Citation: Reyes, V.E. Helicobacter pylori and Its Role in Gastric Cancer. Microorganisms 2023, 11, 1312. https://doi.org/10.3390/ microorganisms11051312 Academic Editors: Vincenzo Scarlato, Fabio Verginelli, Shimaa Hassan AbdelAziz Soliman and Diana Liberata Esposito Received: 17 April 2023 Revised: 8 May 2023 Accepted: 15 May 2023 Published: 17 May 2023 Copyright: © 2023 by the author. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). microorganisms Review Helicobacter pylori and Its Role in Gastric Cancer Victor E. Reyes Department of Pediatrics and Microbiology & Immunology, University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555-0372, USA; vreyes@utmb.edu; Tel.: +1-409-772-3824 Abstract: Gastric cancer is a challenging public health concern worldwide and remains a leading cause of cancer-related mortality. The primary risk factor implicated in gastric cancer development is infection with Helicobacter pylori. H. pylori induces chronic inflammation affecting the gastric epithelium, which can lead to DNA damage and the promotion of precancerous lesions. Disease manifestations associated with H. pylori are attributed to virulence factors with multiple activities, and its capacity to subvert host immunity. One of the most significant H. pylori virulence determinants is the cagPAI gene cluster, which encodes a type IV secretion system and the CagA toxin. This secretion system allows H. pylori to inject the CagA oncoprotein into host cells, causing multiple cellular perturbations. Despite the high prevalence of H. pylori infection, only a small percentage of affected individuals develop significant clinical outcomes, while most remain asymptomatic. Therefore, understanding how H. pylori triggers carcinogenesis and its immune evasion mechanisms is critical in preventing gastric cancer and mitigating the burden of this life-threatening disease. This review aims to provide an overview of our current understanding of H. pylori infection, its association with gastric cancer and other gastric diseases, and how it subverts the host immune system to establish persistent infection. Keywords: gastric cancer; Helicobacter pylori; cag pathogenicity island; cytotoxin-associated gene A; oncoprotein; vacuolating toxin A; immune evasion 1. Introduction Gastric cancer (GC) remains among the deadliest cancers worldwide, taking close to one million lives annually. GC is the fourth leading cause of cancer-related deaths [1]. According to the American Cancer Society’s (ACS) estimates for 2022, in the United States, there are 26,380 new cases and 11,090 deaths attributed to GC [2]. Worldwide, in 2020 the incidence of GC was 1,089,103 and claimed 768,793 lives [3]. Although its incidence in the United States is declining, the prognosis for patients with GC is bleak since their five-year survival rate is low. The poor prognosis for these patients is because most GC cases (90%) are diagnosed at an advanced stage due to our inadequate understanding of the underlying mechanisms that regulate carcinogenesis and the lack of routine screening for GC. H. pylori was initially described by Australian scientists Barry Marshall and Robin Warren in 1982 [4]. Their work with human gastric specimens identified H. pylori as the primary cause of chronic gastritis and peptic ulcer disease (PUD). Their research challenged the prevailing medical dogma that ulcers result from stress and lifestyle factors. Before their discovery, they treated peptic ulcers primarily using antacids and diet modification, such as avoiding spicy and acidic foods. However, these treatments were inadequate, and often vagotomy or surgery to remove the affected portion of the stomach or duodenum was the next step to reduce acid secretion. The work of Marshall and Warren transformed the treatment of PUD and has helped save many lives. Their efforts were recognized with the Nobel Prize in Physiology or Medicine in 2005. The infection is treated with antibiotics to eradicate the bacteria and acid-suppressing drugs. The primary risk factor for GC is Helicobacter pylori, a microaerophilic, spiral-shaped Gram-negative bacterium classified as a class I carcinogen [5]. H. pylori is perhaps the Microorganisms 2023, 11, 1312. https://doi.org/10.3390/microorganisms11051312 https://www.mdpi.com/journal/microorganisms