''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 wall ...
,
microaerophilic
A microaerophile is a microorganism that requires environments containing lower levels of dioxygen than that are present in the atmosphere (i.e. < 21% O2; typically 2–10% O2) for optimal growth.[ A more re ...]
,
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 extant taxon, living and fossil organisms as well as Virus classification#ICTV classification, viruses. In the hierarchy of biological classification, genus com ...
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
Barry James Marshall (born 30 September 1951) is an Australian physician, Nobel Prize Laureate in Physiology or Medicine, Professor of Clinical Microbiology and Co-Director of the Marshall Centre at the University of Western Australia. Marsha ...
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 t ...
.
''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 trac ...
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 antibody, antibodies. It is the most common form of non-Hodgkin lymphoma among adults, with an annual Incidence (epidemiology), in ...
).
''H. pylori'' infection usually has no symptoms but sometimes causes
gastritis
Gastritis is inflammation of the lining of the stomach. It may occur as a short episode or may be of a long duration. There may be no symptoms but, when symptoms are present, the most common is upper abdominal pain (see dyspepsia). Other possi ...
(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 organ (biology), organs of the digestive syste ...
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
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 i ...
. 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 eff ...
infection may appear as an acute gastritis
Gastritis is inflammation of the lining of the stomach. It may occur as a short episode or may be of a long duration. There may be no symptoms but, when symptoms are present, the most common is upper abdominal pain (see dyspepsia). Other possi ...
with abdominal pain
Abdominal pain, also known as a stomach ache, is a symptom
Signs and symptoms are the observed or detectable signs, and experienced symptoms of an illness, injury, or condition. A sign for example may be a higher or lower temperature than ...
(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 the ...
. Where this develops into chronic gastritis, the symptoms, if present, are often those of non-ulcer dyspepsia
Indigestion, also known as dyspepsia or upset stomach, is a condition of impaired digestion. Symptoms may include upper abdominal fullness, heartburn, nausea, belching, or upper abdominal pain. People may also experience feeling full earlier t ...
: Stomach pains, nausea, bloating
Abdominal bloating (or simply bloating) is a short-term disease that affects the gastrointestinal tract. Bloating is generally characterized by an excess buildup of gas, air or fluids in the stomach. A person may have feelings of tightness, press ...
, belching
Burping (also called belching and eructation) is the release of gas from the upper digestive tract (esophagus and stomach) of animals through the mouth. It is usually audible.
In humans, burping can be caused by normal eating processes, or as ...
, 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 Human nose, nose.
Vomiting can be the result of ailments like Food-poisoning, foo ...
. 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
Hematemesis is the vomiting of blood. It is always an important sign. It can be confused with hemoptysis (coughing up blood) or epistaxis (nosebleed), which are more common. The source is generally the upper gastrointestinal tract, typically abo ...
, 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
The pylorus ( or ), or pyloric part, connects the stomach to the duodenum. The pylorus is considered as having two parts, the ''pyloric antrum'' (opening to the body of the stomach) and the ''pyloric canal'' (opening to the duodenum). The ''pylori ...
, 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
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 ...
ulcers, while inflammation of the corpus
Corpus is Latin for "body". It may refer to:
Linguistics
* Text corpus, in linguistics, a large and structured set of texts
* Speech corpus, in linguistics, a large set of speech audio files
* Corpus linguistics, a branch of linguistics
Music
* ...
(i.e. body of the stomach) is more likely to lead to gastric
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 ...
ulcers. Individuals infected with ''H. pylori'' may also develop colorectal or gastric polyps
A polyp in zoology is one of two forms found in the phylum Cnidaria, the other being the medusa. Polyps are roughly cylindrical in shape and elongated at the axis of the vase-shaped body. In solitary polyps, the aboral (opposite to oral) end is ...
, 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 is ...
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 antibody, antibodies. It is the most common form of non-Hodgkin lymphoma among adults, with an annual Incidence (epidemiology), in ...
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 Gastrointestinal tract, gut in others. The adult human rectum is about long, and begins at the rectosigmoid junction (the end of the s ...
, 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 the ...
, 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 a p ...
, 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 epithelium ...
, 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 eyel ...
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 helices, ...
-shaped (classified as a curved rod, not spirochaete
A spirochaete () or spirochete is a member of the phylum Spirochaetota (), (synonym Spirochaetes) which contains distinctive diderm (double-membrane) gram-negative bacteria, most of which have long, helically coiled (corkscrew-shaped or s ...
) 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 wall ...
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 ...
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 f ...
at the same location; all gastric and enterohepatic ''Helicobacter
''Helicobacter'' is a genus of Gram-negative bacteria possessing a characteristic helical shape. They were initially considered to be members of the genus '' Campylobacter'', but in 1989, Goodwin ''et al.'' published sufficient reasons to justif ...
'' 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
A microaerophile is a microorganism that requires environments containing lower levels of dioxygen than that are present in the atmosphere (i.e. < 21% O2; typically 2–10% O2) for optimal growth.[ A more re ...]
– 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 as wel ...
, 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 s ...
. It contains a hydrogenase A hydrogenase is an enzyme that catalyses the reversible oxidation of molecular hydrogen (H2), as shown below:
Hydrogen uptake () is coupled to the reduction of electron acceptors such as oxygen, nitrate, sulfate, carbon dioxide (), and fumara ...
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-toxic, an ...
(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 gut mic ...
. It produces oxidase
In biochemistry, an oxidase is an enzyme that catalyzes oxidation-reduction reactions, especially one involving dioxygen (O2) as the electron acceptor. In reactions involving donation of a hydrogen atom, oxygen is reduced to water (H2O) or hydro ...
, 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-containin ...
.
''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 typ ...
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 outer m ...
(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
The term human blood group systems is defined by the International Society of Blood Transfusion (ISBT) as systems in the human species where cell-surface antigens—in particular, those on blood cells—are "controlled at a single gene locus or by ...
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 mem ...
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 ge ...
s have been completely sequenced
In genetics and biochemistry, sequencing means to determine the primary structure (sometimes incorrectly called the primary sequence) of an unbranched biopolymer. Sequencing results in a symbolic linear depiction known as a sequence which suc ...
. 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 DNA ...
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
Transcription refers to the process of converting sounds (voice, music etc.) into letters or musical notes, or producing a copy of something in another medium, including:
Genetics
* Transcription (biology), the copying of DNA into RNA, the fir ...
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 biomolecules wi ...
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 c ...
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 ca ...
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-containin ...
(ure) operon or the cag pathogenicity island (see below). More importantly, this study identified a total of 1,907 transcriptional start sites, 337 primary operon
In genetics, an operon is a functioning unit of DNA containing a cluster of genes under the control of a single promoter. The genes are transcribed together into an mRNA strand and either translated together in the cytoplasm, or undergo splic ...
s, and 126 additional suboperons, and 66 monocistron
A cistron is an alternative term for "gene". The word cistron is used to emphasize that genes exhibit a specific behavior in a cis-trans test; distinct positions (or loci) within a genome are cistronic.
History
The words ''cistron'' and ''gene ...
s. 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 readin ...
s, including many housekeeping gene
In molecular biology, housekeeping genes are typically constitutive genes that are required for the maintenance of basic cellular function, and are expressed in all cells of an organism under normal and patho-physiological conditions. Although ...
s. 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
The Shine–Dalgarno (SD) sequence is a ribosomal binding site in bacterial and archaeal messenger RNA, generally located around 8 bases upstream of the start codon AUG. The RNA sequence helps recruit the ribosome to the messenger RNA (mRNA) to ini ...
in ''H. pylori''.
Genes involved in virulence and pathogenesis
Study of the ''H. pylori'' genome is centered on attempts to understand pathogenesis
Pathogenesis is the process by which a disease or disorder develops. It can include factors which contribute not only to the onset of the disease or disorder, but also to its progression and maintenance. The word comes from Greek πάθος ''pat ...
, 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 ...
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 asy ...
.
The ''cagA
''Helicobacter pylori'' virulence factor CagA (cytotoxin-associated gene A) is a 120–145kDa protein encoded on the 40kb ''cag'' pathogenicity island (PAI). ''H. pylori'' strains can be divided into CagA positive or negative strains. Approximately ...
'' 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 ca ...
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 am ...
) 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 o ...
of the ''cag'' PAI relative to the rest of the ''Helicobacter'' genome suggests the island was acquired by horizontal transfer from another bacterial species. The serine protease HtrA also plays a major role in the pathogenesis of ''H. pylori''. The HtrA protein enables the bacterium to transmigrate across the host cells' epithelium, and is also needed for the translocation of CagA.
The ''vacA'' () 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, respo ...
s of ''H. pylori'' have been systematically analyzed by multiple studies. As a consequence, more than 70% of its proteome
The proteome is the entire set of proteins that is, or can be, expressed by a genome, cell, tissue, or organism at a certain time. It is the set of expressed proteins in a given type of cell or organism, at a given time, under defined conditions. ...
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 use ...
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 c ...
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 ...
(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 intercellula ...
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 ( ...
. 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-containin ...
, 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 transpar ...
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 was ...
. 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
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 ...
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 incl ...
), and certain phospholipases
A phospholipase is an enzyme that hydrolyzes phospholipids into fatty acids and other lipophilic substances. Acids trigger the release of bound calcium from cellular stores and the consequent increase in free cytosolic Ca2+, an essential step in ...
. 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
Gastritis is inflammation of the lining of the stomach. It may occur as a short episode or may be of a long duration. There may be no symptoms but, when symptoms are present, the most common is upper abdominal pain (see dyspepsia). Other possi ...
, 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
Pepsin is an endopeptidase that breaks down proteins into smaller peptides. It is produced in the gastric chief cells of the stomach lining and is one of the main digestive enzymes in the digestive systems of humans and many other animals, w ...
to overwhelm the mechanisms that protect the stomach and duodenal mucous membranes
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 is ...
. 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
The pylorus ( or ), or pyloric part, connects the stomach to the duodenum. The pylorus is considered as having two parts, the ''pyloric antrum'' (opening to the body of the stomach) and the ''pyloric canal'' (opening to the duodenum). The ''pylori ...
(exit to the duodenum) to avoid the acid-secreting parietal cells
Parietal cells (also known as oxyntic cells) are epithelial cells in the stomach that secrete hydrochloric acid (HCl) and intrinsic factor. These cells are located in the gastric glands found in the lining of the fundus and body regions of the ...
at the fundus (near the entrance to the stomach). G-cells express relatively high levels of PD-L1
Programmed death-ligand 1 (PD-L1) also known as cluster of differentiation 274 (CD274) or B7 homolog 1 (B7-H1) is a protein that in humans is encoded by the ''CD274'' gene.
Programmed death-ligand 1 (PD-L1) is a 40kDa type 1 transmembrane protei ...
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
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 molecu ...
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 antrum ...
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.
Gastrin ...
, which travels through the bloodstream to parietal cells in the fundus. Gastrin stimulates the parietal cells to secrete more acid into the stomach lumen, and over time increases the number of parietal cells, as well. The increased acid load damages the duodenum, which may eventually result in ulcers forming in the duodenum.
When ''H. pylori'' colonizes other areas of the stomach, the inflammatory response can result in atrophy
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 t ...
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 the ...
expressed by the ''cag'' PAI "injects" the inflammation
Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a protective response involving im ...
-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 ...
, 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 mech ...
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, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a protective response involving im ...
.
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 classical ...
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 compos ...
, 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 desc ...
, and other cellular activities. Once inside the cell, the CagA protein is phosphorylated
In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, whi ...
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
Protein tyrosine phosphatases (EC 3.1.3.48, systematic name protein-tyrosine-phosphate phosphohydrolase) are a group of enzymes that remove phosphate groups from phosphorylated tyrosine residues on proteins:
: proteintyrosine phosphate + H2O = ...
/protooncogene
An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels. 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 huma ...
. 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 recept ...
(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
* Do ...
. 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. The ...
in host epithelial cells that may contribute to pathogenesis. A C-terminal
The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...
region of the CagA protein (amino acids 873–1002) has also been suggested to be able to regulate host cell gene transcription
Transcription is the process of copying a segment of DNA into RNA. The segments of DNA transcribed into RNA molecules that can encode proteins are said to produce messenger RNA (mRNA). Other segments of DNA are copied into RNA molecules calle ...
, 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, mi ...
. 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 be ...
proteins. ''H. pylori'' has been proposed to induce inflammation
Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a protective response involving im ...
and locally high levels of TNF-α
Tumor necrosis factor (TNF, cachexin, or cachectin; formerly known as tumor necrosis factor alpha or TNF-α) is an adipokine and a cytokine. TNF is a member of the TNF superfamily, which consists of various transmembrane proteins with a homolog ...
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 red ...
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 cel ...
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
Gastritis is inflammation of the lining of the stomach. It may occur as a short episode or may be of a long duration. There may be no symptoms but, when symptoms are present, the most common is upper abdominal pain (see dyspepsia). Other possi ...
. 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, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a protective response involving im ...
, 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 in ...
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 cel ...
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
Reactive nitrogen species (RNS) are a family of antimicrobial molecules derived from nitric oxide (•NO) and superoxide (O2•−) produced via the enzymatic activity of inducible nitric oxide synthase 2 ( NOS2) and NADPH oxidase respectivel ...
(ROS/RNS). The substantial presence of ROS/RNS causes DNA damage including 8-oxo-2'-deoxyguanosine
8-Oxo-2'-deoxyguanosine (8-oxo-dG) is an oxidized derivative of deoxyguanosine. 8-Oxo-dG is one of the major products of DNA oxidation. Concentrations of 8-oxo-dG within a cell are a measurement of oxidative stress.
In DNA
Steady-state leve ...
(8-OHdG).[ If the infecting ''H. pylori'' carry the cytotoxic ]cagA
''Helicobacter pylori'' virulence factor CagA (cytotoxin-associated gene A) is a 120–145kDa protein encoded on the 40kb ''cag'' pathogenicity island (PAI). ''H. pylori'' strains can be divided into CagA positive or negative strains. Approximately ...
gene (present in about 60% of Western isolates and a higher percentage of Asian isolates), they can increase the level of 8-OHdG in gastric cells by 8-fold, while if the ''H. pylori'' do not carry the cagA gene, the increase in 8-OHdG is about 4-fold. In addition to the oxidative DNA damage 8-OHdG, ''H. pylori'' infection causes other characteristic DNA damages including DNA double-strand breaks.
''H. pylori'' also causes many epigenetic
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 "o ...
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 "o ...
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. miRN ...
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
DNA excision repair protein ERCC-1 is a protein that in humans is encoded by the ''ERCC1'' gene. Together with ERCC4, ERCC1 forms the ERCC1-XPF enzyme complex that participates in DNA repair and DNA recombination.
Many aspects of these two gene ...
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 bands ...
, was severely reduced once ''H. pylori'' infection had progressed to cause dyspepsia
Indigestion, also known as dyspepsia or upset stomach, is a condition of impaired digestion. Symptoms may include upper abdominal fullness, heartburn, nausea, belching, or upper abdominal pain. People may also experience feeling full earlier t ...
. 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 MLH1 h ...
, 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 of ...
and MRE11
Double-strand break repair protein MRE11 is an enzyme that in humans is encoded by the ''MRE11'' gene. The gene has been designated ''MRE11A'' to distinguish it from the pseudogene ''MRE11B'' that is nowadays named ''MRE11P1''.
Function
This ge ...
. 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 phagocyte
Phagocytes are cells that protect the body by ingesting harmful foreign particles, bacteria, and dead or dying cells. Their name comes from the Greek ', "to eat" or "devour", and "-cyte", the suffix in biology denoting "cell", from the Greek ...
s 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
Transformation may refer to:
Science and mathematics
In biology and medicine
* Metamorphosis, the biological process of changing physical form after birth or hatching
* Malignant transformation, the process of cells becoming cancerous
* Trans ...
(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. 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 i ...
or low-grade gastric MALT lymphoma
MALT lymphoma (MALToma) is a form of lymphoma involving the mucosa-associated lymphoid tissue (MALT), frequently of the stomach, but virtually any mucosal site can be affected. It is a cancer originating from B cells in the marginal zone of the MAL ...
(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 insert ...
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. Lymph ...
, for first-degree relatives with gastric cancer, and in certain cases of dyspepsia
Indigestion, also known as dyspepsia or upset stomach, is a condition of impaired digestion. Symptoms may include upper abdominal fullness, heartburn, nausea, belching, or upper abdominal pain. People may also experience feeling full earlier t ...
. 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 c ...
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 the ...
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 response. ...
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 r ...
, 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 transpar ...
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
Histology,
also known as microscopic anatomy or microanatomy, is the branch of biology which studies the microscopic anatomy of biological tissues. Histology is the microscopic counterpart to gross anatomy, which looks at larger structures vis ...
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 diseas ...
, combined with either a rapid urease test
Rapid urease test, also known as the CLO test (Campylobacter-like organism test), is a rapid diagnostic test for diagnosis of ''Helicobacter pylori''. The basis of the test is the ability of ''H. pylori'' to secrete the urease enzyme, which catalyz ...
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 fecal ...
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 relati ...
, 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 be ...
, 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 bet ...
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 Dosage form, preparation that provides active acquired immunity to a particular infectious disease, infectious or cancer, malignant disease. The safety and effectiveness of vaccines has been widely studied and verifie ...
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
* Analgesic ...
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
Cost-effectiveness analysis (CEA) is a form of economic analysis that compares the relative costs and outcomes (effects) of different courses of action. Cost-effectiveness analysis is distinct from cost–benefit analysis, which assigns a monetar ...
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
Histopathology (compound of three Greek words: ''histos'' "tissue", πάθος ''pathos'' "suffering", and -λογία ''-logia'' "study of") refers to the microscopic examination of tissue in order to study the manifestations of disease. Spec ...
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
Metaplasia ( gr, "change in form") is the transformation of one differentiated cell type to another differentiated cell type. The change from one type of cell to another may be part of a normal maturation process, or caused by some sort of abno ...
, 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 te ...
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 study, longitudinal cohort study that follows over time a group of similar individuals (cohort (statistics), cohorts) who differ with respect to certain factors under study, to determine how these fact ...
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
A retrospective cohort study, also called a historic cohort study, is a longitudinal cohort study used in medical and psychological research. A cohort of individuals that share a common exposure factor is compared with another group of equivalen ...
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 me ...
, 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 of ...
plus 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 inhibitors ...
drug regimens are used to eradicate the bacterium and thereby successfully treat the disorder with triple-drug therapy consisting of clarithromycin
Clarithromycin, sold under the brand name Biaxin among others, is an antibiotic used to treat various bacterial infections. This includes strep throat, pneumonia, skin infections, ''H. pylori'' infection, and Lyme disease, among others. Clarith ...
, 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
A therapy or medical treatment (often abbreviated tx, Tx, or Tx) is the attempted remediation of a health problem, usually following a medical diagnosis.
As a rule, each therapy has indications and contraindications. There are many different ...
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 inhibitors ...
s such as omeprazole
Omeprazole, sold under the brand names Prilosec and Losec, among others, is a medication used in the treatment of gastroesophageal reflux disease (GERD), peptic ulcer disease, and Zollinger–Ellison syndrome. It is also used to prevent upper g ...
and the antibiotics clarithromycin
Clarithromycin, sold under the brand name Biaxin among others, is an antibiotic used to treat various bacterial infections. This includes strep throat, pneumonia, skin infections, ''H. pylori'' infection, and Lyme disease, among others. Clarith ...
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
The P-type ATPases, also known as E1-E2 ATPases, are a large group of evolutionarily related ion and lipid pumps that are found in bacteria, archaea, and eukaryotes. P-type ATPases are α-helical bundle primary transporters named based upon their ...
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-containin ...
.) 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 heali ...
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 ef ...
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 using ...
. 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 alumi ...
, 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 (chemistry), 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 ...
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
Bismuth subsalicylate, sold generically as pink bismuth and under the brand names Pepto-Bismol and BisBacter, is an antacid medication used to treat temporary discomforts of the stomach and gastrointestinal tract, such as nausea, heartburn, indig ...
. 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. Macrol ...
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 (chemistry), 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 ...
, 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 vulgaris, acne, cholera, brucellosis, plague (disease), plague, malaria, and sy ...
, 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 chemi ...
for 10–14 days is a recommended first-line treatment option. For the treatment of clarithromycin
Clarithromycin, sold under the brand name Biaxin among others, is an antibiotic used to treat various bacterial infections. This includes strep throat, pneumonia, skin infections, ''H. pylori'' infection, and Lyme disease, among others. Clarith ...
-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
Lactobacillales are an order of gram-positive, low-GC, acid-tolerant, generally nonsporulating, nonrespiring, either rod-shaped (bacilli) or spherical (cocci) bacteria that share common metabolic and physiological characteristics. These bacte ...
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 diver ...
''- and ''Bifidobacterium
''Bifidobacterium'' is a genus of gram-positive, nonmotile, often branched anaerobic bacteria. They are ubiquitous inhabitants of the gastrointestinal tract though strains have been isolated from the vagina and mouth ('' B. dentium'') of mammal ...
''-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
The cell envelope comprises the inner cell membrane and the cell wall of a bacterium. In gram-negative bacteria an outer membrane is also included. This envelope is not present in the Mollicutes where the cell wall is absent.
Bacterial cell env ...
of ''H. pylori'' by inducing regulatory T cell
The regulatory T cells (Tregs or Treg cells), formerly known as suppressor T cells, are a subpopulation of T cells that modulate the immune system, maintain tolerance to self-antigens, and prevent autoimmune disease. Treg cells are immunosup ...
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 reg ...
) 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 an ...
called LL-37
Cathelicidin antimicrobial peptide (CAMP) is a polypeptide that is primarily stored in the lysosomes of macrophages and polymorphonuclear leukocytes (PMNs); in humans, the ''CAMP'' gene encodes the peptide precursor CAP-18 (18 kDa), which is proce ...
, which arises through its action as a histone deacetylase inhibitor
Histone deacetylase inhibitors (HDAC inhibitors, HDACi, HDIs) are chemical compounds that inhibit histone deacetylases.
HDIs have a long history of use in psychiatry and neurology as mood stabilizers and anti-epileptics. More recently they are bei ...
.
The substance sulforaphane
Sulforaphane (sometimes sulphoraphane in British English) is a compound within the isothiocyanate group of organosulfur compounds. It is produced when the enzyme myrosinase transforms glucoraphanin, a glucosinolate, into sulforaphane upon damage ...
, 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 cl ...
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 – the ...
, has been proposed as a treatment. Periodontal therapy or scaling and root planing
Scaling and root planing, also known as conventional periodontal therapy, non-surgical periodontal therapy or deep cleaning, is a procedure involving removal of dental plaque and calculus (scaling or debridement) and then smoothing, or planing, o ...
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 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 inhibitors ...
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. Radia ...
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 ''expec ...
or, if symptomatic, with the immunotherapy
Immunotherapy or biological therapy is the treatment of disease by activating or suppressing the immune system. Immunotherapies designed to elicit or amplify an immune response are classified as ''activation immunotherapies,'' while immunotherap ...
drug, rituximab
Rituximab, sold under the brand name Rituxan among others, is a monoclonal antibody medication used to treat certain autoimmune diseases and types of cancer. It is used for non-Hodgkin lymphoma, chronic lymphocytic leukemia (in non-geriatric p ...
, (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. Chemotherap ...
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
Rituximab, sold under the brand name Rituxan among others, is a monoclonal antibody medication used to treat certain autoimmune diseases and types of cancer. It is used for non-Hodgkin lymphoma, chronic lymphocytic leukemia (in non-geriatric p ...
. 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
Chop, CHOP, Chops, or CHOPS may refer to:
Art
*Embouchure, in music, a synonym for chops (and later, more broadly, musical skill or ability)
*CHOPS, an Asian-American hip hop producer, rapper and member of rap group Mountain Brothers
* ''Chops'' ...
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
Gastritis is inflammation of the lining of the stomach. It may occur as a short episode or may be of a long duration. There may be no symptoms but, when symptoms are present, the most common is upper abdominal pain (see dyspepsia). Other possi ...
, 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. Lymph ...
and a less than 1% risk of gastric MALT lymphoma
MALT lymphoma (MALToma) is a form of lymphoma involving the mucosa-associated lymphoid tissue (MALT), frequently of the stomach, but virtually any mucosal site can be affected. It is a cancer originating from B cells in the marginal zone of the MAL ...
.
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
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 t ...
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 gastroesophageal reflux disease, acid reflux disease, Barrett's esophagus, and esophageal cancer 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 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, obesity, and asthma. His group has recently shown that ''H. pylori'' colonization is associated with a lower incidence (epidemiology), 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 has much higher infection rates than the developed one (notably Western Europe, North America, Australasia), 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 Developed country, 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-American and Hispanic and Latino Americans, Hispanic 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 ef ...
- and clarithromycin
Clarithromycin, sold under the brand name Biaxin among others, is an antibiotic used to treat various bacterial infections. This includes strep throat, pneumonia, skin infections, ''H. pylori'' infection, and Lyme disease, among others. Clarith ...
-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 in ''H. pylori'', like that of its host, decreases with geographic distance from Eastern Africa, East Africa. Using the genetic diversity data, researchers have created simulations that indicate the bacteria seem to have spread from East Africa around 58,000 years ago. Their results indicate modern humans were already infected 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
Gastritis is inflammation of the lining of the stomach. It may occur as a short episode or may be of a long duration. There may be no symptoms but, when symptoms are present, the most common is upper abdominal pain (see dyspepsia). Other possi ...
and ulcers in 1982 by Drs. Barry Marshall
Barry James Marshall (born 30 September 1951) is an Australian physician, Nobel Prize Laureate in Physiology or Medicine, Professor of Clinical Microbiology and Co-Director of the Marshall Centre at the University of Western Australia. Marsha ...
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 t ...
of Perth, Western Australia. 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.
Before the research of Marshall and Warren, German scientists found spiral-shaped bacteria in the lining of the human stomach in 1875, but they were unable to Microbiological culture, culture them, and the results were eventually forgotten. The Italian researcher Giulio Bizzozero described similarly shaped bacteria living in the acidic environment of the stomach of dogs in 1893. Professor Walery Jaworski of the Jagiellonian University in Kraków investigated sediments of gastric washings obtained by Gastric lavage, lavage 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 incubating for five days over the Easter weekend. In their original paper, Warren and Marshall contended that most stomach ulcers and gastritis were caused by bacterial infection and not by stress (medicine), stress or Spice, 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 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 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 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.[). When 16S ribosomal RNA DNA sequencing, gene sequencing and other research showed in 1989 that the bacterium did not belong in the genus ''Campylobacter'', it was placed in its own ]genus
Genus ( plural genera ) is a taxonomic rank used in the biological classification of extant taxon, living and fossil organisms as well as Virus classification#ICTV classification, viruses. In the hierarchy of biological classification, genus com ...
, ''Helicobacter
''Helicobacter'' is a genus of Gram-negative bacteria possessing a characteristic helical shape. They were initially considered to be members of the genus '' Campylobacter'', but in 1989, Goodwin ''et al.'' published sufficient reasons to justif ...
'' from the ancient Greek ''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.
Research
Results from ''in vitro'' studies suggest that fatty acids, mainly polyunsaturated fatty acids, have a bactericidal effect against ''H. pylori'', but their ''in vivo'' effects have not been proven.
See also
*List of oncogenic bacteria
*Infectious causes of cancer
Explanatory footnotes
References
External links
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{{DEFAULTSORT:Helicobacter Pylori
Helicobacter pylori,
Bacteria described in 1989
Conditions diagnosed by stool test
Infectious causes of cancer