Rohit Raina

Background: Helicobacter pylori (H. pylori) is a gram-negative bacterium present that is orally transferred and present in upwards of four billion people in the world^1,2,3. H. pylori accounts for more than 60% of diagnosed gastric cancers, resulting in the classification of this bacterium as a group 1 carcinogen³. In addition, H. pylori has slowly developed antibiotic resistance to current “triple therapy” treatments of Clarithromycin, Amoxicillin, and a proton pump inhibitor¹. A link towards endothelial dysfunction in atherosclerosis and gastric carcinomas has been speculated to be due to the formation of Radical Oxidative Species (ROS)^5,6. These findings could suggest H. pylori can induce ROS to induce pathogenicity and could suggest novel therapeutics to mitigate ROS^5,6,7,8. In studies, some mice and some gastric epithelial cell lines were transfected with the CagA plasmid (a known gene involved in H. pylori’s virulence, where it can alter cell morphology)⁵.

Objective: In this review, we dove into the mechanisms by which Radical Oxidative Species can exacerbate pathogenicity in an H. pylori infection.

Search Methods: An online search was conducted using the PubMed database. The time period 2016-2023 was set and these keywords were used: “H. pylori”, “ROS”, “CagA”, and “NLRP3”.

Results: The NLRP3 inflammasome pathway and PI3K/Akt pathway were studied as they have noted to be upregulated pathways in both cellular dysfunction, DNA damage, and ROS production^5,7. There was an increase in both the expression of NLRP3 and Caspase-1 (a pro-pyroptotic protein), indicating upregulation in the production of ROS⁵. Confirmation of the upregulation in the aforementioned study was done by flow cytometry, indicating a rise in pyroptosis linked to ROS; both studies indicated a significant rise in only mice transfected with CagA⁵. In addition, an increase in Akt phosphorylation has been correlated with DNA damage: this upregulation in Akt phosphorylation was found in CagA⁺ mice⁷. To determine the presence of endothelial dysfunction, mice were monitored to model an acute and chronic infection. CagA⁺ mice., when compared to CagA^– mice, had significant endothelial dysfunction and were significant for a reduction in aortic relaxation in a dose-dependent manner, and an increase in aortic lesion size⁶. In hopes of reducing the endothelial dysfunction by ROS, an anti-oxidant was tested. N-acetylcysteine (NAC) was administered in studies interested in mitigating ROS. NAC was able to reduce the prevalence of ROS in a dose-dependent fashion in each study as well as restore aortic relaxation, but these changes were only evident in mice/cell lines with the CagA transfection^5,6,7. NAC was unable to reverse/mitigate the effects of ROS once dysplasia/metaplasia had occurred to the cell line⁷.

Conclusions: In conclusion, studies indicate that infection with H. pylori correlates with an increase in ROS. H. pylori is able to harness ROS through various pathways inducing endothelial dysfunction, thereby accelerating the formation of atherosclerosis, as well as impacting the gastric epithelium and eventually causing gastric ulcers and carcinomas. Action on eradication with antibiotics and controlling the infection through anti-oxidants before severe damage is of utmost importance when dealing with this infection.

Works Cited:

1. de Brito BB, da Silva FAF, Soares AS, et al. Pathogenesis and clinical management of Helicobacter pylori gastric infection. World J Gastroenterol. 2019;25(37):5578-5589. doi:10.3748/wjg.v25.i37.5578
2. O’Brien VP, Koehne AL, Dubrulle J, et al. Sustained Helicobacter pylori infection accelerates gastric dysplasia in a mouse model. Life Sci Alliance. 2020;4(2):e202000967. Published 2020 Dec 11. doi:10.26508/lsa.202000967
3. Alipour M. Molecular Mechanism of Helicobacter pylori-Induced Gastric Cancer. J Gastrointest Cancer. 2021;52(1):23-30. doi:10.1007/s12029-020-00518-5
4. Smyth EC, Nilsson M, Grabsch HI, van Grieken NC, Lordick F. Gastric cancer. Lancet. 2020;396(10251):635-648. doi:10.1016/S0140-6736(20)31288-5
5. Zhang X, Li C, Chen D, et al. H. pylori CagA activates the NLRP3 inflammasome to promote gastric cancer cell migration and invasion. Inflamm Res. 2022;71(1):141-155. doi:10.1007/s00011-021-01522-6
6. Xia X, Zhang L, Wu H, et al. CagA⁺Helicobacter pylori, Not CagA^–Helicobacter pylori, Infection Impairs Endothelial Function Through Exosomes-Mediated ROS Formation. Front Cardiovasc Med. 2022;9:881372. Published 2022 Mar 31. doi:10.3389/fcvm.2022.881372
7. Xie C, Yi J, Lu J, et al. N-Acetylcysteine Reduces ROS-Mediated Oxidative DNA Damage and PI3K/Akt Pathway Activation Induced by Helicobacter pyloriOxid Med Cell Longev. 2018;2018:1874985. Published 2018 Apr 26. doi:10.1155/2018/1874985
8. Mera RM, Bravo LE, Camargo MC, et al. Dynamics of Helicobacter pyloriinfection as a determinant of progression of gastric precancerous lesions: 16-year follow-up of an eradication trial. Gut. 2018;67(7):1239-1246. doi:10.1136/gutjnl-2016-311685