agent that is able to kill the invading pathogens directly. alterations in the availability of l-arginine and its metabolism into polyamines contribute significantly to the dysregulation of the host immune response to h. pylori infection. inflammation, gastritis and ulcer 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. cytotoxin associated gene caga can also cause inflammation and is potentially a carcinogen. 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. h. pylori has been shown to increase the levels of cox2 in h. pylori positive gastritis. chronic gastritis is likely to underlie h. pylori-related diseases. ulcers in the stomach and duodenum result when the consequences of inflammation allow stomach acid and the digestive enzyme pepsin to overwhelm the mechanisms that protect 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. 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). g-cells express relatively high levels of pd-l1 that protects these cells from h. pylori-induced immune destruction. 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. gastrin stimulates the parietal cells to secrete more acid into the stomach lumen, and over time increases the number of parietal cells, as well. 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. cag pathogenicity island the pathogenicity 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. 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. 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. 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. 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. 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. a great deal of diversity exists between strains of h. pylori, and the strain that infects a person can predict the outcome. cancer 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", 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. 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. 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. h. pylori is a major source of worldwide cancer mortality. 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. 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. since 1% to 3% of infected individuals are likely to develop gastric cancer, h. pylori-induced gastric cancer is the third highest cause of worldwide cancer mortality as of 2018. infection by h. pylori causes no symptoms in about 80% of those infected. about 75% of individuals infected with h. pylori develop gastritis. thus, the usual consequence of h. pylori infection is chronic asymptomatic gastritis. 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. 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). the substantial presence of ros/rns causes dna damage including 8-oxo-2'-deoxyguanosine (8-ohdg). 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. in addition to the oxidative dna damage 8-ohdg, h. pylori infection causes other characteristic dna damages including dna double-strand breaks. h. pylori also causes many epigenetic alterations linked to cancer development. these epigenetic alterations are due to h. pylori-induced methylation of cpg sites in promoters of genes and h. pylori-induced altered expression of multiple micrornas. as reviewed by santos and ribeiro 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. 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. in addition, as reviewed by raza et al., 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. survival of helicobacter pylori the pathogenesis of h. pylori depends on its ability to survive in the harsh gastric environment characterized by acidity, peristalsis, and attack by phagocytes accompanied by release of reactive oxygen species. in particular, h. pylori elicits an oxidative stress response during host colonization. this oxidative stress response induces potentially lethal and mutagenic oxidative dna adducts in the h. pylori genome. vulnerability to oxidative stress and oxidative dna damage occurs commonly in many studied bacterial pathogens, including neisseria gonorrhoeae, hemophilus influenzae, streptococcus pneumoniae, s. mutans, and h. pylori. for each of these pathogens, surviving the dna damage induced by oxidative stress appears supported by transformation-mediated recombinational repair. thus, transformation and recombinational repair appear to contribute to successful infection. 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. all organisms encode genetic programs for response to stressful conditions including those that cause dna damage. 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, 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. similarly, recn protein plays an important role in dsb repair in h. pylori. 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. 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 disorders of the upper gastrointestinal tract. testing is recommended if peptic ulcer disease or low-grade gastric malt lymphoma (maltoma) is present, after endoscopic resection of early gastric cancer, for first-degree relatives with gastric cancer, and in certain cases of dyspepsia. several methods of testing exist, including invasive and noninvasive testing methods. noninvasive tests for h. pylori infection may be suitable and include blood antibody tests, stool antigen tests, or the carbon urea breath test (in which the patient drinks 14c – or 13c-labelled urea, which the bacterium metabolizes, producing labelled carbon dioxide that can be detected in the breath). it is not known for sure which non-invasive test is more accurate for diagnosing a h. pylori infection but indirect comparison puts urea breath test as a higher accuracy than others. however, after an eradication therapy an immune test will still be positive. therefore a breath test is used for therapy control. 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. transmission helicobacter pylori is contagious, although the exact route of transmission is idiopathic. person-to-person transmission by either the oral–oral (kissing, mouth feeding) or fecal–oral route is most likely. consistent with these transmission routes, the bacteria have been isolated from feces, saliva, and dental plaque of some infected people. findings suggest