helicobacter pylori helicobacter pylori helicobacter pylori, previously known as campylobacter pylori, is a gram-negative, microaerophilic, spiral (helical) bacterium usually found in the stomach. its helical shape (from which the genus name, helicobacter, derives) is thought to have evolved in order to penetrate the mucoid lining of the stomach and thereby establish infection. the bacterium was first identified in 1982 by the australian doctors barry marshall and robin warren. h. pylori has been associated with cancer of the mucosa-associated lymphoid tissue in the stomach, esophagus, colon, rectum, or tissues around the eye (termed extranodal marginal zone b-cell lymphoma of the cited organ), and of lymphoid tissue in the stomach (termed diffuse large b-cell lymphoma). helicobacter pylori infectionother namesh. pylori infectionimmunohistochemical staining of h. pylori (brown) from a gastric biopsypronunciation/ˈhɛlɪkoʊˌbæktər paɪˈlɔːraɪ, pɪ-, -ri/ specialtyinfectious disease, gastroenterologysymptomshematemesis, melena, abdominal pain, nauseacomplicationsgastritis, stomach ulcer, stomach cancercauseshelicobacter pylori spread by oral–oral and fecal oral routesdiagnostic methodurea breath test, fecal antigen assay, tissue biopsymedicationproton pump inhibitor, clarithromycin, amoxicillin, metronidazolefrequency>50% (2015) h. pylori infection usually has no symptoms but sometimes causes gastritis (stomach inflammation) or ulcers of the stomach or first part of the small intestine. the infection is also associated with the development of certain cancers. many investigators have suggested that h. pylori causes or prevents a wide range of other diseases, but many of these relationships remain controversial. 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. other studies suggest that non-pathogenic strains of h. pylori may beneficially normalize stomach acid secretion, and regulate appetite. in 2015, it was estimated that over 50% of the world's population had h. pylori in their upper gastrointestinal tracts with this infection (or colonization) being more common in developing countries. in recent decades, however, the prevalence of h. pylori colonization of the gastrointestinal tract has declined in many countries. signs and symptoms up to 90% of people infected with h. pylori never experience symptoms or complications. however, individuals infected with h. pylori have a 10% to 20% lifetime risk of developing peptic ulcers. acute infection may appear as an acute gastritis with abdominal pain (stomach ache) or nausea. where this develops into chronic gastritis, the symptoms, if present, are often those of non-ulcer dyspepsia: stomach pains, nausea, bloating, belching, and sometimes vomiting. pain typically occurs when the stomach is empty, between meals, and in the early morning hours, but it can also occur at other times. less common ulcer symptoms 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. individuals infected with h. pylori may also develop colorectal or gastric 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 while colorectal polyps may be the cause of rectal bleeding, anemia, constipation, diarrhea, weight loss, and abdominal pain. individuals with chronic h. pylori infection have an increased risk of acquiring a cancer that is directly related to this infection. these cancers are stomach adenocarcinoma, less commonly diffuse large b-cell lymphoma of the stomach, or extranodal marginal zone b-cell lymphomas of the stomach, or, more rarely, of the colon, rectum, esophagus, or ocular adenexa (i.e. orbit, conjunctiva, and/or eyelids). microbiology helicobacter pylori electron micrograph of h. pylori possessing multiple flagella (negative staining) scientific 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 morphology helicobacter pylori is a helix-shaped (classified as a curved rod, not spirochaete) gram-negative bacterium about 3 μm long with a diameter of about 0.5 μm. h. pylori can be demonstrated in tissue by gram stain, giemsa stain, haematoxylin–eosin stain, warthin-starry silver stain, acridine orange stain, and phase-contrast microscopy. it is capable of forming biofilms and can convert from spiral to a possibly viable but nonculturable coccoid form. helicobacter pylori has four to six flagella at the same location; all gastric and enterohepatic helicobacter species are highly motile owing to flagella. the characteristic sheathed flagellar filaments of helicobacter are composed of two copolymerized flagellins, flaa and flab. 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. it produces oxidase, catalase, and urease. h. pylori possesses five major outer membrane protein families. 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. the outer membrane also contains cholesterol glucosides, which are present in few other bacteria. genome helicobacter pylori consists of a large diversity of strains, and hundreds of genomes have been completely sequenced. the genome of the strain "26695" consists of about 1.7 million base pairs, with some 1,576 genes. the pan-genome, that is a combined set of 30 sequenced strains, encodes 2,239 protein families (orthologous groups, ogs). 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 (i.e., ogs present in only one strain). 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). more importantly, this study identified a total of 1,907 transcriptional start sites, 337 primary operons, and 126 additional suboperons, and 66 monocistrons. until 2010, only about 55 transcriptional 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. 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. genes involved in virulence and pathogenesis study of the h. pylori genome is centered on attempts to understand pathogenesis, the ability of this organism to cause disease. about 29% of the loci have a colonization defect when mutated. two of sequenced strains have an around 40 kb-long cag pathogenicity island (a common gene sequence believed responsible for pathogenesis) that contains over 40 genes. this pathogenicity island is usually absent from h. pylori strains isolated from humans who are carriers of h. pylori, but remain asymptomatic. the caga gene codes for one of the major h. pylori virulence proteins. bacterial strains with the caga gene are associated with an ability to cause ulcers. 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. 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. 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. 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. 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. 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. pathophysiology adaptation to the stomach diagram showing how h. pylori reaches the epithelium of the stomach to avoid the acidic environment of the interior of the stomach (lumen), h. pylori uses its flagella to burrow into the mucus lining of the stomach to reach the epithelial cells underneath, where it is less acidic. h. pylori is able to sense the ph gradient in the mucus and move towards the less acidic region (chemotaxis). this also keeps the bacteria from being swept away into the lumen with the bacteria's mucus environment, which is constantly moving from its site of creation at the epithelium to its dissolution at the lumen interface. h. pylori urease enzyme diagram h. pylori is found in the mucus, on the inner surface of the epithelium, and occasionally inside the epithelial cells themselves. it adheres to the epithelial cells by producing adhesins, which bind to lipids and carbohydrates in the epithelial cell membrane. one such adhesin, baba, binds to the lewis b antigen displayed on the surface of stomach epithelial cells. h. pylori adherence via baba is acid sensitive and can be fully reversed by 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. another such adhesin, saba, binds to increased levels of sialyl-lewis x (slex) antigen expressed on gastric mucosa. in addition to using chemotaxis to avoid areas of low ph, h. pylori also neutralizes the acid in its environment by producing large amounts of urease, 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. urease knockout mutants are incapable of colonization. in fact, urease expression is not only required for establishing initial colonization but also for maintaining chronic infection. adaptation of h. pylori to high acidity of stomach as mentioned above, h. pylori produce large amounts of urease to produce ammonia as one of its adaptation methods to overcome stomach acidity. helicobacter pylori arginase, a bimetallic enzyme binuclear mn2-metalloenzyme arginase, crucial for pathogenesis of the bacterium in human stomach, a member of the ureohydrolase family, catalyzes the conversion of l-arginine to l-ornithine and urea, where ornithine is further converted into polyamines, which are essential for various critical metabolic processes. this provides acid resistance and is thus important for colonization of the bacterium in the gastric epithelial cells. arginase of h. pylori also plays a role in evasion of the pathogen from the host immune system mainly by various proposed mechanisms, arginase competes with host-inducible nitric oxide (no) synthase for the common substrate l-arginine, and thus reduces the synthesis of no, an important component of innate immunity and an effective antimicrobial