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''Helicobacter pylori'', previously known as ''Campylobacter pylori'', is a
gram-negative Gram-negative bacteria are bacteria that do not retain the crystal violet stain used in the Gram staining method of bacterial differentiation. They are characterized by their cell envelopes, which are composed of a thin peptidoglycan cell wa ...
, microaerophilic, spiral (helical) bacterium usually found in the
stomach The stomach is a muscular, hollow organ in the gastrointestinal tract of humans and many other animals, including several invertebrates. The stomach has a dilated structure and functions as a vital organ in the digestive system. The stomach i ...
. Its helical shape (from which the
genus Genus ( plural genera ) is a taxonomic rank used in the biological classification of living and fossil organisms as well as viruses. In the hierarchy of biological classification, genus comes above species and below family. In binomial nom ...
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 John Robin Warren (born 11 June 1937, in Adelaide) is an Australian pathologist, Nobel Laureate and researcher who is credited with the 1979 re-discovery of the bacterium '' Helicobacter pylori'', together with Barry Marshall. The duo proved ...
. ''H. pylori'' has been associated with
cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
of the
mucosa-associated lymphoid tissue The mucosa-associated lymphoid tissue (MALT), also called mucosa-associated lymphatic tissue, is a diffuse system of small concentrations of lymphoid tissue found in various submucosal membrane sites of the body, such as the gastrointestinal tr ...
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 Diffuse large B-cell lymphoma (DLBCL) is a cancer of B cells, a type of lymphocyte that is responsible for producing antibodies. It is the most common form of non-Hodgkin lymphoma among adults, with an annual incidence of 7–8 cases per 100,00 ...
). ''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 tract The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans and ...
s with this infection (or
colonization Colonization, or colonisation, constitutes large-scale population movements wherein migrants maintain strong links with their, or their ancestors', former country – by such links, gain advantage over other inhabitants of the territory. When ...
) being more common in
developing countries A developing country is a sovereign state with a lesser developed industrial base and a lower Human Development Index (HDI) relative to other countries. However, this definition is not universally agreed upon. There is also no clear agreem ...
. 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 Acute may refer to: Science and technology * Acute angle ** Acute triangle ** Acute, a leaf shape in the glossary of leaf morphology * Acute (medicine), a disease that it is of short duration and of recent onset. ** Acute toxicity, the adverse ef ...
infection may appear as an acute gastritis with
abdominal pain Abdominal pain, also known as a stomach ache, is a symptom associated with both non-serious and serious medical issues. Common causes of pain in the abdomen include gastroenteritis and irritable bowel syndrome. About 15% of people have a m ...
(stomach ache) or
nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of th ...
. 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 Vomiting (also known as emesis and throwing up) is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be the result of ailments like food poisoning, gastroenter ...
. 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 Haematochezia is the passage of fresh blood through the anus path, usually in or with stools (contrast with melena). The term is from Greek αἷμα ("blood") and χέζειν ("to defaecate"). Hematochezia is commonly associated with lower gastro ...
, or
melena Melena or melaena refers to the dark black, tarry feces that are associated with upper gastrointestinal bleeding. The black color and characteristic strong odor are caused by hemoglobin in the blood being altered by digestive enzymes and intest ...
may occur. Inflammation of the pyloric antrum, which connects the stomach to the
duodenum The duodenum is the first section of the small intestine in most higher vertebrates, including mammals, reptiles, and birds. In fish, the divisions of the small intestine are not as clear, and the terms anterior intestine or proximal intestine m ...
, 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 membrane A mucous membrane or mucosa is a membrane that lines various cavities in the body of an organism and covers the surface of internal organs. It consists of one or more layers of epithelial cells overlying a layer of loose connective tissue. It i ...
s 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 Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
that is directly related to this infection. These cancers are stomach adenocarcinoma, less commonly
diffuse large B-cell lymphoma Diffuse large B-cell lymphoma (DLBCL) is a cancer of B cells, a type of lymphocyte that is responsible for producing antibodies. It is the most common form of non-Hodgkin lymphoma among adults, with an annual incidence of 7–8 cases per 100,00 ...
of the stomach, or extranodal marginal zone B-cell lymphomas of the
stomach The stomach is a muscular, hollow organ in the gastrointestinal tract of humans and many other animals, including several invertebrates. The stomach has a dilated structure and functions as a vital organ in the digestive system. The stomach i ...
, or, more rarely, of the colon,
rectum The rectum is the final straight portion of the large intestine in humans and some other mammals, and the gut in others. The adult human rectum is about long, and begins at the rectosigmoid junction (the end of the sigmoid colon) at the l ...
,
esophagus The esophagus (American English) or oesophagus (British English; both ), non-technically known also as the food pipe or gullet, is an organ in vertebrates through which food passes, aided by peristaltic contractions, from the pharynx to t ...
, or ocular adenexa (i.e.
orbit In celestial mechanics, an orbit is the curved trajectory of an object such as the trajectory of a planet around a star, or of a natural satellite around a planet, or of an artificial satellite around an object or position in space such as ...
,
conjunctiva The conjunctiva is a thin mucous membrane that lines the inside of the eyelids and covers the sclera (the white of the eye). It is composed of non-keratinized, stratified squamous epithelium with goblet cells, stratified columnar epithel ...
, and/or
eyelid An eyelid is a thin fold of skin that covers and protects an eye. The levator palpebrae superioris muscle retracts the eyelid, exposing the cornea to the outside, giving vision. This can be either voluntarily or involuntarily. The human eye ...
s). The signs, symptoms, pathophysiology, and diagnoses of these cancers are given in the cited linkages.


Microbiology


Morphology

''Helicobacter pylori'' is a
helix A helix () is a shape like a corkscrew or spiral staircase. It is a type of smooth space curve with tangent lines at a constant angle to a fixed axis. Helices are important in biology, as the DNA molecule is formed as two intertwined helic ...
-shaped (classified as a curved rod, not spirochaete)
Gram-negative Gram-negative bacteria are bacteria that do not retain the crystal violet stain used in the Gram staining method of bacterial differentiation. They are characterized by their cell envelopes, which are composed of a thin peptidoglycan cell wa ...
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
biofilm A biofilm comprises any syntrophic consortium of microorganisms in which cells stick to each other and often also to a surface. These adherent cells become embedded within a slimy extracellular matrix that is composed of extracellular po ...
s and can convert from spiral to a possibly
viable but nonculturable Viable but nonculturable (VBNC) bacteria refers as to bacteria that are in a state of very low metabolic activity and do not divide, but are alive and have the ability to become culturable once resuscitated. Bacteria in a VBNC state cannot grow on ...
coccoid form. ''Helicobacter pylori'' has four to six
flagella A flagellum (; ) is a hairlike appendage that protrudes from certain plant and animal sperm cells, and from a wide range of microorganisms to provide motility. Many protists with flagella are termed as flagellates. A microorganism may have fro ...
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 Oxygen is the chemical element with the symbol O and atomic number 8. It is a member of the chalcogen group in the periodic table, a highly reactive nonmetal, and an oxidizing agent that readily forms oxides with most elements ...
, but at lower concentration than in the
atmosphere An atmosphere () is a layer of gas or layers of gases that envelop a planet, and is held in place by the gravity of the planetary body. A planet retains an atmosphere when the gravity is great and the temperature of the atmosphere is low. A ...
. It contains a hydrogenase that can produce energy by oxidizing molecular
hydrogen Hydrogen is the chemical element with the symbol H and atomic number 1. Hydrogen is the lightest element. At standard conditions hydrogen is a gas of diatomic molecules having the formula . It is colorless, odorless, tasteless, non-to ...
(H2) made by
intestinal bacteria Gut microbiota, gut microbiome, or gut flora, are the microorganisms, including bacteria, archaea, fungi, and viruses that live in the digestive tracts of animals. The gastrointestinal metagenome is the aggregate of all the genomes of the ...
. It produces oxidase,
catalase Catalase is a common enzyme found in nearly all living organisms exposed to oxygen (such as bacteria, plants, and animals) which catalyzes the decomposition of hydrogen peroxide to water and oxygen. It is a very important enzyme in protecting t ...
, and
urease Ureases (), functionally, belong to the superfamily of amidohydrolases and phosphotriesterases. Ureases are found in numerous bacteria, fungi, algae, plants, and some invertebrates, as well as in soils, as a soil enzyme. They are nickel-contai ...
. ''H. pylori'' possesses five major outer membrane protein families. The largest family includes known and putative
adhesins Adhesins are cell-surface components or appendages of bacteria that facilitate adhesion or adherence to other cells or to surfaces, usually in the host they are infecting or living in. Adhesins are a type of virulence factor. Adherence is an essent ...
. The other four families are porins, iron transporters,
flagellum A flagellum (; ) is a hairlike appendage that protrudes from certain plant and animal sperm cells, and from a wide range of microorganisms to provide motility. Many protists with flagella are termed as flagellates. A microorganism may have f ...
-associated proteins, and proteins of unknown function. Like other typical Gram-negative bacteria, the outer membrane of ''H. pylori'' consists of
phospholipids Phospholipids, are a class of lipids whose molecule has a hydrophilic "head" containing a phosphate group and two hydrophobic "tails" derived from fatty acids, joined by an alcohol residue (usually a glycerol molecule). Marine phospholipids ...
and
lipopolysaccharide Lipopolysaccharides (LPS) are large molecules consisting of a lipid and a polysaccharide that are bacterial toxins. They are composed of an O- antigen, an outer core, and an inner core all joined by a covalent bond, and are found in the out ...
(LPS). The
O antigen Lipopolysaccharides (LPS) are large molecules consisting of a lipid and a polysaccharide that are bacterial toxins. They are composed of an O-antigen, an outer core, and an inner core all joined by a covalent bond, and are found in the outer ...
of LPS may be fucosylated and mimic Lewis blood group antigens found on the gastric epithelium. The outer membrane also contains
cholesterol Cholesterol is any of a class of certain organic molecules called lipids. It is a sterol (or modified steroid), a type of lipid. Cholesterol is biosynthesized by all animal cells and is an essential structural component of animal cell memb ...
glucosides, which are present in few other bacteria.


Genome

''Helicobacter pylori'' consists of a large diversity of strains, and hundreds of
genome In the fields of molecular biology and genetics, a genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding ...
s have been completely sequenced. The genome of the strain "26695" consists of about 1.7 million
base pair A base pair (bp) is a fundamental unit of double-stranded nucleic acids consisting of two nucleobases bound to each other by hydrogen bonds. They form the building blocks of the DNA double helix and contribute to the folded structure of both D ...
s, 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 Nucleotides are organic molecules consisting of a nucleoside and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecu ...
resolution by differential
RNA-seq RNA-Seq (named as an abbreviation of RNA sequencing) is a sequencing technique which uses next-generation sequencing (NGS) to reveal the presence and quantity of RNA in a biological sample at a given moment, analyzing the continuously changing ...
that confirmed the known acid induction of major
virulence Virulence is a pathogen's or microorganism's ability to cause damage to a host. In most, especially in animal systems, virulence refers to the degree of damage caused by a microbe to its host. The pathogenicity of an organism—its ability to ...
loci, such as the
urease Ureases (), functionally, belong to the superfamily of amidohydrolases and phosphotriesterases. Ureases are found in numerous bacteria, fungi, algae, plants, and some invertebrates, as well as in soils, as a soil enzyme. They are nickel-contai ...
(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 mono cistrons. 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 frame In molecular biology, open reading frames (ORFs) are defined as spans of DNA sequence between the start and stop codons. Usually, this is considered within a studied region of a prokaryotic DNA sequence, where only one of the six possible readi ...
s, 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 In biology, an organism () is any living system that functions as an individual entity. All organisms are composed of cells ( cell theory). Organisms are classified by taxonomy into groups such as multicellular animals, plants, and fu ...
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 Pathogenicity islands (PAIs), as termed in 1990, are a distinct class of genomic islands acquired by microorganisms through horizontal gene transfer. Pathogenicity islands are found in both animal and plant pathogens. Additionally, PAIs are found i ...
(a common
gene sequence In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
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 In medicine, any disease is classified asymptomatic if a patient tests as carrier for a disease or infection but experiences no symptoms. Whenever a medical condition fails to show noticeable symptoms after a diagnosis it might be considered a ...
. The '' cagA'' gene codes for one of the major ''H. pylori''
virulence Virulence is a pathogen's or microorganism's ability to cause damage to a host. In most, especially in animal systems, virulence refers to the degree of damage caused by a microbe to its host. The pathogenicity of an organism—its ability to ...
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 Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ...
) 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 In molecular biology and genetics, GC-content (or guanine-cytosine content) is the percentage of nitrogenous bases in a DNA or RNA molecule that are either guanine (G) or cytosine (C). This measure indicates the proportion of G and C bases out ...
of the ''cag'' PAI relative to the rest of the ''Helicobacter'' genome suggests the island was acquired by
horizontal transfer Horizontal gene transfer (HGT) or lateral gene transfer (LGT) is the movement of genetic material between unicellular and/or multicellular organisms other than by the ("vertical") transmission of DNA from parent to offspring (reproduction). HG ...
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'' () 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 Mucolipin-1 also known as TRPML1 (transient receptor potential cation channel, mucolipin subfamily, member 1) is a protein that in humans is encoded by the ''MCOLN1'' gene. It is a member of the small family of the TRPML channels, a subgroup of ...
.


Proteome

The
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
s 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 Mass spectrometry (MS) is an analytical technique that is used to measure the mass-to-charge ratio of ions. The results are presented as a '' mass spectrum'', a plot of intensity as a function of the mass-to-charge ratio. Mass spectrometry is u ...
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 complex A protein complex or multiprotein complex is a group of two or more associated polypeptide chains. Protein complexes are distinct from multienzyme complexes, in which multiple catalytic domains are found in a single polypeptide chain. Protein ...
es 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 Ribosomes ( ) are macromolecular machines, found within all cells, that perform biological protein synthesis (mRNA translation). Ribosomes link amino acids together in the order specified by the codons of messenger RNA (mRNA) molecules to fo ...
(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

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 Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercellu ...
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 Chemotaxis (from '' chemo-'' + '' taxis'') is the movement of an organism or entity in response to a chemical stimulus. Somatic cells, bacteria, and other single-cell or multicellular organisms direct their movements according to certain chemica ...
). 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'' 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 Adhesins are cell-surface components or appendages of bacteria that facilitate adhesion or adherence to other cells or to surfaces, usually in the host they are infecting or living in. Adhesins are a type of virulence factor. Adherence is an essent ...
, which bind to lipids and carbohydrates in the epithelial
cell membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment (t ...
. 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 Ureases (), functionally, belong to the superfamily of amidohydrolases and phosphotriesterases. Ureases are found in numerous bacteria, fungi, algae, plants, and some invertebrates, as well as in soils, as a soil enzyme. They are nickel-contai ...
, which breaks down the urea present in the stomach to
carbon dioxide Carbon dioxide ( chemical formula ) is a chemical compound made up of molecules that each have one carbon atom covalently double bonded to two oxygen atoms. It is found in the gas state at room temperature. In the air, carbon dioxide is t ...
and
ammonia Ammonia is an inorganic compound of nitrogen and hydrogen with the formula . A stable binary hydride, and the simplest pnictogen hydride, ammonia is a colourless gas with a distinct pungent smell. Biologically, it is a common nitrogenous ...
. 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 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 A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalyzes (increases reaction rate or "speeds up") proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the for ...
, vacuolating cytotoxin A (VacA) (this damages epithelial cells, disrupts tight junctions and causes
apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes ( morphology) and death. These changes in ...
), 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 cell In anatomy, the G cell or gastrin cell, is a type of cell in the stomach and duodenum that secretes gastrin. It works in conjunction with gastric chief cells and parietal cells. G cells are found deep within the pyloric glands of the stomach antru ...
s in the antrum to secrete the hormone
gastrin Gastrin is a peptide hormone that stimulates secretion of gastric acid (HCl) by the parietal cells of the stomach and aids in gastric motility. It is released by G cells in the pyloric antrum of the stomach, duodenum, and the pancreas. Gast ...
, 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 Atrophy is the partial or complete wasting away of a part of the body. Causes of atrophy include mutations (which can destroy the gene to build up the organ), poor nourishment, poor circulation, loss of hormonal support, loss of nerve supply ...
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 Pathogenicity islands (PAIs), as termed in 1990, are a distinct class of genomic islands acquired by microorganisms through horizontal gene transfer. Pathogenicity islands are found in both animal and plant pathogens. Additionally, PAIs are found i ...
; 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 The bacterial type IV secretion system, also known as the type IV secretion system or the T4SS, is a secretion protein complex found in gram negative bacteria, gram positive bacteria, and archaea. It is able to transport proteins and DNA across ...
expressed by the ''cag'' PAI "injects" the
inflammation Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molec ...
-inducing agent,
peptidoglycan Peptidoglycan or murein is a unique large macromolecule, a polysaccharide, consisting of sugars and amino acids that forms a mesh-like peptidoglycan layer outside the plasma membrane, the rigid cell wall (murein sacculus) characteristic of most ba ...
, from their own
cell wall A cell wall is a structural layer surrounding some types of cells, just outside the cell membrane. It can be tough, flexible, and sometimes rigid. It provides the cell with both structural support and protection, and also acts as a filtering mec ...
s into the epithelial cells. The injected peptidoglycan is recognized by the cytoplasmic
pattern recognition receptor Pattern recognition receptors (PRRs) play a crucial role in the proper function of the innate immune system. PRRs are germline-encoded host sensors, which detect molecules typical for the pathogens. They are proteins expressed, mainly, by cells of ...
(immune sensor) Nod1, which then stimulates expression of
cytokines Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...
that promote
inflammation Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molec ...
. The type-IV
secretion 440px Secretion is the movement of material from one point to another, such as a secreted chemical substance from a cell or gland. In contrast, excretion is the removal of certain substances or waste products from a cell or organism. The classic ...
apparatus also injects the ''cag'' PAI-encoded protein CagA into the stomach's epithelial cells, where it disrupts the
cytoskeleton The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is co ...
, adherence to adjacent cells, intracellular signaling,
cell polarity Cell polarity refers to spatial differences in shape, structure, and function within a cell. Almost all cell types exhibit some form of polarity, which enables them to carry out specialized functions. Classical examples of polarized cells are des ...
, and other cellular activities. Once inside the cell, the CagA protein is phosphorylated on tyrosine residues by a host cell membrane-associated
tyrosine kinase A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to the tyrosine residues of specific proteins inside a cell. It functions as an "on" or "off" switch in many cellular functions. Tyrosine kinases belong to a larger cla ...
(TK). CagA then allosterically activates protein tyrosine phosphatase/ protooncogene
Shp2 Tyrosine-protein phosphatase non-receptor type 11 (PTPN11) also known as protein-tyrosine phosphatase 1D (PTP-1D), Src homology region 2 domain-containing phosphatase-2 (SHP-2), or protein-tyrosine phosphatase 2C (PTP-2C) is an enzyme that in hum ...
. Pathogenic strains of ''H. pylori'' have been shown to activate the
epidermal growth factor receptor The epidermal growth factor receptor (EGFR; ErbB-1; HER1 in humans) is a transmembrane protein that is a receptor for members of the epidermal growth factor family (EGF family) of extracellular protein ligands. The epidermal growth factor re ...
(EGFR), a
membrane protein Membrane proteins are common proteins that are part of, or interact with, biological membranes. Membrane proteins fall into several broad categories depending on their location. Integral membrane proteins are a permanent part of a cell membrane ...
with a TK
domain Domain may refer to: Mathematics *Domain of a function, the set of input values for which the (total) function is defined ** Domain of definition of a partial function ** Natural domain of a partial function **Domain of holomorphy of a function * ...
. Activation of the EGFR by ''H. pylori'' is associated with altered
signal transduction Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately results in a cellula ...
and
gene expression Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product that enables it to produce end products, protein or non-coding RNA, and ultimately affect a phenotype, as the final effect. T ...
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 Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
are under investigation. One mechanism involves the enhanced production of
free radical A daughter category of ''Ageing'', this category deals only with the biological aspects of ageing. Ageing Ailments of unknown cause Biogerontology Biological processes Causes of death Cellular processes Gerontology Life extension Metabo ...
s near ''H. pylori'' and an increased rate of host cell
mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, m ...
. 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 Adhesion is the tendency of dissimilar particles or surfaces to cling to one another ( cohesion refers to the tendency of similar or identical particles/surfaces to cling to one another). The forces that cause adhesion and cohesion can ...
proteins. ''H. pylori'' has been proposed to induce
inflammation Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molec ...
and locally high levels of TNF-α and/or
interleukin 6 Interleukin 6 (IL-6) is an interleukin that acts as both a pro-inflammatory cytokine and an anti-inflammatory myokine. In humans, it is encoded by the ''IL6'' gene. In addition, osteoblasts secrete IL-6 to stimulate osteoclast formation. Smooth ...
(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 gene A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results in a loss or re ...
s, 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
macrophage Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer ce ...
s 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 Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molec ...
, characterized by infiltration of
neutrophil Neutrophils (also known as neutrocytes or heterophils) are the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying ...
s and
macrophage Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer ce ...
s to the gastric epithelium, which favors the accumulation of pro-inflammatory cytokines and
reactive oxygen species In chemistry, reactive oxygen species (ROS) are highly reactive chemicals formed from diatomic oxygen (). Examples of ROS include peroxides, superoxide, hydroxyl radical, singlet oxygen, and alpha-oxygen. The reduction of molecular oxygen () p ...
/ 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 DNA oxidation is the process of oxidative damage of deoxyribonucleic acid. As described in detail by Burrows et al., 8-oxo-2'-deoxyguanosine (8-oxo-dG) is the most common oxidative lesion observed in duplex DNA because guanine has a lower one-el ...
8-OHdG, ''H. pylori'' infection causes other characteristic DNA damages including DNA double-strand breaks. ''H. pylori'' also causes many
epigenetic In biology, epigenetics is the study of stable phenotypic changes (known as ''marks'') that do not involve alterations in the DNA sequence. The Greek prefix '' epi-'' ( "over, outside of, around") in ''epigenetics'' implies features that are ...
alterations linked to cancer development. These
epigenetic In biology, epigenetics is the study of stable phenotypic changes (known as ''marks'') that do not involve alterations in the DNA sequence. The Greek prefix '' epi-'' ( "over, outside of, around") in ''epigenetics'' implies features that are ...
alterations are due to ''H. pylori''-induced methylation of CpG sites in promoters of genes and ''H. pylori''-induced altered expression of multiple
microRNA MicroRNA (miRNA) are small, single-stranded, non-coding RNA molecules containing 21 to 23 nucleotides. Found in plants, animals and some viruses, miRNAs are involved in RNA silencing and post-transcriptional regulation of gene expression. mi ...
s. 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 Mismatch repair endonuclease PMS2 is an enzyme that in humans is encoded by the ''PMS2'' gene. Function This gene is one of the PMS2 gene family members which are found in clusters on chromosome 7. Human PMS2 related genes are located at band ...
, 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 DNA mismatch repair protein Mlh1 or MutL protein homolog 1 is a protein that in humans is encoded by the MLH1 gene located on chromosome 3. It is a gene commonly associated with hereditary nonpolyposis colorectal cancer. Orthologs of human MLH ...
,
MGMT MGMT () is an American indie rock band formed in 2002 in Middletown, Connecticut. It was founded by multi-instrumentalists Andrew VanWyngarden and Ben Goldwasser. Alongside VanWyngarden and Goldwasser, MGMT's live lineup currently consists o ...
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

Colonization with ''H. pylori'' is not a disease in itself, but a condition associated with a number of disorders of the
upper gastrointestinal tract The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans an ...
. Testing is recommended if
peptic ulcer disease Peptic ulcer disease (PUD) is a break in the inner lining of the stomach, the first part of the small intestine, or sometimes the lower esophagus. An ulcer in the stomach is called a gastric ulcer, while one in the first part of the intestines ...
or low-grade gastric MALT lymphoma (MALToma) is present, after
endoscopic An endoscopy is a procedure used in medicine to look inside the body. The endoscopy procedure uses an endoscope to examine the interior of a hollow organ or cavity of the body. Unlike many other medical imaging techniques, endoscopes are inse ...
resection of early
gastric cancer Stomach cancer, also known as gastric cancer, is a cancer that develops from the lining of the stomach. Most cases of stomach cancers are gastric carcinomas, which can be divided into a number of subtypes, including gastric adenocarcinomas. Lym ...
, 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 Blood is a body fluid in the circulatory system of humans and other vertebrates that delivers necessary substances such as nutrients and oxygen to the cells, and transports metabolic waste products away from those same cells. Blood in the cir ...
antibody An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of t ...
tests, stool
antigen In immunology, an antigen (Ag) is a molecule or molecular structure or any foreign particulate matter or a pollen grain that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune respon ...
tests Test(s), testing, or TEST may refer to: * Test (assessment), an educational assessment intended to measure the respondents' knowledge or other abilities Arts and entertainment * ''Test'' (2013 film), an American film * ''Test'' (2014 film), ...
, or the carbon urea breath test (in which the patient drinks 14C – or 13C-labelled
urea Urea, also known as carbamide, is an organic compound with chemical formula . This amide has two amino groups (–) joined by a carbonyl functional group (–C(=O)–). It is thus the simplest amide of carbamic acid. Urea serves an important ...
, which the bacterium metabolizes, producing labelled
carbon dioxide Carbon dioxide ( chemical formula ) is a chemical compound made up of molecules that each have one carbon atom covalently double bonded to two oxygen atoms. It is found in the gas state at room temperature. In the air, carbon dioxide is t ...
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. 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 A biopsy is a medical test commonly performed by a surgeon, interventional radiologist, or an interventional cardiologist. The process involves extraction of sample cells or tissues for examination to determine the presence or extent of a dise ...
, combined with either a rapid urease test or microbial culture.


Transmission

''Helicobacter pylori'' is contagious, although the exact route of transmission is not known. Person-to-person transmission by either the oral–oral (kissing, mouth feeding) or
fecal–oral route The fecal–oral route (also called the oral–fecal route or orofecal route) describes a particular route of transmission of a disease wherein pathogens in fecal particles pass from one person to the mouth of another person. Main causes of fec ...
is most likely. Consistent with these transmission routes, the bacteria have been isolated from
feces Feces ( or faeces), known colloquially and in slang as poo and poop, are the solid or semi-solid remains of food that was not digested in the small intestine, and has been broken down by bacteria in the large intestine. Feces contain a rela ...
,
saliva Saliva (commonly referred to as spit) is an extracellular fluid produced and secreted by salivary glands in the mouth. In humans, saliva is around 99% water, plus electrolytes, mucus, white blood cells, epithelial cells (from which DNA can ...
, and
dental plaque Dental plaque is a biofilm of microorganisms (mostly bacteria, but also fungi) that grows on surfaces within the mouth. It is a sticky colorless deposit at first, but when it forms tartar, it is often brown or pale yellow. It is commonly found be ...
of some infected people. Findings suggest ''H. pylori'' is more easily transmitted by gastric mucus than saliva. Transmission occurs mainly within families in developed nations, yet can also be acquired from the community in developing countries. ''H. pylori'' may also be transmitted orally by means of fecal matter through the ingestion of waste-tainted water, so a hygienic environment could help decrease the risk of ''H. pylori'' infection.


Prevention

Due to ''H. pylori'' role as a major cause of certain diseases (particularly cancers) and its consistently increasing
antibiotic resistance Antimicrobial resistance (AMR) occurs when microbes evolve mechanisms that protect them from the effects of antimicrobials. All classes of microbes can evolve resistance. Fungi evolve antifungal resistance. Viruses evolve antiviral resistance. ...
, there is a clear need for new therapeutic strategies to prevent or remove the bacterium from colonizing humans. Much work has been done on developing viable
vaccine A vaccine is a biological preparation that provides active acquired immunity to a particular infectious or malignant disease. The safety and effectiveness of vaccines has been widely studied and verified.
s aimed at providing an alternative strategy to control ''H. pylori'' infection and related diseases. Researchers are studying different
adjuvant In pharmacology, an adjuvant is a drug or other substance, or a combination of substances, that is used to increase the efficacy or potency of certain drugs. Specifically, the term can refer to: * Adjuvant therapy in cancer management * Analgesi ...
s,
antigens In immunology, an antigen (Ag) is a molecule or molecular structure or any foreign particulate matter or a pollen grain that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response. ...
, and routes of immunization to ascertain the most appropriate system of immune protection; however, most of the research only recently moved from animal to human trials. An economic evaluation of the use of a potential ''H. pylori'' vaccine in babies found its introduction could, at least in the Netherlands, prove cost-effective for the prevention of peptic ulcer and stomach adenocarcinoma. A similar approach has also been studied for the United States. Notwithstanding this proof-of-concept (i.e. vaccination protects children from acquisition of infection with ''H. pylori''), as of late 2019 there have been no advanced vaccine candidates and only one vaccine in a Phase I clinical trial. Furthermore, development of a vaccine against ''H. pylori'' has not been a current priority of major pharmaceutical companies. Many investigations have attempted to prevent the development of ''Helicobacter pylori''-related diseases by eradicating the bacterium during the early stages of its infestation using antibiotic-based drug regimens. Studies find that such treatments, when effectively eradicating ''H. pylori'' from the stomach, reduce the inflammation and some of the histopathological abnormalities associated with the infestation. However studies disagree on the ability of these treatments to alleviate the more serious histopathological abnormalities in ''H. pylori'' infections, e.g. gastric atrophy and metaplasia, both of which are precursors to gastric adenocarcinoma. There is similar disagreement on the ability of antibiotic-based regiments to prevent gastric adenocarcinoma. A meta-analysis (i.e. a statistical analysis that combines the results of multiple
randomized controlled trial A randomized controlled trial (or randomized control trial; RCT) is a form of scientific experiment used to control factors not under direct experimental control. Examples of RCTs are clinical trials that compare the effects of drugs, surgical t ...
s) published in 2014 found that these regimens did not appear to prevent development of this adenocarcinoma. However, two subsequent
prospective cohort studies A prospective cohort study is a longitudinal cohort study that follows over time a group of similar individuals (cohorts) who differ with respect to certain factors under study, to determine how these factors affect rates of a certain outcome. F ...
conducted on high-risk individuals in China and Taiwan found that eradication of the bacterium produced a significant decrease in the number of individuals developing the disease. These results agreed with a retrospective cohort study done in Japan and published in 2016 as well as a
meta-analysis A meta-analysis is a statistical analysis that combines the results of multiple scientific studies. Meta-analyses can be performed when there are multiple scientific studies addressing the same question, with each individual study reporting m ...
, also published in 2016, of 24 studies conducted on individuals with varying levels of risk for developing the disease. These more recent studies suggest that the eradication of ''H. pylori'' infection reduces the incidence of ''H. pylori''-related gastric adenocarcinoma in individuals at all levels of baseline risk. Further studies will be required to clarify this issue. In all events, studies agree that antibiotic-based regimens effectively reduce the occurrence of metachronous ''H. pylori''-associated gastric adenocarcinoma. (Metachronous cancers are cancers that reoccur 6 months or later after resection of the original cancer.) It is suggested that antibiotic-based drug regimens be used after resecting ''H. pylori''-associated gastric adenocarcinoma in order to reduce its metachronus reoccurrence.


Treatment


Gastritis

Superficial gastritis, either acute or chronic, is the most common manifestation of ''H. pylori'' infection. The signs and symptoms of this gastritis have been found to remit spontaneously in many individuals without resorting to ''Helicobacter pylori'' eradication protocols. The ''H. pylori'' bacterial infection persists after remission in these cases. Various
antibiotic An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and prevention ...
plus proton pump inhibitor drug regimens are used to eradicate the bacterium and thereby successfully treat the disorder with triple-drug therapy consisting of clarithromycin,
amoxicillin Amoxicillin is an antibiotic medication used to treat a number of bacterial infections. These include middle ear infection, strep throat, pneumonia, skin infections, and urinary tract infections among others. It is taken by mouth, or less c ...
, and a proton-pump inhibitor given for 14–21 days often being considered first line treatment.


Peptic ulcers

Once ''H. pylori'' is detected in a person with a peptic ulcer, the normal procedure is to eradicate it and allow the ulcer to heal. The standard first-line therapy is a one-week "triple therapy" consisting of
proton-pump inhibitor Proton-pump inhibitors (PPIs) are a class of medications that cause a profound and prolonged reduction of stomach acid production. They do so by irreversibly inhibiting the stomach's H+/K+ ATPase proton pump. They are the most potent inhibitor ...
s such as omeprazole and the antibiotics clarithromycin and
amoxicillin Amoxicillin is an antibiotic medication used to treat a number of bacterial infections. These include middle ear infection, strep throat, pneumonia, skin infections, and urinary tract infections among others. It is taken by mouth, or less c ...
. (The actions of proton pump inhibitors against H. pylori may reflect their direct bacteriostatic effect due to inhibition of the bacterium's P-type ATPase and/or
urease Ureases (), functionally, belong to the superfamily of amidohydrolases and phosphotriesterases. Ureases are found in numerous bacteria, fungi, algae, plants, and some invertebrates, as well as in soils, as a soil enzyme. They are nickel-contai ...
.) Variations of the triple therapy have been developed over the years, such as using a different proton pump inhibitor, as with
pantoprazole Pantoprazole, sold under the brand name Protonix, among others, is a proton pump inhibitor used for the treatment of stomach ulcers, short-term treatment of erosive esophagitis due to gastroesophageal reflux disease (GERD), maintenance of heal ...
or
rabeprazole Rabeprazole, sold under the brand name Aciphex, among others, is a medication that decreases stomach acid. It is used to treat peptic ulcer disease, gastroesophageal reflux disease, and excess stomach acid production such as in Zollinger–Elli ...
, or replacing amoxicillin with
metronidazole Metronidazole, sold under the brand name Flagyl among others, is an antibiotic and antiprotozoal medication. It is used either alone or with other antibiotics to treat pelvic inflammatory disease, endocarditis, and bacterial vaginosis. It is ...
for people who are allergic to
penicillin Penicillins (P, PCN or PEN) are a group of β-lactam antibiotics originally obtained from '' Penicillium'' moulds, principally '' P. chrysogenum'' and '' P. rubens''. Most penicillins in clinical use are synthesised by P. chrysogenum usin ...
. In areas with higher rates of clarithromycin resistance, other options are recommended. Such a therapy has revolutionized the treatment of peptic ulcers and has made a cure to the disease possible. Previously, the only option was symptom control using
antacids An antacid is a substance which neutralizes stomach acidity and is used to relieve heartburn, indigestion or an upset stomach. Some antacids have been used in the treatment of constipation and diarrhea. Marketed antacids contain salts of alu ...
, H2-antagonists or proton pump inhibitors alone.


Antibiotic-resistant disease

An increasing number of infected individuals are found to harbor
antibiotic-resistant Antimicrobial resistance (AMR) occurs when microbes evolve mechanisms that protect them from the effects of antimicrobials. All classes of microbes can evolve resistance. Fungi evolve antifungal resistance. Viruses evolve antiviral resistance. ...
bacteria. This results in initial treatment failure and requires additional rounds of antibiotic therapy or alternative strategies, such as a quadruple therapy, which adds a
bismuth Bismuth is a chemical element with the symbol Bi and atomic number 83. It is a post-transition metal and one of the pnictogens, with chemical properties resembling its lighter group 15 siblings arsenic and antimony. Elemental bismuth occurs ...
colloid A colloid is a mixture in which one substance consisting of microscopically dispersed insoluble particles is suspended throughout another substance. Some definitions specify that the particles must be dispersed in a liquid, while others extend ...
, such as bismuth subsalicylate. In patients with any previous
macrolide The Macrolides are a class of natural products that consist of a large macrocyclic lactone ring to which one or more deoxy sugars, usually cladinose and desosamine, may be attached. The lactone rings are usually 14-, 15-, or 16-membered. Ma ...
exposure or who are allergic to penicillin, a quadruple therapy that consisting of a proton pump inhibitor,
bismuth Bismuth is a chemical element with the symbol Bi and atomic number 83. It is a post-transition metal and one of the pnictogens, with chemical properties resembling its lighter group 15 siblings arsenic and antimony. Elemental bismuth occurs ...
,
tetracycline Tetracycline, sold under various brand names, is an oral antibiotic in the tetracyclines family of medications, used to treat a number of infections, including acne, cholera, brucellosis, plague, malaria, and syphilis. Common side effects in ...
, and a
nitroimidazole 5-Nitroimidazole is an organic compound with the formula O2NC3H2N2H. The nitro group at position 5 on the imidazole ring is the most common positional isomer. The term nitroimidazole also refers to a class of antibiotics that share similar ch ...
for 10–14 days is a recommended first-line treatment option. For the treatment of clarithromycin-resistant strains of ''H. pylori'', the use of
levofloxacin Levofloxacin, sold under the brand name Levaquin among others, is an antibiotic medication. It is used to treat a number of bacterial infections including acute bacterial sinusitis, pneumonia, H. pylori (in combination with other medications), ...
as part of the therapy has been suggested. Ingesting lactic acid bacteria exerts a suppressive effect on ''H. pylori'' infection in both animals and humans, and supplementing with ''
Lactobacillus ''Lactobacillus'' is a genus of Gram-positive, aerotolerant anaerobes or microaerophilic, rod-shaped, non-spore-forming bacteria. Until 2020, the genus ''Lactobacillus'' comprised over 260 phylogenetically, ecologically, and metabolically div ...
''- and '' Bifidobacterium''-containing yogurt improved the rates of eradication of ''H. pylori'' in humans. Symbiotic butyrate-producing bacteria which are normally present in the intestine are sometimes used as probiotics to help suppress ''H. pylori'' infections as an adjunct to antibiotic therapy.
Butyrate The conjugate acids are in :Carboxylic acids. {{Commons category, Carboxylate ions, Carboxylate anions Carbon compounds Oxyanions ...
itself is an antimicrobial which destroys the cell envelope of ''H. pylori'' by inducing regulatory T cell expression (specifically,
FOXP3 FOXP3 ( forkhead box P3), also known as scurfin, is a protein involved in immune system responses. A member of the FOX protein family, FOXP3 appears to function as a master regulator of the regulatory pathway in the development and function of ...
) and synthesis of an
antimicrobial peptide Antimicrobial peptides (AMPs), also called host defence peptides (HDPs) are part of the innate immune response found among all classes of life. Fundamental differences exist between prokaryotic and eukaryotic cells that may represent targets for a ...
called LL-37, which arises through its action as a histone deacetylase inhibitor. The substance sulforaphane, which occurs in
broccoli Broccoli (''Brassica oleracea'' var. ''italica'') is an edible green plant in the cabbage family (family Brassicaceae, genus ''Brassica'') whose large flowering head, stalk and small associated leaves are eaten as a vegetable. Broccoli is cla ...
and
cauliflower Cauliflower is one of several vegetables in the species ''Brassica oleracea'' in the genus '' Brassica'', which is in the Brassicaceae (or mustard) family. It is an annual plant that reproduces by seed. Typically, only the head is eaten – t ...
, has been proposed as a treatment. Periodontal therapy or scaling and root planing has also been suggested as an additional treatment.


Cancers


Extranodal marginal zone B-cell lymphomas

Extranodal marginal zone B-cell lymphomas (also termed MALT lymphomas) are generally indolent malignancies. Recommended treatment of ''H. pylori''-positive extranodal marginal zone B-cell lymphoma of the stomach, when localized (i.e. Ann Arbor stage I and II), employs one of the
antibiotic An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and prevention ...
- proton pump inhibitor regiments listed in the ''H. pylori'' eradication protocols. If the initial regimen fails to eradicate the pathogen, patients are treated with an alternate protocol. Eradication of the pathogen is successful in 70–95% of cases. Some 50-80% of patients who experience eradication of the pathogen develop within 3–28 months a remission and long-term clinical control of their lymphoma.
Radiation therapy Radiation therapy or radiotherapy, often abbreviated RT, RTx, or XRT, is a therapy using ionizing radiation, generally provided as part of cancer treatment to control or kill malignant cells and normally delivered by a linear accelerator. Rad ...
to the stomach and surrounding (i.e. peri-gastric) lymph nodes has also been used to successfully treat these localized cases. Patients with non-localized (i.e. systemic Ann Arbor stage III and IV) disease who are free of symptoms have been treated with
watchful waiting Watchful waiting (also watch and wait or WAW) is an approach to a medical problem in which time is allowed to pass before medical intervention or therapy is used. During this time, repeated testing may be performed. Related terms include ''expe ...
or, if symptomatic, with the immunotherapy drug, rituximab, (given for 4 weeks) combined with the
chemotherapy Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemother ...
drug,
chlorambucil Chlorambucil, sold under the brand name Leukeran among others, is a chemotherapy medication used to treat chronic lymphocytic leukemia (CLL), Hodgkin lymphoma, and non-Hodgkin lymphoma. For CLL it is a preferred treatment. It is given by mouth. ...
, for 6–12 months; 58% of these patients attain a 58% progression-free survival rate at 5 years. Frail stage III/IV patients have been successfully treated with rituximab or the chemotherapy drug,
cyclophosphamide Cyclophosphamide (CP), also known as cytophosphane among other names, is a medication used as chemotherapy and to suppress the immune system. As chemotherapy it is used to treat lymphoma, multiple myeloma, leukemia, ovarian cancer, breast cancer ...
, alone. Only rare cases of ''H. pylori''-positive extranodal marginal zone B-cell lymphoma of the colon have been successfully treated with an antibiotic-proton pump inhibitor regimen; the currently recommended treatments for this disease are surgical resection, endoscopic resection, radiation, chemotherapy, or, more recently, rituximab. In the few reported cases of ''H. pylori''-positive extranodal marginal zone B-cell lymphoma of the esophagus, localized disease has been successfully treated with antibiotic-proton pump inhibitor regimens; however, advanced disease appears less responsive or unresponsive to these regimens but partially responsive to rituximab. Antibiotic-proton pump inhibitor eradication therapy and localized radiation therapy have been used successfully to treat H. pylori-positive extranodal marginal zone B-cell lymphomas of the rectum; however radiation therapy has given slightly better results and therefore been suggested to be the disease' preferred treatment. The treatment of localized ''H. pylori''-positive extranodal marginal zone B-cell lymphoma of the ocular adenexa with antibiotic/proton pump inhibitor regimens has achieved 2 year and 5 year failure-free survival rates of 67% and 55%, respectively, and a 5-year progression-free rate of 61%. However, the generally recognized treatment of choice for patients with systemic involvement uses various chemotherapy drugs often combined with rituximab.


Diffuse large B-cell lymphoma

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


Stomach adenocarcinoma

Helicobacter pylori is linked to the majority of gastric adenocarcinoma cases, particularly those that are located outside of the stomach's
cardia The stomach is a muscular, hollow organ in the gastrointestinal tract of humans and many other animals, including several invertebrates. The stomach has a dilated structure and functions as a vital organ in the digestive system. The stomach is ...
(i.e. esophagus-stomach junction). The treatment for this cancer is highly aggressive with even localized disease being treated sequentially with chemotherapy and radiotherapy before surgical resection. Since this cancer, once developed, is independent of ''H. pylori'' infection, antibiotic-proton pump inhibitor regimens are not used in its treatment.


Prognosis

''Helicobacter pylori'' colonizes the stomach and induces chronic gastritis, a long-lasting inflammation of the stomach. The bacterium persists in the stomach for decades in most people. Most individuals infected by ''H. pylori'' never experience clinical symptoms, despite having chronic gastritis. About 10–20% of those colonized by ''H. pylori'' ultimately develop gastric and duodenal ulcers. ''H. pylori'' infection is also associated with a 1–2% lifetime risk of
stomach cancer Stomach cancer, also known as gastric cancer, is a cancer that develops from the lining of the stomach. Most cases of stomach cancers are gastric carcinomas, which can be divided into a number of subtypes, including gastric adenocarcinomas. Ly ...
and a less than 1% risk of gastric MALT lymphoma. In the absence of treatment, ''H. pylori'' infection – once established in its gastric niche – is widely believed to persist for life. In the elderly, however, infection likely can disappear as the stomach's mucosa becomes increasingly atrophic and inhospitable to colonization. The proportion of acute infections that persist is not known, but several studies that followed the natural history in populations have reported apparent spontaneous elimination. It is possible for ''H. pylori'' to re-establish in a person after eradication. This ''recurrence'' can be caused by the original strain (''recrudescence''), or be caused by a different strain (''reinfection''). According to a 2017 meta-analysis by Hu et al., the global per-person annual rates of recurrence, reinfection, and recrudescence is 4.3%, 3.1%, and 2.2% resepctively. It is unclear what the main risk factors are. Mounting evidence suggests ''H. pylori'' has an important role in protection from some diseases. The incidence of acid reflux disease,
Barrett's esophagus Barrett's esophagus is a condition in which there is an abnormal ( metaplastic) change in the mucosal cells lining the lower portion of the esophagus, from stratified squamous epithelium to simple columnar epithelium with interspersed goblet cells ...
, and
esophageal cancer Esophageal cancer is cancer arising from the esophagus—the food pipe that runs between the throat and the stomach. Symptoms often include difficulty in swallowing and weight loss. Other symptoms may include pain when swallowing, a hoarse voi ...
have been rising dramatically at the same time as ''H. pylori''s presence decreases. In 1996, Martin J. Blaser advanced the hypothesis that ''H. pylori'' has a beneficial effect by regulating the acidity of the stomach contents. The hypothesis is not universally accepted as several
randomized controlled trials A randomized controlled trial (or randomized control trial; RCT) is a form of scientific experiment used to control factors not under direct experimental control. Examples of RCTs are clinical trials that compare the effects of drugs, surgical t ...
failed to demonstrate worsening of acid reflux disease symptoms following eradication of ''H. pylori''. Nevertheless, Blaser has reasserted his view that ''H. pylori'' is a member of the normal flora of the stomach. He postulates that the changes in gastric physiology caused by the loss of ''H. pylori'' account for the recent increase in incidence of several diseases, including
type 2 diabetes Type 2 diabetes, formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent urinatio ...
,
obesity Obesity is a medical condition, sometimes considered a disease, in which excess body fat has accumulated to such an extent that it may negatively affect health. People are classified as obese when their body mass index (BMI)—a person's ...
, and asthma. His group has recently shown that ''H. pylori'' colonization is associated with a lower incidence of childhood asthma.


Epidemiology

At least half the world's population is infected by the bacterium, making it the most widespread infection in the world. Actual infection rates vary from nation to nation; the
developing world A developing country is a sovereign state with a lesser developed industrial base and a lower Human Development Index (HDI) relative to other countries. However, this definition is not universally agreed upon. There is also no clear agreeme ...
has much higher infection rates than the developed one (notably
Western Europe Western Europe is the western region of Europe. The region's countries and territories vary depending on context. The concept of "the West" appeared in Europe in juxtaposition to "the East" and originally applied to the ancient Mediterranean ...
,
North America North America is a continent in the Northern Hemisphere and almost entirely within the Western Hemisphere. It is bordered to the north by the Arctic Ocean, to the east by the Atlantic Ocean, to the southeast by South America and th ...
,
Australasia Australasia is a region that comprises Australia, New Zealand and some neighbouring islands in the Pacific Ocean. The term is used in a number of different contexts, including geopolitically, physiogeographically, philologically, and ecologic ...
), where rates are estimated to be around 25%. 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. Infections are usually acquired in early childhood in all countries. However, the infection rate of children in developing nations is higher than in industrialized nations, probably due to poor sanitary conditions, perhaps combined with lower antibiotics usage for unrelated pathologies. In developed nations, it is currently uncommon to find infected children, but the percentage of infected people increases with age, with about 50% infected for those over the age of 60 compared with around 10% between 18 and 30 years. The higher prevalence among the elderly reflects higher infection rates in the past when the individuals were children rather than more recent infection at a later age of the individual. In the United States, prevalence appears higher in
African-American African Americans (also referred to as Black Americans and Afro-Americans) are an ethnic group consisting of Americans with partial or total ancestry from sub-Saharan Africa. The term "African American" generally denotes descendants of ensl ...
and
Hispanic The term ''Hispanic'' ( es, hispano) refers to people, cultures, or countries related to Spain, the Spanish language, or Hispanidad. The term commonly applies to countries with a cultural and historical link to Spain and to viceroyalties for ...
populations, most likely due to socioeconomic factors. The lower rate of infection in the West is largely attributed to higher hygiene standards and widespread use of antibiotics. Despite high rates of infection in certain areas of the world, the overall frequency of ''H. pylori'' infection is declining. However,
antibiotic resistance Antimicrobial resistance (AMR) occurs when microbes evolve mechanisms that protect them from the effects of antimicrobials. All classes of microbes can evolve resistance. Fungi evolve antifungal resistance. Viruses evolve antiviral resistance. ...
is appearing in ''H. pylori''; many
metronidazole Metronidazole, sold under the brand name Flagyl among others, is an antibiotic and antiprotozoal medication. It is used either alone or with other antibiotics to treat pelvic inflammatory disease, endocarditis, and bacterial vaginosis. It is ...
- and clarithromycin-resistant strains are found in most parts of the world.


History

''Helicobacter pylori'' migrated out of Africa along with its human host ''circa'' 60,000 years ago. Recent research states that
genetic diversity Genetic diversity is the total number of genetic characteristics in the genetic makeup of a species, it ranges widely from the number of species to differences within species and can be attributed to the span of survival for a species. It is dis ...
in ''H. pylori'', like that of its host, decreases with geographic distance from
East Africa East Africa, Eastern Africa, or East of Africa, is the eastern subregion of the African continent. In the United Nations Statistics Division scheme of geographic regions, 10-11-(16*) territories make up Eastern Africa: Due to the historica ...
. Using the genetic diversity data, researchers have created simulations that indicate the bacteria seem to have spread from East Africa around 58,000 years ago. Their results indicate modern humans were already infected by ''H. pylori'' before their migrations out of Africa, and it has remained associated with human hosts since that time. ''H. pylori'' was first discovered in the stomachs of patients with gastritis and ulcers in 1982 by Drs.  Barry Marshall and
Robin Warren John Robin Warren (born 11 June 1937, in Adelaide) is an Australian pathologist, Nobel Laureate and researcher who is credited with the 1979 re-discovery of the bacterium '' Helicobacter pylori'', together with Barry Marshall. The duo proved ...
of
Perth, Western Australia Perth is the capital and largest city of the Australian state of Western Australia. It is the fourth most populous city in Australia and Oceania, with a population of 2.1 million (80% of the state) living in Greater Perth in 2020. Perth is ...
. At the time, the conventional thinking was that no bacterium could live in the acid environment of the human stomach. In recognition of their discovery, Marshall and Warren were awarded the 2005 
Nobel Prize in Physiology or Medicine The Nobel Prize in Physiology or Medicine is awarded yearly by the Nobel Assembly at the Karolinska Institute for outstanding discoveries in physiology or medicine. The Nobel Prize is not a single prize, but five separate prizes that, accordi ...
. Before the research of Marshall and Warren, German scientists found spiral-shaped
bacteria Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were am ...
in the lining of the human stomach in 1875, but they were unable to
culture Culture () is an umbrella term which encompasses the social behavior, institutions, and norms found in human societies, as well as the knowledge, beliefs, arts, laws, customs, capabilities, and habits of the individuals in these groups ...
them, and the results were eventually forgotten. The Italian researcher
Giulio Bizzozero Giulio Bizzozero (; 20 March 1846 – 8 April 1901) was an Italian doctor and medical researcher. He was a pioneer of histology and is credited with the coining of the term platelets and identifying their function in coagulation. Background ...
described similarly shaped bacteria living in the acidic environment of the stomach of dogs in 1893. Professor Walery Jaworski of the
Jagiellonian University The Jagiellonian University ( Polish: ''Uniwersytet Jagielloński'', UJ) is a public research university in Kraków, Poland. Founded in 1364 by King Casimir III the Great, it is the oldest university in Poland and the 13th oldest university in ...
in
Kraków Kraków (), or Cracow, is the second-largest and one of the oldest cities in Poland. Situated on the Vistula, Vistula River in Lesser Poland Voivodeship, the city dates back to the seventh century. Kraków was the official capital of Poland un ...
investigated sediments of gastric washings obtained by
lavage In medicine, therapeutic irrigation or lavage ( or ) is cleaning or rinsing. Types Specific types include: * Antiseptic lavage * Bronchoalveolar lavage * Gastric lavage * Diagnostic peritoneal lavage, Peritoneal lavage * Arthroscopic lavage * Duc ...
from humans in 1899. Among some rod-like bacteria, he also found bacteria with a characteristic spiral shape, which he called ''Vibrio rugula''. He was the first to suggest a possible role of this organism in the pathogenesis of gastric diseases. His work was included in the ''Handbook of Gastric Diseases'', but it had little impact, as it was written in Polish. 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. Interest in the bacteria waned, however, when an American study published in 1954 failed to observe the bacteria in 1180 stomach biopsies. 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. The bacteria had also been observed in 1979, by Robin Warren, who researched it further with Barry Marshall from 1981. After unsuccessful attempts at culturing the bacteria from the stomach, they finally succeeded in visualizing colonies in 1982, when they unintentionally left their
Petri dishes A Petri dish (alternatively known as a Petri plate or cell-culture dish) is a shallow transparent lidded dish that biologists use to hold growth medium in which cells can be cultured,R. C. Dubey (2014): ''A Textbook Of Biotechnology For Class-XI ...
incubating for five days over the
Easter Easter,Traditional names for the feast in English are "Easter Day", as in the '' Book of Common Prayer''; "Easter Sunday", used by James Ussher''The Whole Works of the Most Rev. James Ussher, Volume 4'') and Samuel Pepys''The Diary of Samue ...
weekend. In their original paper, Warren and Marshall contended that most stomach ulcers and gastritis were caused by bacterial infection and not by
stress Stress may refer to: Science and medicine * Stress (biology), an organism's response to a stressor such as an environmental condition * Stress (linguistics), relative emphasis or prominence given to a syllable in a word, or to a word in a phrase ...
or spicy food, as had been assumed before. Some skepticism was expressed initially, but within a few years multiple research groups had verified the association of ''H. pylori'' with gastritis and, to a lesser extent, ulcers. To demonstrate ''H. pylori'' caused gastritis and was not merely a bystander, Marshall drank a beaker of ''H. pylori'' culture. He became ill with nausea and vomiting several days later. An
endoscopy An endoscopy is a procedure used in medicine to look inside the body. The endoscopy procedure uses an endoscope to examine the interior of a hollow organ or cavity of the body. Unlike many other medical imaging techniques, endoscopes are inse ...
10 days after inoculation revealed signs of gastritis and the presence of ''H. pylori''. These results suggested ''H. pylori'' was the causative agent. Marshall and Warren went on to demonstrate antibiotics are effective in the treatment of many cases of gastritis. In 1994, the
National Institutes of Health The National Institutes of Health, commonly referred to as NIH (with each letter pronounced individually), is the primary agency of the United States government responsible for biomedical and public health research. It was founded in the lat ...
stated most recurrent duodenal and gastric ulcers were caused by ''H. pylori'', and recommended antibiotics be included in the treatment regimen. The bacterium was initially named ''Campylobacter pyloridis'', then renamed ''C. pylori'' in 1987 (''pylori'' being the
genitive In grammar, the genitive case ( abbreviated ) is the grammatical case that marks a word, usually a noun, as modifying another word, also usually a noun—thus indicating an attributive relationship of one noun to the other noun. A genitive can a ...
of '' pylorus'', the circular opening leading from the stomach into the
duodenum The duodenum is the first section of the small intestine in most higher vertebrates, including mammals, reptiles, and birds. In fish, the divisions of the small intestine are not as clear, and the terms anterior intestine or proximal intestine m ...
, from the Ancient Greek word ''πυλωρός'', which means
gatekeeper A gatekeeper is a person who controls access to something, for example via a city gate or bouncer, or more abstractly, controls who is granted access to a category or status. Gatekeepers assess who is "in or out", in the classic words of manage ...
.). When 16S ribosomal RNA
gene sequencing Gene Sequencing may refer to: * DNA sequencing * or a comprehensive variant of it: Whole genome sequencing Whole genome sequencing (WGS), also known as full genome sequencing, complete genome sequencing, or entire genome sequencing, is the pr ...
and other research showed in 1989 that the bacterium did not belong in the genus ''
Campylobacter ''Campylobacter'' (meaning "curved bacteria") is a genus of Gram-negative bacteria. ''Campylobacter'' typically appear comma- or s-shaped, and are motile. Some ''Campylobacter'' species can infect humans, sometimes causing campylobacteriosis, ...
'', it was placed in its own
genus Genus ( plural genera ) is a taxonomic rank used in the biological classification of living and fossil organisms as well as viruses. In the hierarchy of biological classification, genus comes above species and below family. In binomial nom ...
, '' Helicobacter'' from the
ancient Greek Ancient Greek includes the forms of the Greek language used in ancient Greece and the ancient world from around 1500 BC to 300 BC. It is often roughly divided into the following periods: Mycenaean Greek (), Dark Ages (), the Archaic pe ...
''έλιξ'' (''hělix'') "spiral" or "coil". In October 1987, a group of experts met in Copenhagen to found the European ''Helicobacter'' Study Group (EHSG), an international multidisciplinary research group and the only institution focused on ''H. pylori''. The Group is involved with the Annual International Workshop on Helicobacter and Related Bacteria, the Maastricht Consensus Reports (European Consensus on the management of ''H. pylori''), and other educational and research projects, including two international long-term projects: * European Registry on ''H. pylori'' Management (Hp-EuReg) – a database systematically registering the routine clinical practice of European gastroenterologists. * Optimal ''H. pylori'' management in primary care (OptiCare) – a long-term educational project aiming to disseminate the evidence based recommendations of the Maastricht IV Consensus to primary care physicians in Europe, funded by an educational grant from
United European Gastroenterology The United European Gastroenterology (UEG) is a non-profit organisation combining European societies concerned with digestive health. About Founded in 1992 United European Gastroenterology (UEG) is the leading non-profit organisation for exce ...
.


Research

Results from ''
in vitro ''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called " test-tube experiments", these studies in biology a ...
'' studies suggest that
fatty acid In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, f ...
s, mainly polyunsaturated fatty acids, have a bactericidal effect against ''H. pylori'', but their ''
in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and p ...
'' effects have not been proven.


See also

* List of oncogenic bacteria * Infectious causes of cancer


Explanatory footnotes


References


External links

* * * * {{DEFAULTSORT:Helicobacter Pylori Bacteria described in 1989 Conditions diagnosed by stool test Infectious causes of cancer