A punch in the gut
How microbes promote liver cancer in the overweight
OBESITY brings problems—notably heart disease, diabetes and cancer. It is not hard to understand its connection with heart disease and diabetes: excess fat clogs arteries and messes around with the metabolism. Its link with cancer is less intuitive. Shin Yoshimoto of the Japanese Foundation for Cancer Research, in Tokyo, and his colleagues suspect this is at least partly because researchers have been looking for that link in the wrong place. Most work in the field is focused on the cells of the human body. But researchers should, Dr Yoshimoto believes, be at least as interested in the cells of the microbiome, the collection of 100 trillion bacteria that live in the gut.
Mostly, the microbiome is beneficial. It helps with digestion and enables people to extract a lot more calories from their food than would otherwise be possible. Research over the past few years, however, has implicated it in diseases from atherosclerosis to asthma to autism. Dr Yoshimoto and his colleagues would like to add liver cancer to that list.
Their paper making this accusation is published in this week’s Nature, and it is a careful, step-by-step analysis of the matter. They start from the facts that fat animals (people included) have different gut bacteria from thin ones; that some bacteria produce inflammatory molecules as part of their metabolism; and that inflammation promotes cancer.
They began their experiments by feeding laboratory mice a fatty diet, to make them obese. Such mice, they found, are no more likely to develop cancer than those fed an abstemious diet. Obesity alone, then, does not seem to cause tumours. But it might still promote them.
Their next experiment therefore started by giving the mice a carcinogen known to trigger tumour formation throughout the body. One group was then fed standard fare while another got the high-fat diet. After 30 weeks, just 5% of the slim group had developed tumours, not in the liver but in the lungs. In the obese group, every animal had developed liver cancer.
To understand how this happened, the researchers began with the tumours and worked backwards. First, they found that the cancerous liver cells in their mice were generally accompanied by cells that had the symptoms of old age (they had, for example, stopped replicating). Such cells also emit chemical signals which promote inflammation, and thus encourage tumours.
The researchers suspected that these cells were being made senescent by something produced by gut bacteria. That suspicion was confirmed when they served some of their mice a cocktail of four antibiotics, to prune the animals’ microbiomes. This treatment lowered the number of senescent and cancerous cells, suggesting the microbes were indeed to blame for promoting cancer.
Dr Yoshimoto and his team then started to focus on which bacteria were causing the problem. First, they discovered they could get the same cancer-suppressing effect using just vancomycin, an antibiotic that kills only “Gram-positive” bacteria. They also observed, as prior research had suggested, that a fatty diet raised levels of a chemical called deoxycholic acid (DCA) and that antibiotics lowered it. Previous research had demonstrated too that DCA damages DNA in a way that promotes senescence. Dr Yoshimoto showed that lowering DCA levels in mice did indeed reduce the development of liver cancer.
Certain types of gut bacteria, including strains of Clostridium (a Gram-positive genus), are known to burp out DCA. And further detective work, including examination of the mice’s faeces, revealed higher levels of a strain of Clostridium called OUT-1105 in the fat mice than in the thin ones. This strain, Dr Yoshimoto thinks, is the most likely culprit.
There is, then, a chain of causation leading from the gut to the liver that promotes tumours in obese mice. And the chances are good that something similar pertains in Homo sapiens. Humans are not mice, of course. But the two species’ microbiomes often do behave in the same way.
If cancer does end up being added to the growing list of problems which an upset microbiome can cause, that may stimulate research into ways of tweaking it to stop it causing disease. It will also, once again, emphasise the microbiome’s role, for both good and ill, as an adjunct part of the human body.
Mostly, the microbiome is beneficial. It helps with digestion and enables people to extract a lot more calories from their food than would otherwise be possible. Research over the past few years, however, has implicated it in diseases from atherosclerosis to asthma to autism. Dr Yoshimoto and his colleagues would like to add liver cancer to that list.
Their paper making this accusation is published in this week’s Nature, and it is a careful, step-by-step analysis of the matter. They start from the facts that fat animals (people included) have different gut bacteria from thin ones; that some bacteria produce inflammatory molecules as part of their metabolism; and that inflammation promotes cancer.
They began their experiments by feeding laboratory mice a fatty diet, to make them obese. Such mice, they found, are no more likely to develop cancer than those fed an abstemious diet. Obesity alone, then, does not seem to cause tumours. But it might still promote them.
Their next experiment therefore started by giving the mice a carcinogen known to trigger tumour formation throughout the body. One group was then fed standard fare while another got the high-fat diet. After 30 weeks, just 5% of the slim group had developed tumours, not in the liver but in the lungs. In the obese group, every animal had developed liver cancer.
To understand how this happened, the researchers began with the tumours and worked backwards. First, they found that the cancerous liver cells in their mice were generally accompanied by cells that had the symptoms of old age (they had, for example, stopped replicating). Such cells also emit chemical signals which promote inflammation, and thus encourage tumours.
The researchers suspected that these cells were being made senescent by something produced by gut bacteria. That suspicion was confirmed when they served some of their mice a cocktail of four antibiotics, to prune the animals’ microbiomes. This treatment lowered the number of senescent and cancerous cells, suggesting the microbes were indeed to blame for promoting cancer.
Dr Yoshimoto and his team then started to focus on which bacteria were causing the problem. First, they discovered they could get the same cancer-suppressing effect using just vancomycin, an antibiotic that kills only “Gram-positive” bacteria. They also observed, as prior research had suggested, that a fatty diet raised levels of a chemical called deoxycholic acid (DCA) and that antibiotics lowered it. Previous research had demonstrated too that DCA damages DNA in a way that promotes senescence. Dr Yoshimoto showed that lowering DCA levels in mice did indeed reduce the development of liver cancer.
Certain types of gut bacteria, including strains of Clostridium (a Gram-positive genus), are known to burp out DCA. And further detective work, including examination of the mice’s faeces, revealed higher levels of a strain of Clostridium called OUT-1105 in the fat mice than in the thin ones. This strain, Dr Yoshimoto thinks, is the most likely culprit.
There is, then, a chain of causation leading from the gut to the liver that promotes tumours in obese mice. And the chances are good that something similar pertains in Homo sapiens. Humans are not mice, of course. But the two species’ microbiomes often do behave in the same way.
If cancer does end up being added to the growing list of problems which an upset microbiome can cause, that may stimulate research into ways of tweaking it to stop it causing disease. It will also, once again, emphasise the microbiome’s role, for both good and ill, as an adjunct part of the human body.
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