A tantalising tale of obesity, bacteria and liver cancer

How is weight linked to cancer risk?

Could a fatty diet alter the bacteria in your gut, causing them to secrete a chemical that can cause liver cancer?

That’s the question posed by a fascinating new study from Japan, published in this week’s Nature journal.

The research team, led by Eiji Hara from the Japanese Foundation for Cancer Research, discovered that mice develop liver cancer much faster when their guts contain particular bacteria called Clostridium, which seem to favour mice fed a high-fat diet.

The bugs, it seems, convert the mice’s digestive juices into chemicals that cause liver damage.

This new and completely unexpected finding opens up all sorts of avenues for future research. And it could help explain why liver cancer is more common in people who are overweight or obese.

Obviously the usual caveats apply:  it was a study in mice, which may not ultimately be relevant to liver cancer in people. But the idea that fatty diets affecting the bugs in our gut could influence liver cancer risk will certainly raise eyebrows in the research community, particularly as relatively little is known about how obesity increases liver cancer risk.

These are tantalising and exciting findings but, as we’ll see below, the research raises almost as many questions it answers.

Obesity and cancer

Population research has shown that several types of cancers are more common in people who are overweight or obese. The evidence is strongest for cancers like breast and bowel cancer, but also for some of the hardest forms to treat, such as pancreatic and oesophageal cancers.

The question is, why? What is it about being overweight that makes cancer more likely?

There are many theories. Overweight people are less active, and physical activity is known to decrease the risk of some cancers. They often eat poor diets – another link to increased risk. Fat cells make more hormones – particularly oestrogen, for example – and these are known to affect cancer risk, particularly of breast and womb cancers.

But in recent years, the finger has also begun to point to another area – one that’ll be familiar to regular readers of this blog: inflammation.

As we’ve discussed before, inflammation – a series of chemical events set off when a tissue is stressed or damaged – is normally a vital part of our body’s defence system, helping direct our immune system to where it’s needed. But it has a darker side too – if it carries on for long periods it can help generate the conditions necessary for cancers to grow.

Many lines of evidence now suggest that, somehow, obesity causes chemical changes in our tissues that lead to inflammation, and – ultimately – cancer.

It’s likely that all of these things play a role in linking obesity to cancer – with different factors affecting some cancer types more than others.

One cancer where inflammation is a key suspect, whether you’re overweight or not, is liver cancer.

Could there be a link between obesity and inflammation in this disease?

Liver cancer – going viral?

Liver cancer is strongly linked to two lifestyle risk factors – infection with hepatitis, and chronic alcoholism (both of which cause inflammation and cirrhosis of the liver), and these are thought to underpin the majority of cases. Indeed, infection with hepatitis B or C is one of the most important risk factors for the disease.

However, there’s increasing evidence that a third risk factor may be at play – something called ‘non-alcoholic fatty liver disease’. This is caused when fat builds up in the liver, as a result of a poor diet or diabetes – both of which are linked to obesity.

Rates of liver cancer are rising rapidly in the UK – quite possibly as a result of all of the above factors. But as a recent review in the New England Journal of Medicine points out, given the growing rates of obesity in the developed world, “even small increases in risk related to obesity … could translate into a large number of cases”.

Rates of liver cancer are on the rise

Clearly, as waistlines expand around the Western world, understanding the link between obesity and cancers like liver cancer is an urgent public health issue.

How could obesity lead to liver cancer?

With all the above facts in mind, Hara’s team set out to look for answers – and they turned to where researchers frequently turn to for help: laboratory mice.

The researchers began by studying mice that were prone to developing mutations in a key cancer gene, called Ras – known to be one of the trigger events for liver cancer.

They started off by feeding these mice a high-fat diet. Sure enough, as they put on weight, the mice developed more liver cancers than mice fed a healthy diet. But why?

When they subsequently examined the mice’s livers for clues, they spotted something unusual – non-cancerous liver cells near the tumours showing the molecular hallmarks of inflammation.

Was this inflammation causing the tumours? Or was it just a by-product of cancer development? To determine cause and effect, the researchers blocked the production of these inflammatory molecules in cancer-prone mice, who were then fed a high-fat diet. Over the following days, tumours developed at a much slower rate, suggesting that inflammation was indeed driving the disease.

So it seemed that the liver cells of obese mice were reacting to some form of damage, and that this was fuelling the development of cancer.

But where was the damage coming from?

Enter the bacteria

There are species of Clostridium bacteria

To look for answers, Hara’s team drew on an observation made in 2006 – that obese people have a very different range of bacteria in their gut than do people of a healthy weight. Could bacteria be the link between obesity and liver cancer?

As an initial test, Hara’s team gave cancer-prone mice a course of antibiotics, and then fed them a high-fat diet.

Amazingly, these mice developed liver cancer at the same rate as similar mice fed normal diets, and their livers showed no sign of inflammation.

They were on to something.

After a series of elegant and detailed experiments (involving, among other things, the molecular analysis of rather a lot of mousedroppings), the researchers homed in on the suspect: a group of related bacteria collectively called Clostridium cluster XI, present in much higher numbers in the guts of obese mice.

It turns out these bacteria convert the acids produced by our digestive system to a chemical called deoxycholic acid. Hara’s team went on to show that it was this chemical, produced by bacteria in the guts of obese mice, that was ending up in their livers, causing inflammation and, ultimately, cancer.

As a final ‘sense check’, the researchers looked at cells from patients with liver cancer who also had non-alcoholic fatty liver disease. Sure enough, they saw the molecular hallmarks of the type of inflammation they saw in mice.

What next?

Put together, this is a remarkable finding. The idea that obesity changes the bugs in our guts is not new, but the fact that this can affect cancer – at least in mice – most certainly is.

“It’s a quite remarkable story,” says Professor Peter Adams, a researcher at Cancer Research UK’s Beatson Institute in Glasgow who studies some of the pathways this research focused on. Adams does, however, point to a few caveats.

“While this is a potentially very important finding, we need to remember that the idea that this is how liver cancer develops in humans is still somewhat speculative, and there’s a lot more work to do to prove this,” he told us.

Dr Thorsten Hagemann, a London-based researcher from Barts Cancer Institute, and an expert in the role of inflammatory cells and cancer, agrees. “This is a really interesting hypothesis. Certainly we’re becoming more and more aware that the bacteria in our guts have a huge influence on our health,” he says, pointing to research from earlier this year linking gut bacteria to malnutrition.

“So the idea that bacteria could influence obesity, and thus cancer, isn’t too far-fetched. But whether this is definitely linked, in people, needs confirming,” said Hagemann.  It also remains to be seen whether this effect is at play in other obesity-linked cancers, or whether it’s specific to liver cancer.

This story shows, in beautiful detail, the complexity of the relationship between the bacteria in an organism’s gut, its diet, and its subsequent health – something that’s received relatively little attention in cancer research.

And while there’s a lot more work to be done to understand the links between diet, weight and cancer in people, our gut feeling is that it’s a story with many more unexpected twists and turns ahead.

Henry

Reference

• Yoshimoto S., Loo T.M., Atarashi K., Kanda H., Sato S., Oyadomari S., Iwakura Y., Oshima K., Morita H. & Hattori M. & (2013). Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome, Nature, DOI: 10.1038/nature12347
• Images courtesy of puuikibeach, via Flickr, and Wikimedia Commons