Genichiro Fujioka

Background: Peptic ulcer disease (PUD) is a gastrointestinal disease that involves lesions of the stomach or duodenum that extend to at least the submucosal layer.¹ Untreated PUD can lead to many serious and life-threatening complications such as acute upper GI bleeding, perforation, and gastric outlet obstruction.¹ One of the major risk factors for developing PUD is an infection with Helicobacter pyori.¹ Surveys have showed that about 50% of people worldwide may be infected with H. pylori.^1,2,3 Vacuolating Cytotoxin A (VacA) is a virulence factor released by H. pylori that oligomerizes to form chloride-selective ion channels.² This leads to lysosomal and mitochondrial dysfunction in cells.² A focus of current research of H. pylori pathogenesis are the allelic variations of the VacA protein. These findings could help predict the risk for patients infected with H. pylori in developing PUD.

Objective: To further the understanding of how the allelic variations of VacA can affect mucosal cells and the development of PUD.

Search Methods: An online search was conducted on PubMed for articles ranging from 2019 to 2023 with the keywords “H pylori”, “VacA”, and “Peptic Ulcer Disease”.

Results: One of the areas of genetic variation in the VacA protein that is being investigated is the m region.⁴ There is a 55% variance in amino acids in the p55 region between the m1 and m2 variants as well as an amino acid insertion unique to each variant.⁴ Single particle cryo-EM was utilized to assess the oligomerization of the m1 VacA protein and found that the protein formed hexamers that combined to form dodecamers prior to interacting with cell membranes.⁵ The m region was found to contain loops and strands that partake in the formation of dodecamers.⁵ It was predicted that the variations between m1 and m2 could lead to structural changes that affect the protein’s interaction with cell membranes and receptors.⁵ The m1 VacA variant showed significantly greater binding, internalization, and vacuolation on HeLa and AGS gastric epithelial cells compared to that of the m2 variant.⁴ Further experiments showed that this led to a decrease in cellular ATP and greater membrane depolarization in duodenal cells exposed to the m1 variant.⁴ These increased cytotoxic effects of the m1 variant showed decreased cell viability and may lead to a differing level of severity of PUD in patients infected with the m1 or m2 strain.⁶ In a clinical trial in Iran, it was found that a greater proportion of patients infected with the m1 variant of H. pylori developed PUD compared to that of patients infected with the m2 variant.⁷

 Conclusion: The allelic variations of the m region led to structural changes in the VacA protein that altered the cytotoxic effects. Patients infected with H. pylori with the m1 VacA variant may be at greater risk for developing PUD. Assessing the VacA genotypes of H. pylori strains patients are infected with, and establishing the prevalence of the more virulent variants in an area should be considered when evaluating the risk of developing PUD.

Works Cited:

1. Narayanan M, Reddy KM, Marsicano E. Peptic Ulcer Disease and Helicobacter pylori infection. Mo Med. 2018;115(3):219-224.
2. Cho J, Prashar A, Jones NL, Moss SF. Helicobacter pylori Infection. Gastroenterol Clin North Am. 2021;50(2):261-282. doi:10.1016/j.gtc.2021.02.001
3. Xu W, Xu L, Xu C. Relationship between Helicobacter pylori infection and gastrointestinal microecology. Front Cell Infect Microbiol. 2022;12:938608. Published 2022 Aug 18. doi:10.3389/fcimb.2022.938608
4. Caston RR, Sierra JC, Foegeding NJ, et al. Functional properties of Helicobacter pylori VacA toxin m1 and m2 variants. Infect Immun. 2020;88(6):e00032-20. Published 2020 May 20. doi:10.1128/IAI.00032-20
5. Su M, Erwin AL, Campbell AM, et al. Cryo-EM analysis reveals structural basis of Helicobacter pylori VacA toxin oligomerization. J Mol Biol. 2019;431(10):1956-1965. doi:10.1016/j.jmb.2019.03.029
6. Linn AK, Samainukul N, Sakdee S, et al. N-Terminally added tag selectively enhances heterologous expression of VacA cytotoxin variants from Helicobacter pylori. Protein Pept Lett. 2021;28(6):643-650. doi:10.2174/0929866527666201112122831
7. Sheikh AF, Yadyad MJ, Goodarzi H, et al. CagA and vacA allelic combination of Helicobacter pylori in gastroduodenal disorders. Microb Pathog. 2018;122:144-150. doi:10.1016/j.micpath.2018.06.023