The precise mode of transmission of Helicobacter pylori is most likely considered to be through fecal-oral and oral-oral routes, largely through intrafamilial spread (particularly mother-to-child). H. pylori is a noninvasive organism. It is found within the mucus layer overlying surface epithelial cells and also deep within gastric glands, where it interacts with gland base stem/progenitor cells. It colonizes gastric-type epithelium only; it does not colonize normal squamous esophagus or normal duodenal mucosa, but can colonize foci of gastric metaplasia. Chronic infection is the strongest risk factor for non-cardia gastric adenocarcinoma and drives gastric mucosa-associated lymphoid tissue (MALT) lymphoma. Pathogenesis of H. pylori infection depends on bacterial, host and environmental factors.

• The precise mode of transmission of H. pylori remains unclear.^[1][2][3]
• Fecal-oral and oral-oral routes, largely through intrafamilial spread (particularly mother-to-child), are considered the most likely modes of transmission.^[4][5]
• It is almost always acquired during childhood and infection is lifelong if left untreated.^[6]
• Helicobacter pylori is usually transmitted via the following routes:

• Oral-oral route

• Via saliva especially in developed countries^[6]

• Fecal-oral route

• Fecal contamination of water and food may be the source of infection especially in developing countries^[6]

• Iatrogenic

• Via tubes and endoscopes that have been in contact with the gastric mucosa of one individual are used for another patient
• Between patient and staff especially among endoscopists and gastroenterologists

• H. pylori is a WHO/IARC Group 1 carcinogen and the strongest risk factor for non-cardia (distal) gastric adenocarcinoma, to which approximately 90% of non-cardia cases are attributed. By contrast, it is not associated with—and may be inversely associated with—gastric cardia adenocarcinoma.^[7][8]
• H. pylori also drives gastric mucosa-associated lymphoid tissue (MALT) lymphoma. The normal stomach lacks organized lymphoid tissue; chronic infection induces lymphoid follicles, and antigen-driven, T-cell-dependent stimulation promotes clonal B-cell proliferation. H. pylori is detected in up to 90% of gastric MALT lymphomas, and ~75% regress with eradication therapy alone.^[9][10]
• The colonization of H. pylori in gastric mucosa depends on the following factors:

• Motility of H. pylori (The corkscrew motility is due to its multiple flagella and spiral shape)
• Chemotaxis
• Environmental sensing
• Acid resistance
• Iron acquisition

• H. pylori primarily colonizes the gastric mucosa and areas of gastric metaplasia; it has also been detected in the oral cavity/dental plaque, though the clinical significance of extragastric detection is uncertain.

• The pathogenesis involves four important steps. They are:

• Adhesion of H. pylori to host cell
• Alteration of gastric acid secretion (increased in antral-predominant gastritis; decreased in corpus-predominant gastritis/pangastritis)^[11]
• Colonization
• Inflammation

• Based on the location of inflammation, the pathogenesis depends on:^[12]

• Antral-predominant inflammation: The uninflamed corpus produces large amount of acid predisposing to duodenal ulceration
• Corpus-predominant inflammation: This leads to gastric ulceration and adenocarcinoma due to hypochlorhydria

• The sequence of chronic inflammatory and premalignant changes caused by H. pylori is described by the Correa cascade: chronic (superficial) gastritis → atrophic gastritis → intestinal metaplasia → dysplasia → intestinal-type gastric adenocarcinoma. Progressive atrophy and achlorhydria also foster a dysbiotic gastric microbiome that further promotes neoplasia.^[13][14]

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• H. pylori is a non invasive organism. It is found within the mucus layer overlying surface epithelial cells and also deep within gastric glands, where it interacts with gland base stem/progenitor (LGR5+) cells. It colonizes gastric-type epithelium only; it does not colonize normal squamous esophagus or normal duodenal mucosa, but can colonize foci of gastric metaplasia (e.g., duodenal gastric metaplasia).^[15][11] The pathogenesis of H. pylori depends up on the following:^[12]

A. Flagella

H. pylori propels through the mucus layer with the help of flagella and adheres to the gastric epithelial cells through fimbriae which are the extension of bacterial cytoplasm.

B. Bacterial enzymes

The bacterial enzymes associated with pathogenesis of H. pylori infection include:^[16]

• Lipase and protease

• Lipase and protease leads to degradation of protective mucous layer of the stomach
• Protease leads to disintegration of the polymeric structure of mucin
• Phospholipase A2 and lipase leads to loss of mucosal surface hydrophobicity, mucus lipid degradation, and lysophospholipid generation^[17][18]
• Lysophospholipids disrupts the phospholipid rich layer at the apical surface of mucous cells

• Urease

• Gastric acid resistance plays a crucial role in pathogenesis of H.pylori infection.^[19][20]
• Urease is one of the most abundant protein produced by H.pyloi, whose production is regulated by one of the genes associated with gastric acid resistance
• The urease of H.pylori has two subunits, UreA and UreB.^[21][22]
• This enzyme hydrolyzes urea to ammonia and carbon dioxide, which increases the cytoplasmic pH in the micro environment around the organism, hence protects the bacteria from gastric acid
• The H+-gated urea channel(Urel) regulates the urea entry into cytoplasm of H. pylori cell which helps in quick adaptation of organism to acidic environment.^[23]
• Ammonia and ammonium chloride inhibit the growth of gastric cells in S phase, leading to gastric mucosal atrophy^[24]

C. Bacterial Virulence factors

The cytotoxin-associated gene (Cag) pathogenecity island (PAI) and cytotoxin-associated gene A (cagA)

• Large amounts of the pro-inflammatory cytokine interleukin-8 are expressed in H. pylori strains with CagPaI.
• The protein CagA is encoded by CagA gene and type IV bacterial secretion system (T4SS) is encoded by CagPAI.
• Type IV bacterial secretion apparatus helps in translocation of CagA into host target cells and stimulates epithelial cell pro-inflammatory cytokine expression and gastric inflammation
• CagA undergoes phosphorylation in host target cells

The following are the bacterial virulence factors associated with H. pylori pathogenesis:

CagA

• The CagA protein is encoded by CagA gene and is translocated to epithelial cell cytosol through type IV bacterial secretion apparatus.
• It is activated by phosphorylation on tyrosine residues by host scr kinases.^[25][26]
• After phosphorylation, it interacts with SHP-2 and activates MAP kinase signalling leading to abnormal proliferation of gastric epithelial cells.
• The CagA protein also binds to Crk proteins leading to disruption of epithelial cell tight junctions and tissue damage.
• The type and number of CagA tyrosine phosphorylation motifs differ in the individual strains.
• Strains having CagA with more phosphorylation motifs cause atrophy and gastric carcinoma than strains with fewer motifs.^[27][28][29]
• The IL-8 secretion is independent of tyrosine phosphorylation of CagA but dependent on the region having phosphorylation motifs.

Outer inflammatory protein A (OipA)

• OipA strain is associated with duodenal ulceration and gastric cancer^[30][31]
• This protein is regulated by slipped strand mispairing^[32]

Duodenal ulcer promoting gene A (dupA)

This gene is associated with duodenal ulceration but appeared to protect from gastric cancer in patients from columbia, Japan and South Korea.^[33]

Blood group antigen binding adhesion A (BabA)

• BabA2 gene encodes the active form of BabA which binds to fucosylated Le antigens which are expressed on gastric epithelial cells.^[34]
• BabA increases the adhesion of H. pylori to epithelial cells which leading to increased delivery of factors associated with inflammation.
• Active form of BabA is associated with increased association of Cag+ strains with gastric cancer and duodenal ulceration.^[35]

The RNA polymerase β-subunit (RpoB)

• The RpoBThr is associated with increased secretion of IL-8 from MKN45 cells compared to RpoBAla.
• H. pylori strains possessing RpoBThr is seen in 67.6% of East Asians and hence associated with increased risk of development of more severe gastroduodenal diseases.^[36]

The vacuolating cytotoxin (VacA)

• VacA is an exotoxin which is associated with cellular damage rather than pro-inflammatory cytokine release.^[37]
• The active forms of VacA are associated with increased risk of gastric carcinoma

The risk of gastric carcinoma increases due to :^[38][39]

• The stable polymorphisms of several cytokine gens
• Increased expression of IL-1β or tumor necrosis factor-alpha (TNF)α
• The reduced expression of the anti-inflammatory cytokine IL-10 due to single nucleotide polymorphism

The innate immune response

• H. pylori colonization of the gastric mucosa is associated with innate host defense mechanisms leading to the expression of pro-inflammatory and anti-bacterial factors.^[40][41]The expression of these factors results in gastritis.
• The severity of the H. pylori disease and gastric carcinogenesis is associated with the innate immune response.
• The innate immune mechanisms are dependent on the Nod1, which is a pattern recognition receptors (PRR) stimulated by cag+ strains.^[42]
• Defensins are the anti-microbial peptides which are secreted as a response to H. pylori infection. Elevated levels of human β defensin 2 (hBD2) and the neutrophil-derived alpha defensins are detected in gastric juice of infected patients.^[43]
• The infected gastric epithelial cells have increased expression of hBD2, hBD3, angiogenin, adrenomedullin, and the human cationic antimicrobial peptide 18 (LL-37).^[40]
• Due to high secretion of cytokines and chemokines by the gastric epithelial cells, there is increased migration of granulocytes, lymphocytes and monocytes leading to severe inflammatory pathology.^[44]
• The H. pylori after phagocytosis survive inside the phagosome and all phagosomes fuse to become megasomes. This provides a protected intracellular cavity in the macrophage, contributing to the persistence of infection.^[45][46]

The acquired immune response

• H. pylori stimulates the production of mucosal and systemic IgA and IgG antibodies which induces local inflammation and damage by cross reacting with the parietal cell H+,K+-ATPase and antigens on gastric epithelial cells.^[47][48]
• The T-helper 1 (Th1) response in the gastric mucosa dominates the T-cell response to H. pylori. The Th1 cells release type 1 cytokines (IFNγ) which activate macrophages resulting in secretion of pro-inflammatory factors (TNFα, IL-12 and IL-18) and increase bactericidal activity compared to those activated by Th2 cytokines. The severity of gastritis depends on the number of IFNγ-secreting cells in the infected gastric mucosa.^{[49][50][51][52]}
• H. pylori suppress immune and inflammatory responses by eliciting Treg (T-cell regulatory) responses and thus maintain chronic colonization. They also suppress human memory T-cells in response to H. pylori antigens.^[53]

Somatostatin and gastrin changes

• The inflammatory mediators produced due to H. pylori infection, including nitric oxide suppress somatostatin release. The infection is also associated with reduced numbers of somatostatin-producing D cells in the stomach.^[54][55][56]
• The gastrin production from G cells is increased due to direct stimulatory action of cytokines and suppression of somatostatin.
• Hypergastrinemia stimulates MAP kinase which results in up-regulation of the cox-2 gene which is potentially has potentially pro-oncogenic effect. It may also leads to gastric atrophy by up-regulation of the Reg protein.^[57][57]
• Hypergastrinemia leads to excess acid production leading to dyspepsia.

The environmental co-factors associated with H. pylori are:

• Age at infection
• Degree of crowding
• Smoking
• Malnutrition
• High salt intake
• Vitamin deficiency

On gross pathology, H. pylori infection is associated with thickened gastric folds and erythema.^[58]

The microscopic pathology depends on the the following stages:^[59]

Acute H.pylori infection

• Most of the initial H. pylori colonization occur during childhood but new infections may occur in adults occasionally.^[60][61]
• Associated with transient profound gastric hypochlorhydria

Microscopic pathology

• Surface epithelial degeneration
• Heavy neutrophilic infiltration in lamina propria of antrum and corpus and infiltrating the foveolar and surface epithelium
• Gradual infiltration of other inflammatory cells, especially lymphocytes

Chronic H.pylori infection

• Chronic antral predominant inflammation:

• Associated with increased stimulated acid production leading to duodenal ulceration

• Chronic corpus-predominant or pangastritis

• Associated with reduced acid production
• Predisposes to gastric ulceration and gastric adenocarcinoma

Microscopic pathology

• Epithelial degeneration
• Neutrophil infiltration
• predominantly lymphocyte, monocyte and/ or plasma cell infiltration in the superficial lamina propria
• Glandular atrophy
• Intestinal metaplasia
• Lymphoid tissue aggregates

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