Helicobacter pylori
Helicobacter pylori, previously known as Campylobacter pylori, is a gram-negative, flagellated, helical bacterium. Mutants can have a rod or curved rod shape that exhibits less virulence. Its helical body is thought to have evolved to penetrate the mucous lining of the stomach, helped by its flagella, and thereby establish infection. While many earlier reports of an association between bacteria and the ulcers had existed, such as the works of John Lykoudis, it was only in 1983 when the bacterium was formally described for the first time in the English-language Western literature as the causal agent of gastric ulcers by Australian physician-scientists Barry Marshall and Robin Warren. In 2005, the pair was awarded the Nobel Prize in Physiology or Medicine for their discovery.
Infection of the stomach with H. pylori does not necessarily cause illness: over half of the global population is infected, but most individuals are asymptomatic. Persistent colonization with more virulent strains can induce a number of gastric and non-gastric disorders. Gastric disorders due to infection begin with gastritis, or inflammation of the stomach lining. When infection is persistent, the prolonged inflammation will become chronic gastritis. Initially, this will be non-atrophic gastritis, but the damage caused to the stomach lining can bring about the development of atrophic gastritis and ulcers within the stomach itself or the duodenum. At this stage, the risk of developing gastric cancer is high. However, the development of a duodenal ulcer confers a comparatively lower risk of cancer. Helicobacter pylori are class 1 carcinogenic bacteria, and potential cancers include gastric MALT lymphoma and gastric cancer. Infection with H. 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. H. pylori is the only bacterium known to cause cancer.
Extragastric complications that have been linked to H. pylori include anemia due either to iron deficiency or vitamin B12 deficiency, diabetes mellitus, cardiovascular illness, and certain neurological disorders. An inverse association has also been claimed with H. pylori having a positive protective effect against asthma, esophageal cancer, inflammatory bowel disease, and others.
Some studies suggest that H. pylori plays an important role in the natural stomach ecology 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 2023, it was estimated that about two-thirds of the world's population was infected with H. pylori, being more common in developing countries. The prevalence has declined in many countries due to eradication treatments with antibiotics and proton-pump inhibitors, and with increased standards of living.
Microbiology
Helicobacter pylori is a species of gram-negative bacteria in the Helicobacter genus.About half the world's population is infected with H. pylori, but only a few strains are pathogenic. H pylori is a helical bacterium having a predominantly helical shape, also often described as having a spiral or S shape. Its helical shape is better suited for progressing through the viscous mucosa lining of the stomach, and is maintained by several enzymes in the cell wall's peptidoglycan. The bacteria reach the less acidic mucosa by use of their flagella. 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. H. pylori can convert from a helical to an inactive coccoid form that can evade the immune system, and that may possibly become viable, known as viable but nonculturable.
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 made by intestinal bacteria.
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. Biofilms hinder the action of antibiotics and can contribute to treatment failure.
To successfully colonize its host, H. pylori uses many different virulence factors including oxidase, catalase, and urease. Urease is the most abundant protein, its expression representing about 10% of the total protein weight.
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. The O-antigen of LPS may be fucosylated and mimic Lewis blood group antigens found on the gastric epithelium.
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 the combined set of 30 sequenced strains, encodes 2,239 protein families. 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.There are eleven restriction modification systems in the genome of H. pylori. This is an unusually high number providing a defence against bacteriophages.
Transcriptome
using single-cell RNA-Seq gave the complete transcriptome of H. pylori which was published in 2010. This analysis of its transcription confirmed the known acid induction of major virulence loci, including the urease operon and the Cag pathogenicity island. A total of 1,907 transcription start sites 337 primary operons, and 126 additional suboperons, and 66 monocistrons were identified. Until 2010, only about 55 transcription start sites were known in this species. 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. About 50% of the 5 UTRs are 20–40 nucleotides in length and support the AAGGag motif located about 6 nt upstream of start codons as the consensus Shine–Dalgarno sequence in H. pylori.Proteome
The proteome of H. pylori has been systematically analyzed, and more than 70% of its proteins have been detected using SILAC. About 50% of the proteome has been quantified, informing of the number of protein copies in a typical cell.Studies of the interactome have identified more than 3000 protein-protein interactions. This has provided information on how proteins interact with each other, either in stable protein complexes or in more dynamic, transient interactions, which can help to identify the functions of the protein. This, in turn, helps research into the functions of uncharacterized proteins, for example when an uncharacterized protein interacts with several proteins of the ribosome, it is likely to also be involved with ribosome function). About a third of all ~1,500 proteins in H. pylori remain uncharacterized and their functions are largely unknown.
Infection
An infection with Helicobacter pylori can either have no symptoms even when lasting a lifetime, or can harm the stomach and duodenal linings by inflammatory responses induced by several mechanisms associated with several virulence factors. Colonization can initially cause H. pylori induced gastritis, an inflammation of the stomach lining that became a listed disease in ICD11. This will progress to chronic gastritis if left untreated. Chronic gastritis may lead to atrophy of the stomach lining, and the development of peptic ulcers. These changes may be seen as stages in the development of gastric cancer, known as Correa's cascade. Extragastric complications that have been linked to H. pylori include anemia due either to iron-deficiency or vitamin B12 deficiency, diabetes mellitus, cardiovascular, and certain neurological disorders.Peptic ulcers are a consequence of inflammation that allows stomach acid and the digestive enzyme pepsin to overwhelm the protective mechanisms of the 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 to avoid the acid-secreting parietal cells at the fundus. 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 lead to the formation of ulcers.
Helicobacter pylori is a class I carcinogen, and potential cancers include gastric mucosa-associated lymphoid tissue lymphomas and gastric cancer. Less commonly, diffuse large B-cell lymphoma of the stomach is a risk. 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. 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-induced gastric cancer is the third highest cause of worldwide cancer mortality as of 2018. 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.
Chronic inflammation that is a feature of cancer development is characterized by infiltration of neutrophils and macrophages to the gastric epithelium, which favors the accumulation of pro-inflammatory cytokines, reactive oxygen species and reactive nitrogen species that cause DNA damage. The oxidative DNA damage and levels of oxidative stress can be indicated by a biomarker, 8-oxo-dG. Other damage to DNA includes double-strand breaks.
Small gastric and colorectal polyps are adenomas that are more commonly found in association with the mucosal damage induced by H. pylori gastritis. Larger polyps can in time become cancerous. A modest association of H. pylori has been made with the development of colorectal cancers, but as of 2020, causality had yet to be proved.