Helicobacter pylori (H. pylori) bacteria infect about 50% of the human population and colonize the mucosa layer of the stomach. Although in most people the infection is asymptomatic, H. pylori was classified as a carcinogenic agent by the World Health Organization in 1994. It is now accepted that these bacteria are an important cause of gastric cancer worldwide, with a six-fold increased risk of developing gastric cancer in infected people. The genome of some H. pylori strains contains the cagA gene encoding the CagA toxin that alters the architecture of stomach epithelial cells, allowing better attachment of the bacteria to the epithelium, and leads to chronic inflammation. This inflammatory process, combined with more direct effects of the bacteria on the stomach epithelium such as an increase in the mutation rate, are believed to be the two main mechanisms of tumorigenesis linked to H. pylori.
While half of the patients in the Western world are infected by cagA-positive strains that is associated with a higher risk of developing gastric cancer, East Asian populations positive for H. pylori are predominantly infected by these strains. In these populations, the EPIYA-D (East Asian) allele of the cagA gene is associated with a higher risk for gastric cancer. However, several previous studies are contradictory, and the different sample collection methods (stomach mucosa brushing vs stool) may explain at least part of the discrepancies. In order to assess the correlation between stomach and stool bacterial load, Dr. Sarah Talarico and colleagues, from Dr. Nina Salama’s lab (Human Biology and Public Health Sciences divisions), collaborated with the Henan Cancer Hospital in China to collect gastric mucosa and stool from 49 patients who tested positive for H. pylori according to the breath urea test. This pilot study group was composed of 25 patients with gastric cancer and 24 non-cancer patients. The Salama lab used a method of their own, a digital droplet PCR (ddPCR) assay, to study the bacterial load and cagA genotype in patient samples. The results were published in PLOS ONE this month.
Interestingly, although the bacterial load was similar in the stomach of gastric cancer and non-cancer patients, H. pylori was more abundant in the stool from gastric cancer patients, indicating that bacterial shedding in the stool could be a marker of gastric cancer, at least in this population. Next, they wanted to assess the presence of the cagA gene and distinguish between Western and East Asian alleles. In the stomach samples collected at the Henan Cancer Hospital, cagA was detected in all patients positive for H. pylori. They also confirmed that the EPIYA-D allele was significantly correlated with gastric cancer, unlike the Western allele. Interestingly, the EPIYA-D allele positive patients displayed a higher bacterial load in the stool compared to patients with the Western allele, suggesting that EPIYA-D allele, bacterial shedding in the stool and gastric cancer may be strongly correlated in East Asian populations.
The authors now want to confirm their results in a larger study to confidently explore new opportunities, such as the detection in the stool of the East Asian allele as a biomarker for patients with high risk for gastric cancer in this specific population. Dr. Nina Salama commented, “East Asian populations are at high risk for gastric cancer if infected with H. pylori. Our data suggest that those infected with East Asian cagA alleles are at particular risk. However, these data would need to be repeated with large samples to drive public health measures”. In addition, bacteria with the East Asian allele seem to be more prone to shed into the stool compared to the Western allele bacteria, which could provide interesting insights into the bacteria biology and the tumorigenic process. But as Dr. Nina Salama reminds, “our sample size was quite small. It is possible that in a larger study the trend we observed toward higher stool loads would become significant”.
This work was supported by the National Institute of Health and the Henan Science and Technology Breakthrough Project.
Fred Hutch/UW Cancer Consortium faculty members Drs Steve Self and Nina Salama, contributed to this research, in collaboration with Dr. Yuzhou Zhao from The Affiliated Cancer Hospital of Zhengzhou University, China.
Talarico S, Leverich CK, wei B, Ma J, XinGuang C, YongJun G, Han G, Yao L, Self S, Zhao Y, Salama NR. 2018. Increased H. pylori stool shedding and EPIYAD cagA alleles are associated with gastric cancer in an East Asian hospital. PloS ONE 13(9): e0202925.