needed.[139][167]
Helicobacter pylori is a risk factor forgastric adenocarcinomas.[168] Treatment is highly aggressive, with even localized disease being treated sequentially with chemotherapy and radiotherapy before surgical resection.[169] Since this cancer, once developed, is independent ofH. pylori infection, eradication regimens are not used.[170]
MALT lymphomas aremalignancies ofmucosa-associated lymphoid tissue. Early gastric MALTomas due toH. pylori may be successfully treated (70–95% of cases) with one or moreeradication programs.[14] Some 50–80% of patients who experience eradication of the pathogen develop a remission and long-term clinical control of their lymphoma within 3–28 months.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 withwatchful waiting or, if symptomatic, with theimmunotherapy drugrituximab (given for 4 weeks) combined with thechemotherapy drugchlorambucil 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 drugcyclophosphamide alone.[171] 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's preferred treatment.[172] However, the generally recognized treatment of choice for patients with systemic involvement uses various chemotherapy drugs often combined with rituximab.
A MALT lymphoma may rarely transform into a more aggressivediffuse large B-cell lymphoma (DLBCL).[173] Where this is associated withH. pylori infection, the DLBCL is less aggressive and more amenable to treatment.[174][175][176] When limited to the stomach, they have sometimes been successfully treated withH. pylori eradication programs.[54][175][177][176] If unresponsive or showing a deterioration, a more conventional chemotherapy (CHOP), immunotherapy, or local radiotherapy can be considered, and any of these or a combination have successfully treated these more advanced types.[175][176]
Helicobacter pylori colonizes the stomach for decades in most people, and induces chronic gastritis, a long-lasting inflammation of the stomach. In most cases symptoms are never experienced but about 10–20% of those infected will ultimately develop gastric and duodenal ulcers, and have a possible 1–2% lifetime risk of gastric cancer.[65]
H. pylori thrives in a high salt diet, which is seen as an environmental risk factor for its association with gastric cancer. A diet high in salt enhances colonization, increases inflammation, increases the expression ofH. pylori virulence factors, and intensifies chronic gastritis.[178][179] Paradoxically, extracts ofkimchi, a salted probiotic food, has been found to have a preventive effect onH. pylori–associated gastriccarcinogenesis.[180]
In the absence of treatment,H. pylori infection usually persists for life.[181] Infection may disappear in the elderly as the stomach's mucosa becomes increasingly atrophic and inhospitable to colonization. Some studies in young children up to two years of age have shown that infection can be transient in this age group.[182][183]
It is possible forH. 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). A 2017 meta-analysis showed that 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.[184]
Mounting evidence suggestsH. pylori has an important role in protection from some diseases.[16] The incidence ofacid reflux disease,Barrett's esophagus, andesophageal cancer have been rising dramatically at the same time asH. pylori's presence decreases.[185] In 1996,Martin J. Blaser advanced the hypothesis thatH. pylori has a beneficial effect by regulating the acidity of the stomach contents.[51][185] The hypothesis is not universally accepted, as severalrandomized controlled trials failed to demonstrate worsening of acid reflux disease symptoms following eradication ofH. pylori.[186][187] Nevertheless, Blaser has reasserted his view thatH. pylori is a member of the normalgastric microbiota.[17] He postulates that the changes in gastric physiology caused by the loss ofH. pylori account for the recent increase in incidence of several diseases, includingtype 2 diabetes,obesity, and asthma.[17][188] His group has recently shown thatH. pylori colonization is associated with a lowerincidence of childhood asthma.[189]
In 2023, it was estimated that about two-thirds of the world's population were infected withH. pylori infection, being more common indeveloping countries.[20]H. pylori infection is more prevalent in South America, Sub-Saharan Africa, and the Middle East.[153] The global prevalence declined markedly in the decade following 2010, with a particular reduction in Africa.[21]
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.[181] Infections are usually acquired in early childhood in all countries.[32] However, the infection rate of children in developing nations is higher than inindustrialized 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. The higher prevalence among the elderly reflects higher infection rates incurred in childhood.[32] In the United States, prevalence appears higher inAfrican-American andHispanic populations, most likely due to socioeconomic factors.[190][191] 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 ofH. pylori infection is declining.[192] However, antibiotic resistance is appearing inH. pylori; many metronidazole- and clarithromycin-resistant strains are found in most parts of the world.[193]
Helicobacter pylorimigrated out of Africa along with its human host around 60,000 years ago.[194] Research has shown thatgenetic diversity inH. pylori, like that of its host, decreases with geographic distance fromEast 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 byH. pylori before their migrations out of Africa, and it has remained associated with human hosts since that time.[195]
Before the research of Marshall and Warren, German scientists found spiral-shapedbacteria in the lining of the human stomach in 1875, but they were unable toculture them, and the results were eventually forgotten.[185] The Italian researcherGiulio Bizzozero described similarly shaped bacteria living in the acidic environment of the stomach of dogs in 1893.[197] ProfessorWalery Jaworski of theJagiellonian University inKraków investigated sediments of gastric washings obtained bylavage from humans in 1899. Among some rod-like bacteria, he also found bacteria with a characteristic spiral shape, which he calledVibrio rugula. He was the first to suggest a possible role of this organism in the pathogenesis of gastric diseases. His work was included in theHandbook of Gastric Diseases, but it had little impact, as it was published only in Polish.[198] 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.[199] Interest in the bacteria waned, however, when an American study published in 1954 failed to observe the bacteria in 1180 stomach biopsies.[200]
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.[201] 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 theirPetri dishes incubating for five days over theEaster weekend. In their original paper, Warren and Marshall contended that most stomach ulcers and gastritis were caused by bacterial infection and not bystress orspicy food, as had been assumed before.[202]
Some skepticism was expressed initially, but within a few years multiple research groups had verified the association ofH. pylori with gastritis and, to a lesser extent, ulcers.[203] To demonstrateH. pylori caused gastritis and was not merely a bystander, Marshall drank a beaker ofH. 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 ofH. pylori. These results suggestedH. 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, theNational Institutes of Health stated most recurrent duodenal and gastric ulcers were caused byH. pylori, and recommended antibiotics be included in the treatment regimen.[204]
The bacterium was initially namedCampylobacter pyloridis, then renamedC. pylori in 1987 (pylori being thegenitive ofpylorus, the circular opening leading from the stomach into the duodenum, from theAncient Greek wordπυλωρός, which meansgatekeeper[205]).[206] When16S ribosomal RNAgene sequencing and other research showed in 1989 that the bacterium did not belong in the genusCampylobacter, it was placed in its owngenus,Helicobacter from the Ancient Greekέλιξ (hělix) "spiral" or "coil".[205][207]
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 onH. pylori.[208] The Group is involved with the Annual International Workshop on Helicobacter and Related Bacteria,[209] (renamed as the European Helicobacter and Microbiota Study Group[210]), the Maastricht Consensus Reports (European Consensus on the management ofH. pylori),[211][212][213][214] and other educational and research projects, including two international long-term projects:
European Registry onH. pylori Management (Hp-EuReg) – a database systematically registering the routine clinical practice of European gastroenterologists.[215]
OptimalH. 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 fromUnited European Gastroenterology.[216][217]
The antibiotic resistance provided by biofilms has generated much research into targeting the mechanisms ofquorum sensing used in the formation of biofilms.[88]
A suitable vaccine forH. pylori, either prophylactic or therapeutic, is an ongoing research aim.[8] TheMurdoch 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.[147]
^abLi Y, Choi H, Leung K, Jiang F, Graham DY, Leung WK (19 April 2023). "Global prevalence of Helicobacter pylori infection between 1980 and 2022: a systematic review and meta-analysis".The Lancet Gastroenterology & Hepatology.8 (6):553–564.doi:10.1016/S2468-1253(23)00070-5.PMID37086739.S2CID258272798.
^Dixon MF (February 2000). "Patterns of inflammation linked to ulcer disease".Baillière's Best Practice & Research. Clinical Gastroenterology.14 (1):27–40.doi:10.1053/bega.1999.0057.PMID10749087.
^abRaza Y, Khan A, Farooqui A, Mubarak M, Facista A, Akhtar SS, et al. (October 2014). "Oxidative DNA damage as a potential early biomarker of Helicobacter pylori associated carcinogenesis".Pathology & Oncology Research.20 (4):839–46.doi:10.1007/s12253-014-9762-1.PMID24664859.S2CID18727504.
^Dong YF, Guo T, Yang H, Qian JM, Li JN (February 2019). "[Correlations between gastric Helicobacter pylori infection and colorectal polyps or cancer]".Zhonghua Nei Ke Za Zhi (in Chinese).58 (2):139–142.doi:10.3760/cma.j.issn.0578-1426.2019.02.011.PMID30704201.
^Wu Q, Yang ZP, Xu P, Gao LC, Fan DM (July 2013). "Association between Helicobacter pylori infection and the risk of colorectal neoplasia: a systematic review and meta-analysis".Colorectal Disease.15 (7): e352-64.doi:10.1111/codi.12284.PMID23672575.S2CID5444584.
^abYamaoka Y, Saruuljavkhlan B, Alfaray RI, Linz B (2023). "Pathogenomics of Helicobacter pylori".Helicobacter pylori and Gastric Cancer. Current Topics in Microbiology and Immunology. Vol. 444. pp. 117–155.doi:10.1007/978-3-031-47331-9_5.ISBN978-3-031-47330-2.PMID38231217.
^abcHernández VM, Arteaga A, Dunn MF (November 2021). "Diversity, properties and functions of bacterial arginases".FEMS Microbiol Rev.45 (6).doi:10.1093/femsre/fuab034.PMID34160574.
^Morey P, Pfannkuch L, Pang E, Boccellato F, Sigal M, Imai-Matsushima A, et al. (April 2018). "Helicobacter pylori Depletes Cholesterol in Gastric Glands to Prevent Interferon Gamma Signaling and Escape the Inflammatory Response".Gastroenterology.154 (5): 1391–1404.e9.doi:10.1053/j.gastro.2017.12.008.hdl:21.11116/0000-0001-3B12-9.PMID29273450.
^Watanabe T, Takahashi A, Suzuki K, Kurusu-Kanno M, Yamaguchi K, Fujiki H, et al. (15 May 2014). "Epithelial-mesenchymal transition in human gastric cancer cell lines induced by TNF-α-inducing protein of Helicobacter pylori: Cell migration induced by Tipα of H. pylori".International Journal of Cancer.134 (10):2373–2382.doi:10.1002/ijc.28582.PMID24249671.
^Viala J, Chaput C, Boneca IG, Cardona A, Girardin SE, Moran AP, et al. (November 2004). "Nod1 responds to peptidoglycan delivered by the Helicobacter pylori cag pathogenicity island".Nature Immunology.5 (11):1166–74.doi:10.1038/ni1131.PMID15489856.S2CID2898805.
^Hatakeyama M (September 2004). "Oncogenic mechanisms of the Helicobacter pylori CagA protein".Nature Reviews. Cancer.4 (9):688–94.doi:10.1038/nrc1433.PMID15343275.S2CID1218835.
^Kim W, Moss SF (2008). "The role of Helicobacter pylori in the pathogenesis of gastric malignancies".Oncology Reviews.2 (3):131–140.doi:10.1007/s12156-008-0068-y.
^"UniProt".www.uniprot.org. Retrieved21 March 2024.
^Sajib S, Zahra FT, Lionakis MS, German NA, Mikelis CM (February 2018). "Mechanisms of angiogenesis in microbe-regulated inflammatory and neoplastic conditions".Angiogenesis.21 (1):1–14.doi:10.1007/s10456-017-9583-4.PMID29110215.S2CID3346742.
^Delport W, van der Merwe SW (2007). "The transmission of Helicobacter pylori: the effects of analysis method and study population on inference".Best Practice & Research. Clinical Gastroenterology.21 (2):215–36.doi:10.1016/j.bpg.2006.10.001.hdl:2263/4083.PMID17382274.
^Stenström B, Mendis A, Marshall B (August 2008). "Helicobacter pylori--the latest in diagnosis and treatment".Australian Family Physician.37 (8):608–12.PMID18704207.
^Fischbach L, Evans EL (August 2007). "Meta-analysis: the effect of antibiotic resistance status on the efficacy of triple and quadruple first-line therapies for Helicobacter pylori".Alimentary Pharmacology & Therapeutics (Meta-analysis).26 (3):343–57.doi:10.1111/j.1365-2036.2007.03386.x.PMID17635369.S2CID20973127.
^Moon JK, Kim JR, Ahn YJ, Shibamoto T (June 2010). "Analysis and anti-Helicobacter activity of sulforaphane and related compounds present in broccoli ( Brassica oleracea L.) sprouts".Journal of Agricultural and Food Chemistry.58 (11):6672–7.Bibcode:2010JAFC...58.6672M.doi:10.1021/jf1003573.PMID20459098.
^Sathianarayanan S, Ammanath AV, Biswas R, B A, Sukumaran S, Venkidasamy B (July 2022). "A new approach against Helicobacter pylori using plants and its constituents: A review study".Microb Pathog.168: 105594.doi:10.1016/j.micpath.2022.105594.PMID35605740.S2CID248975163.
^Laird-Fick HS, Saini S, Hillard JR (August 2016). "Gastric adenocarcinoma: the role of Helicobacter pylori in pathogenesis and prevention efforts".Postgraduate Medical Journal.92 (1090):471–7.doi:10.1136/postgradmedj-2016-133997.PMID27222587.S2CID20739020.
^Kobayashi T, Takahashi N, Hagiwara Y, Tamaru J, Kayano H, Jin-nai I, et al. (January 2008). "Successful radiotherapy in a patient with primary rectal mucosa-associated lymphoid tissue lymphoma without the API2-MALT1 fusion gene: a case report and review of the literature".Leukemia Research.32 (1):173–5.doi:10.1016/j.leukres.2007.04.017.PMID17570523.
^Casulo C, Friedberg J (2017). "Transformation of marginal zone lymphoma (and association with other lymphomas)".Best Practice & Research. Clinical Haematology.30 (1–2):131–138.doi:10.1016/j.beha.2016.08.029.PMID28288708.
^Smoak BL, Kelley PW, Taylor DN (March 1994). "Seroprevalence of Helicobacter pylori infections in a cohort of US Army recruits".American Journal of Epidemiology.139 (5):513–9.doi:10.1093/oxfordjournals.aje.a117034.PMID8154475.
^Egan BJ, O'Morain CA (2007). "A historical perspective of Helicobacter gastroduodenitis and its complications".Best Practice & Research. Clinical Gastroenterology.21 (2):335–46.doi:10.1016/j.bpg.2006.12.002.PMID17382281.
^Mégraud F, et al. (European Helicobacter Study Group) (November 2007). "Evolution of Helicobacter pylori research as observed through the workshops of the European Helicobacter Study Group".Helicobacter. 12 Suppl 2 (Suppl 2):1–5.doi:10.1111/j.1523-5378.2007.00581.x.PMID17991169.S2CID45841196.
^"EHMSG".Ehmsg2019.Archived from the original on 11 January 2024. Retrieved11 January 2024.
^Malfertheiner P, Mégraud F, O'Morain C, Hungin AP, Jones R, Axon A, et al. (European Helicobacter Pylori Study Group (EHPSG)) (February 2002). "Current concepts in the management of Helicobacter pylori infection--the Maastricht 2-2000 Consensus Report".Alimentary Pharmacology & Therapeutics.16 (2):167–80.doi:10.1046/j.1365-2036.2002.01169.x.PMID11860399.S2CID6166458.
^Malfertheiner P, Mégraud F, O'Morain C, Bell D, Bianchi Porro G, Deltenre M, et al. (European Helicobacter Pylori Study Group (EHPSG)) (January 1997). "Current European concepts in the management of Helicobacter pylori infection--the Maastricht Consensus Report. The European Helicobacter Pylori Study Group (EHPSG)".European Journal of Gastroenterology & Hepatology.9 (1):1–2.doi:10.1097/00042737-199701000-00002.PMID9031888.S2CID36930542.
^McNicholl AG, Gasbarrini A, Tepes B, et al. (September 2014). "Pan-European registry onH. pylori management (Hp-EuReg): Interim analysis of 5,792 patients".Helicobacter.2014: 69.
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