01(25): The fascinating story of Helicobacter pylori

Ask any kid what he thinks of when he comes across the word “scientist”. It is not surprising to hear scientists being described as weird, introverted, bespectacled old men with grey hair in white lab coats who do crazy stuff involving explosive chemical reactions in the laboratory. This stereotypical portrayal is perpetuated by the abundance of children’s books, cartoons and the mass media. Sometimes, these scientists go to extreme lengths to prove a particular point. For example, they might use their own bodies as experimental vessels to test their hypotheses simply because ethics committees wouldn’t allow them to test their hypotheses on the bodies of others as it would be “unethical”. Would you knowingly infect yourself with dangerous bacteria to test a hypothesis?

I thought so.

Neither would I. Yet, this is exactly what Dr Barry Marshall did. The Australian doctor infected himself with bacteria. Due to what he did, he demonstrated that most stomach ulcers are actually an infectious disease. This valuable information has helped save many lives.

Peptic ulcers are open sores found in the endothelial lining of the stomach and/or the upper portion of the small intestine. The most common symptom associated with these ulcers is abdominal pain. If things get bad enough, one can start bleeding, or even have one’s stomach burst.

Back in the 1970s, ulcers were most common in middle-aged men who smoked and drank alcohol. Having ulcers seemed to run in the family. As such, doctors assumed that ulcers occurred when there was overproduction of acid in the stomach, and the ulcers were a result of stress, and perhaps some genetic defect. As such, the typical advice was for the patient to relax, watch what he consumes, and take some antacids.

Most notably, it was assumed that the stomach was sterile (ie completely bacteria-free). It is understandable to see why people thought that. After all, the pH of the stomach lumen is around 2-2.5, indicating its high acidity. What organism could possibly survive such an acidic environment?

Then, in 1979, an Australian doctor, Dr Robin Warren began to have his doubts. This was because the pathologist began to regularly see comma-shaped bacteria in the samples from patients who had gastritis. In that same year, Dr Barry Marshall was appointed as “Registrar in Medicine” at the Royal Perth Hospital (RPH). Dr Warren and Dr Marshall met in 1981 while Dr Marshall was doing his internal medicine fellowship training at the RPH.

In 1982, the duo established a formal study and found that a majority of all their ulcer patients had been infected with the bacteria too. They identified the bug as Helicobacter pylori, and suspected that its presence was the true reason for peptic ulcers and gastritis.

NB: At the time of the study, this bug wasn’t known as H. pylori. It was first known as Campylobacter pyloridis. However, in 1987, it was re-named Campylobacter pyloris. This was because ‘pylori’ is the genitive case of the Latin nominative ‘pylorus’, which is the circular opening leading from the stomach into the duodenum. As mentioned in the paper, ‘pyloridis’ is a linguistic error that had to be corrected. The Latin word ‘pylorus’ in turn comes from the Greek word ‘πυλωρός’, transliterated ‘puloros’, which means ‘gatekeeper’.

Then, when 16S rRNA (component of the 30S small subunit of a prokaryotic ribosome) gene sequencing and other research showed two years later (by October 1989) that the bacterium didn’t belong in the genus Campylobacter, the bacterium was placed in its own genus Helicobacter. As you might have guessed, the prefix of the new genus name ‘helico-‘ comes from the ancient Greek word helix.

Anyway, back to the study. The hypothesis was absurd for its time and I’m sure very few of the duo’s peers were convinced that anything useful could come out of it. How could anything survive the highly acidic environment of the stomach? If this were true, why hadn’t someone discovered it earlier? The odds seemed to be against Dr Warren and Dr Marshall.

By 1984, Marshall was convinced of his results and must have been exasperated that others were not convinced. This was because in 1983, the previous year, the duo had submitted their findings hitherto to the Gastroenterological Society of Australia. However, the reviewers turned the papers down, rating it in the bottom 10% of the papers received in 1983.

So, Marshall did something radical. After ensuring he had no H. pylori of his own, he became his own guinea pig, and in one gulp of meat broth at 10:00 am, he purposefully swallowed a whole load of the bacteria. Unsurprisingly, he began to experience indigestion, nausea, bad breath, and began vomiting in the coming days. Although he hadn’t developed an ulcer, it was close. It was gastritis. H. pylori penetrates the mucosa layer of the stomach lumen and exposes the submucosa epithelial cells to all that acid in the lumen.

The infection usually takes a while to cause a problem, and the symptoms can be exacerbated by things like smoking and stress. This could be why older men with less-than-stellar health records seemed the most susceptible. Nevertheless, correlation is not the same as causation. Without H. pylori, most people would never even get peptic ulcers. Marshall and Warren also went on to demonstrate that certain drugs could get rid of H. pylori. In recognition of this groundbreaking work, the Australian duo was awarded the 2005 Nobel Prize in Physiology or Medicine. Marshall is the younger of the two.

This disco-era discovery turned out to have an even bigger impact than anyone imagined. Today, the World Health Organization recognises H. pylori as a carcinogen. The same damage the bacteria does to the lining of the stomach with an ulcer also causes gastric cancer. As more people got antibiotics to cure their ulcers, gastric cancer incidence rates plummeted.

Yet, the situation turned out to be not that simple. While most ulcers are caused by H. pylori, most people with H. pylori don’t develop ulcers, and even fewer get gastric cancer. The presence of H. pylori might even help as it seems to protect people from developing heartburn, and protect people from getting cancer in the oesophagus. Unfortunately, we can’t get the best of both worlds. The strains of H. pylori that are the most dangerous to the stomach are also the most protective to the oesophagus. As such, the current consensus among doctors seems to be to keep the status quo unless H. pylori starts causing problems. If it does cause problems, then green lights to the most common initial treatment – a ‘triple therapy’ for one week:

1) Amoxicillin, a penicillin-type antibiotic, which means that it is similar to penicillin. So, if the patient is allergic to penicillin, he should avoid all drugs in the penicillin family and take something like metronidazole.
2) Clarithromycin, which is an acid-stable macrolide with a broad spectrum of antibacterial activity, well absorbed with a wide tissue distribution and with mild side effects. Clarithromycin has a low minimum inhibitory concentration (MIC50) for H. pylori and its effect is potentiated by acid inhibition.
3) Proton pump inhibitor (eg omeprazole). It works by irreversibly inhibiting H+/K+ ATPase on gastric parietal cells.

However, even this may not be sufficient. The main reasons for the eradication failure of the standard ‘triple therapy’ above include escalating antibiotic resistance, poor compliance, and rapid metabolism of proton pump inhibitor. Generally, resistance to clarithromycin and metronidazole has been on the rise. Interestingly, though amoxicillin is one of the most commonly used antibiotics, resistance to amoxicillin remains extremely low (<5%) in most countries. If the rates of clarithromycin resistance are known to be > 15%, then bismuth-based quadruple therapy can be tried.

You might still be wondering how H. pylori is able to survive the acidic environment of the stomach lumen. The answer lies in the specific adaptations that H. pylori has developed.

Do you see the things that look like tails? They are called flagella (plural of ‘flagellum’). The flagella confer H. pylori motility. With the flagella, H. pylori burrows into the gastric mucin gel to reach the epithelial cells, where it is less acidic. This is possible because of chemotaxis. H. pylori senses the pH gradient in the mucus and tends to move towards the region of lower acidity.

In addition to chemotaxis, H. pylori produces lots of an enzyme called urease. As its name suggests, the cytosolic urease catalyses the conversion of urea (found within the stomach) to ammonia and carbon dioxide:

(NH2)2CO + H2O → CO2 + 2NH3

The ammonia reacts with the strong acid in the vicinity of H. pylori to give rise to a relatively neutralised buffer zone that surrounds H. pylori. Thus, with these adaptations, H. pylori is able to endure the acidity of its environment.

In fact, the cytosolic urease in H. pylori is the very basis of the urea breath test: a rapid diagnostic procedure used to identify infections by H. pylori. For the test, patients swallow urea labelled with an uncommon isotope. The detection of isotope-labelled carbon dioxide in exhaled breath indicates that the urea was split, which in turn indicates that urease (the enzyme that H. pylori uses to metabolise urea) is present in the stomach) is present. This thus corresponds to the presence of H. pylori.

Interesting, isn’t it?

Yours faithfully,
Nic Loh
16 April 2019

1. https://en.wikipedia.org/wiki/Helicobacter_pylori
2. https://www.youtube.com/watch?v=HP6Zf1ff7Sw
3. https://en.wikipedia.org/wiki/Robin_Warren
4. https://en.wikipedia.org/wiki/Barry_Marshall
5. https://www.mayoclinic.org/diseases-conditions/peptic-ulcer/symptoms-causes/syc-20354223
6. https://ijs.microbiologyresearch.org/content/journal/ijsem/10.1099/00207713-39-4-397
7. https://www.flickr.com/photos/nsf_beta/4822021538/in/set-72157621768317570
8. https://en.wikipedia.org/wiki/Proton-pump_inhibitor

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s