I am a microbiologist at heart. As an undergraduate, I chose microbiology as my major and focused in this area for research and coursework. It was a natural flow to become specialized in infectious diseases as a physician and my career path in public health. The article tells of a modern-day tale of scientific discipline and another example of how humans interface with their environment.

Introduction: Helicobacter pylori and Serendipity

The discovery of Helicobacter pylori as the cause of peptic ulcer disease is a modern day story of scientific curiosity and tenacity. What was originally thought of as an innocent bystander was categorically determined to be a pathogen. The research by Drs. Barry Marshall and Robin Warren was conducted between 1979 to 1984, proving that H. pylori was associated with disease. The preliminary data, initially rejected by the Gastroenterological Society of Australia, was later published as two letters in “The Lancet.”

The microbe met all of Koch’s postulates, but the scientific community initially was resistant to these findings. The litmus test confirming it a pathogen was when Marshall himself ingested a sample of H. pylori, developed gastritis, and treated himself with bismuth salts and the antibiotic metronidazole. In 2005, Warren and Marshall were awarded the Nobel Prize in Medicine.

What are Koch’s Postulates?

1. The microbe must be found in the disease process but not in healthy organisms.
2. The microbe must be isolated and grown in pure culture.
3. Introduction of the microbe into a healthy organism should cause disease.
4. The organism must be re-isolated from the diseased tissue.

Robert Koch and Friedrich Loeffler developed the postulates in 1884. Photo from Meike and the Microbiome Bunch available on Amazon.

It started in Dr. Robbin Warren’s lab, when he discovered clearly delineated microbes in a pathology specimen from an ulcer. He continued his search in other samples, including from patients with active chronic gastritis. Other samples were prepared for electron microscopy. Again, he demonstrated their presence. He examined normal gastric mucosal samples and did not see the bacteria. All of this was contrary to the dogma of the time that gastritis was not infectious.

Dr. Marshall collaborated with Dr. Warren on this quest. They were ultimately able to culture it on media, and they confirmed that the organism was the same one seen on histology. They originally considered it a Campylobacter-like microbe and began treating patients with confirmed gastritis with the appropriate antibiotics. They demonstrated resolution of the symptoms and findings with post-treatment endoscopy. Ongoing clinical research ultimately led to the determination of triple and quadruple regimens for H. pylori treatment as a standard.

Marshall went the step further and infected himself with the bacteria, despite the recommendations of his colleagues. One week later, he developed vomiting and nausea. A before and after endoscopy showed a new gastritis, which was culture and biopsy proven. He treated the disease and a third endoscopy a month later showed normal histology. Thus, Marshall, applying measured tenacity, confirmed with scientific rigor all of Koch’s postulates. Ultimately, the organism was classified as Helicobacter pylori. You can refer to an excellent article on this topic in the link provided.

Helicobacter pylori and Upper GI Disease

H. pylori is a part of the normal human microbiome

It isn’t always mentioned that H. pylori is normal bacteria of the human gut microbiome. A nutshell summary of the microbiome is in this link. The bacteria is found in the upper GI tract in an estimated two-thirds of the world’s population. The niche of H. pylori is the lining of the stomach, where there is little competition with other microbes. It also can reside above and below the stomach, in the lower esophagus and duodenum. As with all bacteria of the microbiome, humans acquire H. pylori at a young age from the environment. Interestingly, for unclear reasons, the prevalence of H. pylori is lower in industrialized countries.

Having H. pylori may actually confer benefits to the host. Firstly, it is less common to find gastroesophageal reflux, Barrett’s esophagus (a cancer precursor), and esophageal adenocarcinoma in a person who is colonized with it. Secondly, there may be a decrease in asthma and allergy disorders associated with colonization. Finally, these bacteria may activate the immune system and protect against certain infections, like diarrheal disease.

The bacteria survive in the acidic environment of the stomach, because they possess an enzyme (urease) that changes urea to ammonia, reducing the acid. The ammonia causes damage to the mucosal lining of the stomach. But why wouldn’t H. pylori not cause ulcers in all who are colonized? Although it is still not completely understood, some studies suggest that it may be related to the overgrowth of disease-specific strains.

Helicobacter pylori and Disease

As with all infections, the disease is a combination of the host and the pathogen. The lining of the gut is a surface where blood vessels interface with the mucosa. The presence of the bacteria turns on innate immunity and leads to inflammation of the lining, increasing the risk of disease.

The following diseases have been associated with H. pylori:

1. Gastritis. The bacteria primarily is associated with chronic gastritis with inflammation of the lining of the stomach.
2. Ulcers. They occur in both stomach and duodenum. The bacteria digest the layer that protects the tissues, allowing the acid to cause injury. H. pylori causes 80% of stomach ulcers and 90% of duodenal ulcers.
3. Functional dyspepsia, or non-ulcer dyspepsia. This condition is associated with bouts of indigestion without an ulcer or inflammation. It is not always associated with H. pylori or will it always improve after treating the bacteria.
4. Gastric cancer. Persons with H. pylori have a six-fold higher risk of gastric cancer (non-cardia). Interestingly, the risk of gastric cardia and esophageal cancer is lower for unclear reasons.
5. Other: Gastric MALT lymphoma, Platelet disorders, Iron deficiency anemia, B12 deficiency.

When to Consider that You Might Have Helicobacter pylori Infection

Only about 20% of those colonized with H. pylori ever develop an infection. There may be a range of signs and symptoms, depending on the disease:

• Abdominal burning, aching, or pain, worse at night or on an empty stomach
• Nausea
• Decreased Appetite and Weight Loss
• Increased Gas with Bloating and Burping
• With more significant disease, the pain may worsen, bleeding may run through the gut causing black or bloody stools (called melena)

If you are having any dark tarry stools, purple, or bloody stools, and/or persistent abdominal pain and weight loss, consult your doctor to discuss further evaluation.

The Infection vs. Colonization Conundrum: Further Insights

Further studies may shed light on the reason why H. pylori causes disease in some, while not in others. It’s differential association with certain cancers alludes to the possibility that parts of the gastric micro-environment become altered, enabling certain strains to overgrow. Studies have shown that a series of strains associated with disease have a core genome that they share in common.

Dietary factors impact the prevalence of H. pylori infection, particularly one that is high in carbohydrates and sweets. High salt intake also correlates with a higher prevalence of H. pylori infections and risk of gastric carcinoma. When exposed to a higher salt environment, the bacteria increases the expression of a known virulence factor (cagA). A recent study showed that a high whole-grains and vegetable diet high may be the most protective against H. pylori infection.

Other Resources

Mayo Clinic Website

Patient Info

Johns Hopkins Medicine

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