H. pylori’s relationship with gastric cancer? It’s complicated

Does eradicating Helicobacter pylori prevent gastric cancer?

The answer is yes, sometimes – but it depends on where you live, and what other bacteria coexist in your gut microbiome.

The overall view is a positive one said at the meeting sponsored by the American Gastroenterological Association. A very large, recent meta analysis confirms it.

That’s great news – but there’s a big caveat said the University, Nashville, Tenn.

“The benefit was dependent on what your baseline risk was. For those with a high baseline risk, the benefit was tremendous. For those with a low baseline risk, it was not statistically significant.”

There are long-term data suggesting that treating H. pylori sooner rather than later is the way to go. A 2005 study followed more than 700 patients with preneoplastic gastric lesions for 12 years. It found that the treatment effect was cumulative: The longer the patients were free of H.pylori, the more reliably healing occurred.

At baseline, the patients were randomized to nutritional supplements or to a combination of amoxicillin, metdonidazole, and bismuth subsalicylate. At six years, the trial was unblinded and all patients were offered treatment. Patients were followed for another six years. Those who were H. pylori negative at 12 years had 15 percent more regression and 14 percent less progression than subjects who were positive at 12 years. Among those who received anti-H.pylori treatment at the six-year mark, the effect was smaller and nonsignificant.

Perhaps surprisingly, though, the biggest bang for H.pylori treatment is seen in the antrum of the stomach, not in the corpus. Another meta analysis, this one of 16 studies, found very consistent reductions in the severity of intestinal metaplasia in the antrum after antibiotic treatment – but no difference at all in corpus metaplasia. The reason for that finding isn’t at all clear, the authors of that paper noted.

The bacteria - metaplasia cancer link gets even more complicated when H. pylori is viewed as a contributing member of society, rather than a hermit. The bacterium seems to be a bully in the neighborhood, radically altering the normal gastric microbiome.

In the absence of H. pylori, the gastric microbiome is much more diverse, consisting of about 50 percent Actinobacteria and 25 percent Firmicutes species. Bacteroides and Proteobacteria species make up the remainder, with a small population of Cyanobacteria as well. In its presence, Proteobacteria – a gram-negative genus that includes a wide variety of pathogens – almost completely subsume beneficial bacteria.

Researchers saw this change in action in 2011, when a group at the Massachusetts Institute of Technology, Cambridge, inoculated two mouse populations with H. pyloris and followed them for gastric neoplasms. All the mice were genetically engineered to overexpress human gastrin, a characteristic that invariably leads them to develop gastric cancers.

One group comprised germ-free mice raised in sterile environments. The control group was free of pathogens, but lived in a conventional environment and so had normal gastric flora. Both groups were inoculated with H. pylori.

By 11 months, the microbiome of the control group was strikingly different. It showed a significant increase in the number of Firmicutes bacteria in the stomach, with an associated decrease in the number and variety of other bacteria including Bacteroides. This was especially interesting when viewed in relation to the rate of gastric neoplasia.

These mice are programmed to develop gastric cancer by 6 months of age – and this is what happened in the control mice, which had H.pyloris plus other gastric microbes. But the germ-free mice who were monoinfected with H. pylori showed a much different progression of disease. At 7 months, most showed only a mild hypergastrinemia. Conversely, at 7 months, all of the H.pylori -infected control mice had developed gastric intraepithelial neoplasia, 80 percent of it high grade. Only 10 percent of the monoinfected mice developed cancer, and all of it was low grade.

“It looks like there is active collaboration between H. pylori and other bacteria in stomach,” resulting in this increased cancer risk.

It’s a collaboration that reaches deep into the tumors themselves, he said.

A very interesting study a couple of years ago searched cancer genomes for the presence of bacterial DNA, and found that gastric cancers incorporated the second-highest amount of microbial DNA into their cancer genomes. But it wasn’t just H.pylori. Many other species had integrated their DNA into these tumors.

That study published in 2013, was the first to prove that bacterial DNA into these tumors.

That study, published in 2013, was the first to prove that bacterial DNA can impact carciogenesis. Acute myeloid leukemia showed the highest integration of bacterial DNA, but gastric adenocarcinoma was a close second. Most of the species were of the Proteobacteria lineages (83 percent), with a third of that represented by Psuedomonas, particularly P. fluorescens and P.aeruginosa. Both of those species have been shown to promote gastric tumorigenesis in rats. All of the DNA integrations occurred in five genes; four of these are already known to be upregulated in gastric cancer.

Interestingly, only a few of the sample reads turned up DNA integration with H.pylori.

This reduction in gastric microbial diversity could be an important key to H.pylori’s relation to gastric cancer. He examined this in residents of two towns in Colombia, South America: Tumaco, where the risk of gastric cancer is low, and Tuquerres, where it’s 25 times higher.

What was different was the gastric microbiome of residents. Those living in low-risk Tumaco had much more microbial diversity: 361 varieties, compared with 194 in Tuquerres. And 16 of these group – representative of what’s usually considered a healthy microbiome – were absent in high risk subjects. But Tuquerres residents had two bacteria that weren’t found in Tumaco residents, including Leptorichia wadei, which has been associated with necrotizing enterocolitis.

There was indifference, however, in the prevalence of H.pylori between these high - and low-risk groups.

These new findings illustrate an increasingly complicated interplay of bacteria and gastric cancer. But they also provide a new direction for research.

We have a framework now where we can move forward and try to understand how some of these other strains impact gastric cancer risk.