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Bacterial Flora Concentrations in Stomach Influence Cancer Risk

NEW YORK (GenomeWeb) – Researchers at the University of Liverpool have found that patients with varying levels of reduced stomach acid secretion, known as hypochlorhydria, can lead to altered risks of developing gastric malignancies.

Helicobacter pylori-induced atrophic gastritis normally predisposes a patient to gastric adenocarcinoma. Autoimmune atrophic gastritis is an indicator of type I gastric neuroendocrine tumors, whereas proton pump inhibitor (PPI) use does not usually influence stomach cancer risk.

For their study, which was published today in PLOS Pathogens, the researchers "hypothesised that each of these conditions was associated with specific alterations in the gastric microbiota, and that this influenced subsequent tumor risk." The team selected 95 patients from a group of 1,400 representing normal stomach, PPI treated, H. pylori gastritis, H. pylori-induced atrophic gastritis, and autoimmune atrophic gastritis.

Researchers extracted the RNA from gastric corpus biopsies and analyzed the samples using 16s RNA sequencing, identifying 23 different bacterial phyla.

Samples from normal stomachs and patients treated with PPIs demonstrated similarly high microbial diversity. In general, the microbiota, co-occurrence networks, and predicted pathways in samples from PPI-treated patients were similar to those in normal stomachs. However, samples from PPI-treated patients contained significantly more Streptococcus.

Patients with autoimmune atrophic gastritis showed relatively high microbial diversity, but the samples contained higher amounts of Streptococcus. The stomachs of autoimmune atrophic gastritis patients contained a higher proportion of Streptococcaceae than all other patient groups.

Samples from patients who had autoimmune atrophic gastritis also differed from the others in terms of the presence of specific bacteria, as they were the only samples that showed complete loss or gain of bacteria, rather than simply changes in bacterial proportions.  

"This suggests that changes in the gastric bacterial community during hypochlorhydria usually involve changes in the relative proportions of bacteria that are already present, and only rarely involve the loss or gain of specific bacterial genera," the researchers noted.

H. pylori gastritis, and to some extent H. pylori-induced atrophic gastritis, led to lower bacterial abundances and diversity, but the stomach flora samples were dominated by H. pylori. The majority of changes observed in these samples were due to reductions in non-H. pylori bacteria.

"Pathway analysis suggested that glucose-6-phosphate-dehydrogenase and D-lactate dehydrogenase were overrepresented in H. pylori-induced atrophic gastritis versus autoimmune atrophic gastritis, and that both these groups showed increases in fumarate reductase," the researchers said.

Fumarate reductase is involved in the metabolism of some bacteria and is crucial for colonization by H. pylori in the stomach.

16s rRNA sequencing also identified relatively few alterations in the gastric microbiota in patients receiving PPI therapy compared to healthy patients' microbiota, despite reduced acid secretion. PPI-treated patients also demonstrated more similarities in microbial diversity and abundance to patients who had autoimmune atrophic gastritis than to the patients who had H. pylori-induced atrophic gastritis.

The researchers also noted that autoimmune and H. pylori-induced atrophic gastritis were linked to different gastric microbial profiles.

The study indicated that H. pylori colonization and hypochlorhydria result in changes in gastric bacterial abundance and only rarely in loss and gain of bacteria. PPI treatment did not change the gastric microbiota from that of a normal stomach, despite the serum gastrin concentration being comparable to those found in patients with H. pylori- induced atrophic gastritis.

Microbial patterns appeared not to correlate with gastrin levels, although factors including H. pylori infection status might have undermined the relationship.

Multiple biochemical pathways appeared in similar fashions in both atrophic gastritis groups. For example, researchers saw "that gastric-atrophy was associated with changes in the citric acid cycle, which is a biochemical pathway that is known to be associated with gastric carcinogenesis."

The researchers highlighted as study strengths the relatively large cohort of patients and the subsequent high numbers of samples sequenced. Weaknesses included a lack of patient dietary information and the researcher's inability to match a patient's' age and gender. The investigators stated that future studies will need to elucidate and confirm the predicted pathway analysis.

The findings suggest that the development of gastric cancer is multifactorial, and data from the present study points to non-H. pylori microbiota as a potential participating factor.

"This work may eventually lead to the development of new chemopreventive therapies for stomach cancer that are based on altering the composition of the gastric microbiota," the authors added.