Helicobacter pylori infection pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yamuna Kondapally, M.B.B.S[2]

Overview

Person to person transmission is considered to be the most likely route of transmission of Helicobacter pylori. H. pylori is a non invasive organism. It is found over mucus secreting cells but not in deeper gastric glands. Hence it can only inhabit gastric-type mucus but cannot colonize the esophagus or duodenum. Pathogenesis of H. pylori infection depends on bacterial, host and environmental factors.

Pathophysiology

  • 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
  • Fecal-oral route
  • Fecal contamination of water and food may be the source of infection especially in developing countries[4]
  • Oral-oral route
  • Via saliva especially in developed countries[4]
  • Motility of H. pylori (The corkscrew motility is due to its multiple flagella and spiral shape)
  • Chemotaxis
  • Environmental sensing
  • Acid resistance
  • Iron acquisition

Pathogenesis

The pathogenesis involves four important steps. They are:

Factors Associated With Pathogenesis

Factors Associated With H. pylori Pathogenesis
Bacterial Host Environmental
Flagella Immune response to H.pylori
  • Innate immunity
  • Acquired immunity
  • Age at infection
  • Smoking
  • Degree of crowding
  • Malnutrition
  • High salt intake
  • Vitamin deficiency
Bacterial enzymes
  • Lipase and protease
  • Urease
Hormonal and Acid homeostasis changes
  • Decrease stomatostatin levels
  • Hypergastrinemia
Bacterial Virulence factors
  • CagA
  • Outer inflammatory protein A (OipA)
  • Duodenal ulcer promoting gene A (dupA)
  • Blood group antigen binding adhesion A (BabA)
  • RNA polymerase β-subunit (RpoB)
  • Vacuolating cytotoxin (VacA)

1: Bacterial factors

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:[7]

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

Outer inflammatory protein A (OipA)

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.[24]

Blood group antigen binding adhesion A (BabA)

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.[27]

The vacuolating cytotoxin (VacA)

  • VacA is an exotoxin which is associated with cellular damage rather than pro-inflammatory cytokine release.[28]
  • The active forms of VacA are associated with increased risk of gastric carcinoma

2. Host genetic susceptibility

The risk of gastric carcinoma increases due to :[29][30]

A.The immune response to H.Pylori

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.[31][32]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.[33]
  • Defensins are the antimicrobial 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.[34]
  • The infected gastric epithelial cells have increased expression of hBD2, hBD3, angiogenin adrenomedulin, and the human cationic antimicrobial peptide 18 (LL-37).[31]
  • 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.[35]
  • The H.pylory 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 perisitence of infection.[36][37]

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.[38][39]
  • 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.[40][41][42][43]
  • H.pylori suppress immune and inflammatory responses by eliciting Treg (T-cell regulatory) responses and thus maintain chronic colonization. They also supress human memory T-cells in response to H.pylori antigens.[44]

B. Hormonal changes and acid homeostasis changes

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.[45][46][47]
  • The gastrin production from G cells is increased due to direct stimulatory action of cytokines and supression of somatostatin.
  • Hypergastrinemia stimulates MAP kinase which results in upregulation of the cox-2 gene which is potentially has potentially prooncogenic effect. It may also leads to gastric atrophy by upregulation of the Reg protein.[48][48]
  • Hypergastrinemia leads to excess acid production leading to dyspepsia.

3. Environmental cofactors

The environmental cofactors associated with H.pylori are:

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

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Based on location

Based on the location of inflammation, the pathogenesis depends on:[6]

1: Antral-predominant inflammation: The uninflamed corpus produces large amount of acid predisposing to duodenal ulceration

2: Corpus-predominant inflammation: This leads to gastric ulceration and adenocarcinoma due to hypochlorhydria

Gross pathology

On gross pathology, H.pylori infection is associated with thickened gastric folds and erythema.[49]

Microscopic Histopathological analysis

The microscopic histopathological analysis depends on the the following stages:[50]

Acute H.pylori infection

  • Most of the initial H.pylori colonization occur during childhood but new infections may occur in adults occasionally.[51][52]
  • 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

References

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  2. ↑ Cave DR (1997). "How is Helicobacter pylori transmitted?". Gastroenterology. 113 (6 Suppl): S9–14. PMID 9394753.
  3. ↑ Transmission http://www.who.int/bulletin/archives/79(5)455.pdf (2001) Accessed on December 27, 2016
  4. ↑ 4.0 4.1 4.2 Das JC, Paul N (2007). "Epidemiology and pathophysiology of Helicobacter pylori infection in children". Indian J Pediatr. 74 (3): 287–90. PMID 17401270.
  5. ↑ Jhala NC, Siegal GP, Klemm K, Atkinson BF, Jhala DN (2003). "Infiltration of Helicobacter pylori in the gastric mucosa". Am J Clin Pathol. 119 (1): 101–7. doi:10.1309/YDTX-KE06-XHTH-FNP2. PMID 12520704.
  6. ↑ 6.0 6.1 Atherton JC (2006). "The pathogenesis of Helicobacter pylori-induced gastro-duodenal diseases". Annu Rev Pathol. 1: 63–96. doi:10.1146/annurev.pathol.1.110304.100125. PMID 18039108.
  7. ↑ Smoot DT (1997). "How does Helicobacter pylori cause mucosal damage? Direct mechanisms". Gastroenterology. 113 (6 Suppl): S31–4, discussion S50. PMID 9394757.
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  9. ↑ Mauch F, Bode G, Ditschuneit H, Malfertheiner P (1993). "Demonstration of a phospholipid-rich zone in the human gastric epithelium damaged by Helicobacter pylori". Gastroenterology. 105 (6): 1698–704. PMID 8253346.
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  34. ↑ Isomoto H, Mukae H, Ishimoto H, Date Y, Nishi Y, Inoue K; et al. (2004). "Elevated concentrations of alpha-defensins in gastric juice of patients with Helicobacter pylori infection". Am J Gastroenterol. 99 (10): 1916–23. doi:10.1111/j.1572-0241.2004.40334.x. PMID 15447750.
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  36. ↑ Allen LA, Schlesinger LS, Kang B (2000). "Virulent strains of Helicobacter pylori demonstrate delayed phagocytosis and stimulate homotypic phagosome fusion in macrophages". J Exp Med. 191 (1): 115–28. PMC 2195807. PMID 10620610.
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  38. ↑ Appelmelk BJ, Simoons-Smit I, Negrini R, Moran AP, Aspinall GO, Forte JG; et al. (1996). "Potential role of molecular mimicry between Helicobacter pylori lipopolysaccharide and host Lewis blood group antigens in autoimmunity". Infect Immun. 64 (6): 2031–40. PMC 174033. PMID 8675304.
  39. ↑ Amedei A, Bergman MP, Appelmelk BJ, Azzurri A, Benagiano M, Tamburini C; et al. (2003). "Molecular mimicry between Helicobacter pylori antigens and H+, K+ --adenosine triphosphatase in human gastric autoimmunity". J Exp Med. 198 (8): 1147–56. doi:10.1084/jem.20030530. PMC 2194239. PMID 14568977.
  40. ↑ Bamford KB, Fan X, Crowe SE, Leary JF, Gourley WK, Luthra GK; et al. (1998). "Lymphocytes in the human gastric mucosa during Helicobacter pylori have a T helper cell 1 phenotype". Gastroenterology. 114 (3): 482–92. PMID 9496938.
  41. ↑ D'Elios MM, Manghetti M, De Carli M, Costa F, Baldari CT, Burroni D; et al. (1997). "T helper 1 effector cells specific for Helicobacter pylori in the gastric antrum of patients with peptic ulcer disease". J Immunol. 158 (2): 962–7. PMID 8993017.
  42. ↑ Fan XJ, Chua A, Shahi CN, McDevitt J, Keeling PW, Kelleher D (1994). "Gastric T lymphocyte responses to Helicobacter pylori in patients with H pylori colonisation". Gut. 35 (10): 1379–84. PMC 1375009. PMID 7959191.
  43. ↑ Lehmann FS, Terracciano L, Carena I, Baeriswyl C, Drewe J, Tornillo L; et al. (2002). "In situ correlation of cytokine secretion and apoptosis in Helicobacter pylori-associated gastritis". Am J Physiol Gastrointest Liver Physiol. 283 (2): G481–8. doi:10.1152/ajpgi.00422.2001. PMID 12121897.
  44. ↑ Lundgren A, Suri-Payer E, Enarsson K, Svennerholm AM, Lundin BS (2003). "Helicobacter pylori-specific CD4+ CD25high regulatory T cells suppress memory T-cell responses to H. pylori in infected individuals". Infect Immun. 71 (4): 1755–62. PMC 152046. PMID 12654789.
  45. ↑ Moss SF, Legon S, Bishop AE, Polak JM, Calam J (1992). "Effect of Helicobacter pylori on gastric somatostatin in duodenal ulcer disease". Lancet. 340 (8825): 930–2. PMID 1357347.
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  49. ↑ H.pylori infection https://librepathology.org/wiki/Helicobacter_gastritis (May,2016) Accessed on January 4, 2017
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  51. ↑ Sobala GM, Crabtree JE, Dixon MF, Schorah CJ, Taylor JD, Rathbone BJ; et al. (1991). "Acute Helicobacter pylori infection: clinical features, local and systemic immune response, gastric mucosal histology, and gastric juice ascorbic acid concentrations". Gut. 32 (11): 1415–8. PMC 1379180. PMID 1752479.
  52. ↑ Dixon MF (1995). "Histological responses to Helicobacter pylori infection: gastritis, atrophy and preneoplasia". Baillieres Clin Gastroenterol. 9 (3): 467–86. PMID 8563048.
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