In 1982, an infamous discovery revealed that bacteria could thrive in our acidic stomachs. Two Australian doctors shocked their colleagues with a radical self-experimentation.

They grew bacteria from a patient’s stomach, drank the culture and underwent an endoscopy to prove that the same bacteria colonised their own stomach. They were subsequently awarded the Nobel Prize for Physiology and Medicine. The interesting part was that once the bacterium, Helicobacter pylori, was discovered, it was found nearly everywhere.

Between 1980-1990, the estimated global prevalence was 60%. In fact, we have genetic evidence of H. pylori being present in the stomach of a 5,300-year-old fossilised Iceman, fondly known as ‘Otzi’. In 1994, the World Health Organisation declared H. pylori as a class I carcinogen for its association with stomach cancer; the race was on to understand the clinical implications of this elusive stomach-dweller.

H.pylori  infection – a clinical paradox

Now well known of course is that fact that H. pylori also causes stomach ulcers – and the treatment is therefore to use antibiotics to eradicate the bacteria from the stomach. This works extremely well for curing patients of stomach ulcers, which, prior to 1982, could have proven fatal.

In contrast, understanding how H. pylori causes stomach cancer is complex. The most puzzling part is why only 1% of people infected with H. pylori develop stomach cancer. We know that not all H. pylori strains are equal and that some strains carry proteins that are more virulent than others. However, this doesn’t fully explain why most people can carry a lifelong infection with this bacterium asymptomatically, whilst a minority succumb to stomach cancer.

Gastric adenocarcinoma follows a 5-step process, the first few steps of which involve a severe inflammatory response, initiated by H. pylori. The third step, known as precancer or gastric intestinal metaplasia (GIM), is when ‘micro-intestines’ are formed in the stomach. Essentially, the stem cells that rejuvenate the stomach lining differentiate into intestinal cells. Steps 4 and 5 are the final stages of precancer and cancer, respectively.

Patients with symptoms at steps 1 or 2 are treated to eradicate H. pylori and this significantly reduces the risk of developing stomach cancer. However, antibiotic treatment of patients with precancer is not as effective at reducing the risk of developing cancer. In the UK, patients with precancer are placed on a surveillance list for endoscopy to monitor precancerous changes every 3 years. We urgently need prevention, rather than management, strategies.

Enter the microbiome…

So, why does a state of chronic inflammation turn to precancer in some people? We think the answer lies in our microbiome.

From the ‘gum to the bum’, the amount – and diversity – of bacteria making up the microbiome changes. In recent years, DNA sequencing has become the most powerful tool that scientists can use to identify the, “Who’s, who?” of the gastrointestinal microbiome. Interestingly, much of our biological variation is due to our microbiome, rather than our human cells. However, in the case of the stomach, the number of bacteria are so low that it can be hard to spot variation and patterns. Nonetheless, there was a striking and consistent observation made by several independent researchers – once a healthy stomach turns diseased or cancerous, the number of H. pylori decline. In parallel, the number of other bacteria increases.

Having studied H. pylori for many years myself, this makes intuitive sense. Our stomach cells organise themselves into glands, in which epithelial cells form a root like structure. H. pylori prefers to live in these gastric glands. Once disease progresses, these glands are damaged and so H. pylori essentially loses its home.

New prevention strategies

Given the observations made above by DNA sequencing, my research group were particularly interested in answering a relatively simple question. Now that we know the bacteria are there, where are they? Specifically, where do they localise in the stomach and what human cells are they interacting with?

Spatial biology technologies allow us to map out how different cell types organise themselves within an organ. We use these approaches to visualise bacteria and human cells in the stomach, using small biopsy samples from people with healthy stomachs and those with precancer. We discovered that whilst H. pylori stayed in the gastric glands, other non-H. pylori bacteria had invaded across the stomach lining in precancer. Our hypothesis is that H. pylori acts as the gatekeeper, punching holes in our stomach lining, letting other bacteria invade across – and this is something that we are actively testing in the lab. Nonetheless, this discovery gives us new ways of thinking about, and hopefully treating, precancer.

In the simplest terms, we could treat these invasive bacteria with antibiotics to prevent cancer and, potentially, reverse precancerous changes. However, there is a lot more work to do before we can reach this point. Additionally, an important consideration long-term is that antibiotic resistance is on the rise and therefore, the use of antibiotics is not always an effective treatment.