H. pylori: tackling the germ behind stomach ulcers and cancer

Irish researchers explore helicobacter pylori and its role in gastric cancer

Helicobacter pylori is a Gram-negative, microaerophilic bacterium found in the stomach.

Helicobacter pylori is a Gram-negative, microaerophilic bacterium found in the stomach.

 

The historian Thomas Carlyle (1795-1881) described his stomach as “that diabolical arrangement”, and undoubtedly harsh conditions prevail in the tummy.

In fact, anything we swallow – from a Michelin-starred truffle to a fish supper – gets taken apart by a gang of acids, enzymes and bile salts, all eager for a piece of the digestive action.

Such a hostile environment makes it impossible for bugs to survive down there. At least, that was the accepted wisdom among medical scientists who considered the stomach ulcer as a stress-related condition best treated with long-term medication or surgery.

But they were wrong.

Although aspirin and drugs used for the treatment of arthritis can cause stomach ulcers and ulcer complications, the bacterium Helicobacter pylori not only causes most stomach ulcers but also has a crucial role in the development of gastric cancer. The story of the organism’s discovery begins in Australia, but landmark findings in Ireland contributed greatly to the rapid progress in our understanding of its role in gastric disease.

In 1979, Dr Robin Warren, a pathologist at the Royal Perth Hospital, Australia, was examining a stomach biopsy sample from a patient with dyspepsia when he spotted spiral-shaped bacteria. To investigate its significance, Warren was joined by Dr Barry Marshall, who in 1981 began a six-month gastroenterology assignment.

Warren and Marshall tried and failed several times to grow the organism. Their failure was partly due to faulty incubators and to their habit of discarding agar plates after two days if there was no visible growth. So it was a stroke of luck that brought about a four-day Easter weekend in April 1982. This meant that a culture was incubated for five days – long enough for visible colonies to appear.

In 1983 Warren and Marshall reported their findings in the Lancet journal and suggested that not only might bacteria cause stomach ulcers, but also that patients with ulcers could be treated with antibiotics. This offended both the medical establishment and drug companies: after all, went their reasoning, drugs treated ulcers by reducing acid secretions into the stomach, and the drugs worked, so ulcers must be caused by acidity.

But they were wrong.

It’s thought that H. pylori burrows into the stomach’s mucous layer where it is protected from gastric acids. In some individuals, a combination of infection and acid attack causes a local inflammation which can eventually lead to ulceration and possible gastric cancer.

Determined to prove that H. pylori infection causes gastritis, in July 1984 Marshall – himself free of gastric disease – drank a culture of H. pylori (don’t try this at home). A week later he had breath like a bear, he was vomiting and a biopsy confirmed he had an award-winning bout of gastritis, complete with spiral bacteria.

By 2005, Warren and Marshall had won the Nobel Prize in Physiology or Medicine for their discovery that H. pylori causes most stomach ulcers.

But a major advance was made by Irish researchers. One of them, Prof Colm O’Morain, professor of medicine at Trinity College, Dublin, is a world expert on H. pylori and a founder member of the European Board of Gastroenterology. Prof O’Morain told The Irish Times: “My interest in H. pylori dates back to its discovery in 1982, and it stimulated me to undertake a study on peptic ulcer disease as we had so many patients with the condition.

“We were the first to show that eradication of H. pylori led to a cure of ulcer disease, findings that were published in the Lancet in 1987. One year later, Warren and Marshall, whose Nobel Prize was well deserved, published a report which agreed with our findings.”

In 1987, Prof O’Morain helped found a H. pylori study group to promote research into the organism and the group has drawn up guidelines on who, how and when to treat.  “Our latest initiatives,” explained Prof O’Morain, “are directed to its role in gastric cancer. H. pylori has been described as a class 2 carcinogen by the World Health Organisation. ”

Shift in thinking

Between 1983 and the early 1990s a definite shift in medical thinking on the cause of stomach ulcers occurred. This culminated in 1994 at a Consensus Development Conference in Washington DC convened by the United States National Institutes of Health (NIH). Its purpose was to examine the claim that peptic ulcers are caused by H. pylori. Most of the 22 researchers, including Prof O’Morain, who made presentations to the panel, supported the claim. On February 9th, 1994 the NIH panel concluded that ulcer patients with H. pylori infection should be treated with antimicrobial agents.

However, we are now living in the age of antimicrobial resistance (AMR), and an increase in the prevalence of antibiotic-resistant bacteria has contributed to a fall in Irish eradication rates for H. pylori. This prompted Prof Deirdre McNamara and colleagues at Tallaght Hospital and Trinity College Dublin to question current management strategies and to assess, revise and tailor current available recommendations for adult patients.

On June 22nd, 2016, experts from Ireland and Europe convened in Dublin, where the Irish Helicobacter pylori Working Group (IHPWG) was established.

This year, the IHPWG published 15 statements and recommendations in the European Journal of Gastroenterology & Hepatology. Its report includes the recommendation that all patients with symptoms related to the upper gastrointestinal tract should be tested for H. pylori since eradication of the organism “provides a long-term cure for both duodenal and gastric ulcers in the majority of patients whose ulcers are not associated with non-steroidal anti-inflammatory drugs”.

The IHPWG also recommended that following completion of any therapy for H. pylori a confirmatory urea breath test (UBT) should be performed because “eradication rates for H. pylori are decreasing and symptoms are not a good indicator of treatment success”.

Typically, the treatment of H. pylori infection has involved triple therapy with two antibiotics such as clarithromycin, metronidazole and/or amoxicillin in combination with a drug called a proton pump inhibitor (to reduce the amount of acid in the stomach). However, the IHPWG states that the “standard triple therapy for a duration of seven days can no longer be recommended”, citing a recent Irish study by Prof Sinead Smith reporting an eradication rate for clarithromycin-based triple therapy of only 57 per cent. With European guidelines stating that eradication rates less than 80 per cent are unacceptable, the IHPWG now recommends a 14-day clarithromycin-based triple therapy with a high-dose proton pump inhibitor.

As far as future prospects are concerned, the management and treatment of H. pylori in the age of AMR means that antibiotic therapies which are effective today may not be effective tomorrow because of the development of antibiotic resistance.

It remains to be seen whether a vaccine can be successfully developed – so far it hasn’t – and if it can be, could it be afforded in developing countries?

Finally, ethical issues remain. For example, should there be universal screening for H. pylori, which, after all, causes stomach ulcers and is implicated in gastric cancer?

Investigation of H. pylori continues worldwide, with Irish researchers making substantial contributions to the growing evidence base.

And the IHPWG has launched an app called “H. pylori Care”, which is designed to enhance access to clinical guidelines and provide information to both clinicians and patients.

Helicobacter pylori fact file

· The commonest chronic bacterial infection in humans, thought to affect 50 per cent of the world’s population, with more cases in developing world.

· Infection rates in Ireland are about 20 per cent.

· An Irish study found that H. pylori infection is acquired at a very young age – typically less than 5 years – and new infection is rare in older children and adults.

· Infections are related to poor socioeconomic conditions in childhood, poor hygiene and overcrowding in the home, sharing a bed and having infected parents.

· Mode of transmission is unclear, but probably person-to-person. Parental transmission has been reported. For example, mothers could transmit infection through mouth secretions using common spoons or tasting child’s food.

· The urea breath test (UBT) is accurate, easy to perform and is the recommended non-invasive test for diagnosing H. pylori infection.

· Although infection can be treated with antibiotics, patient non-compliance and antibiotic resistance are the main reasons for treatment failure

· There is no vaccine available.

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