A long-standing question in medical science has been explaining the obesity-cancer link in humans; previous studies have shown that obesity increases the risk for many illnesses such as diabetes and cancer. But the exact biological mechanism that underlies this link has been elusive.
But now, a new study of mice microbiomes (the communities of trillions of microbes that live in the digestive tract) has revealed a DNA-damaging acid that seems to be the key molecule linking excess weight to cancer.
Researchers at the Cancer Institute at the Japanese Foundation for Cancer Research in Tokyo discovered that obesity in mice alters their microbiota — their intestinal “bug” population — which in turn leads to the unregulated production of an acid molecule called deoxycholic that can cause damage to a cells DNA and eventually cancer (e.g., liver cancer).
To uncover the elusive link, the team — led by Eiji Hara — studied two groups of mice: one lean group that was fed a normal diet, and a second group fed a fat-heavy diet (making them obese). To induce cancer in the mice (which normally don’t get much cancer) they exposed both groups to a cancer causing chemical shortly after birth.
Results of these experiments revealed the identical obesity-cancer link noted in humans: only 5% of the mice in the lean group developed cancer later in life, whereas all the obese mice did. But this result does not mean that diet itself is the primary trigger; when the team reproduced the experiment with mice that were genetically altered to become obese (though fed a normal diet), they found that these mice had an increased incidence of cancer. This seems a clear indication that it is obesity, rather than diet, that made the difference.
Pinning Down the Causal Mechanisms
The researchers found that the obese mice were more prone to live cancer and analysis of their tumors showed increased levels of key signaling molecules called pro-inflammatory cytokines which, as the name suggests, promote inflammation (note: Inflammation has been strongly correlated with tumorogenesis in many studies, but whether it is the cause, or effect, of cancer is still debated).
The team also observed that the obese mice had higher levels of deoxycholic acid (DCA), which is a cellular by-product that results when gut microbes break down bile acid (which is manufactured in the liver). The DCA has been shown previously to damage DNA and is associated with some human cancers.
With the confirmation of these two indicators (the elevated DCA and cytokine levels), the researchers next analyzed the mice intestinal tracts. Intriguingly, they observed that the obese mice were host to a different mixture of gut bugs. Specifically, they found that a type of bacteria known as gram-positive bacteria (which have a single, thick cell wall) were far more prevalent in the fatter mice.
When the team treated the obese mice with an antibiotic (vancomycin) that targets gram-positive bacteria, the result was reduced levels of DCA and a reduced incidence of cancer. Further, when they directly targeted the DCA — by slowing bile acid breakdown or stimulating more bile acid secretion into the gut — they again found a reduced incidence of cancer (and giving them increased doses of DCA brought the cancer risk back up).
“I was very surprised by the process,” Hara says. “We never expected that changes in the gut microbiota could cause the higher risk of cancer.” [source]
The gut microbiota has been the focus of intense research just in the past two years and researchers have noted many links between the composition and activity of our microbiomes and various diseases (such as inflammatory bowel disease, certain allergies, and heart disease).
These recent findings by Hara et al lend additional support to the once controversial ‘germ theory” of cancer causation: that bacteria can be primary contributors to the development of cancer (note: the helicobacter pylori bacterium was shown to cause stomach cancer nearly a decade ago). These results may help doctors better predict — and even prevent — the disease.
However, more research is needed to demonstrate that the same mechanisms are at work in humans, who possess different cellular “micro-environments” than mice.
Results of the experiments were reported on-line June 26, 2013, in the journal in Nature.
Some source material for this post cam from the Science NOW article:‘Gut Bugs Could Explain Obesity-Cancer Link’ by Gisela Telis