A bug’s story: H. pylori and stomach cancer

The role of Helicobacter pylori in intestinal metaplasia development of gastric mucosa

By R.N. Sugitha Nadarajah

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scientist recounted the story of his that led to him being awarded a Nobel Prize in 2005: “I had a patient with gastritis. I got the bacteria from his stomach and cultured them… I swizzled the organisms around in a cloudy broth and drank it the next morning.”

He added, “My stomach gurgled, and after five days…I’d run in the bathroom and vomit. After 10 days I had an endoscopy that showed the bacteria were everywhere. There was all this inflammation, and gastritis had developed.”

The Australian physician Dr. Barry Marshall, dubbed “the guinea-pig doctor” after the exploit, drank the germs as a last resort in his attempt to prove that bacteria Helicobacter pylori (or “H. pylori”) caused stomach ulcers which could lead to cancer if left untreated.

Ulcer’s cure is relatively simple – antibiotics – but Dr. Marshall asserted that during his days as a physician, a majority of the medical elites believed that ulcers were caused by stress and dismissed unexplained conditions as “all in the head”. As he was unable conduct his study on mice (H. pylori only affects primates), he ran the experiment on the only human patient who would consent to such a procedure: himself.

More than a decade after the brave doctor infected himself and remedied his self-induced illness with antibiotics, H. pylori remains as one of the most prevalent causes of gastric cancer and has attracted the interest of researchers across multi-disciplines from all over the world.

Precancerous lesion

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A human stomach (Image source: MedlinePlus Medical Encyclopedia)

One such researcher, Dr. Sergii Vernygorodskyi from the Department of Pathological Anatomy at Vinnitsa National Pirogov Memorial Medical University, Ukraine, has studied the role of the infamous corkscrew-shaped “gut bug” in the formation of intestinal metaplasia of the gastric mucosa (mucous membrane layer of the stomach).

Persistent infection of the bacteria H. pylori is an etiological factor of intestinal metaplasia and leads to the formation of gastrointestinal phenotype of intestinal metaplasia, explained Dr. Vernygorodskyi in his paper which was published in the open-access peer reviewed journal Advances in Modern Oncology Research (AMOR).

Intestinal metaplasia (IM), as described by the American Cancer Society, is the abnormal formation of goblet cells on the lining of the esophagus, instead of the intestines where it is normally found. A number of research have shown that intestinal metaplasia is an intermediate precancerous gastric lesion and is also involved in the chronic gastritis cascading into gastric cancer.

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For the purpose of his study, Dr. Vernygorodskyi examined 182 patients with various ailments: normal gastric mucosa, chronic atrophic gastritis (CAG) without IM, CAG with IM, and gastric cancer. He treated the patients with antibiotics to assess the effectiveness of the therapy and to see whether there were any persistence of infection.

The patients were also subjected to biopsies to define the metaplastic changes of the gastric mucosa and had their degree of bacterial contamination evaluated via quantitative methods. In addition, immunohistochemical studies and mucin profiling to estimate intestinal metaplasia mucin expressions, among other tests were also conducted.

Molecular markers

“The highest incidence of H. pylori was revealed in gastritis with incomplete intestinal metaplasia,” observed Dr. Vernygorodskyi, based on the results of the study. “Intestinal metaplasia prevalence was significantly observed in H. pylori-positive gastritis patients with moderate and marked degree of bacterial colonization of the gastric mucosa, in comparison to H. pylori-negative patients,” his research noted.

This finding is important because the depth of H. pylori’s penetration in the gastric mucosal structure was directly proportional to the degree of pathological changes, an evidence of the causal relationship between H. pylori and intestinal metaplasia on the progression of gastric mucosa reconstruction in patients with gastritis.

He further added, “Results in this study showed that H. pylori-positive patients exhibited an increase in MUC6 in surface mucous cells with a reduction in MUC5AC,” stated the researcher in his paper. As the proteins MUC5AC and MUC6 are typically detected in normal mucosa, the study demonstrated that eliminating the infection by treating the patients with suitable antibiotics would lead to a regeneration of normal gastric pattern.

The expression of mucins MUC2 and MUC4 was also measured in this study and showed varying results in different types of cells. This information is crucial because, according to Dr. Vernygorodskyi, “intestinal mucins (MUC2 and MUC4) are detected in gastric adenocarcinomas and during the initial stages of neoplastic transformation.” In addition, isolated MUC2 expression correlates with metastatic progression and poor survival.

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Marked expression of intestinal transcription factor CDX2 in the nuclei of gastric epithelial cells, goblet, and columnar epithelial cells with brush border. (Image source: Sergii Vernygorodskyi)

His study also identified the activation of transcription factor CDX2, with simultaneous inactivation of genes (e.g., SHH, SOX2, and RUNX3) responsible for gastric differentiation, to cause the appearance of IM.

The study found that complete intestinal metaplasia in patients with CAG was characterized by a high expression level of gene transcription factor CDX2. “[H. pylori] inhibits the expression of SOX2 in gastric epithelial cells, hence activating transcription factor CDX2 as a counterpart to MUC5AC gene inhibition and MUC2 gene induction,” elaborated Dr. Vernygorodskyi.

“Hence, differentiated approach based on the usage of molecular biological markers for intestinal metaplasia is not only of scientific interest but is also a fundamental basis for the development of methodical approaches in the prognosis and treatment of patients with intestinal metaplasia of gastric mucosa,” the researcher opined.

Improving diagnostics

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A stomach ulcer diagnosed as cancer on biopsy and surgically removed (Image source: Ed Uthman)

In an exclusive interview with AMOR Media team, Dr. Vernygorodskyi explained, “I chose to focus on this particular topic for my research because the metaplasia and dysplasia of the stomach mucosa in pre-tumor and neoplastic processes and their relationships with H. pylori remain uninvestigated.”

He added that more studies should be done to “clarify the significance of DNA methylation alterations during precancerous processes and gastric carcinogenesis and to understand the genetic basis of precancerous lesions and their relationships with H. Pylori.”

Such studies “will give us the opportunity to narrow group of patients with carcinogenic risk and prevent development of precancerous lesions of gastric mucosa,” according to the researcher.

“The results obtained will be introduced into the work of the pathological, gastroenterological and therapeutical departments for the sake of improving the diagnostics and ways of managing patients with the stomach mucosa dysplasis and metaplasia for prevention of stomach cancer,” he concluded.

Read more of Dr. Sergii Vernygorodskyi’s research on AMOR website at http://www.advmodoncolres.com/.

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