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Obesity promotes Liver Cancer development through the Gut Microbiome

Obesity has been a growing health concern across the world. Obesity can make one more susceptible to developing all kinds of diseases: heart disease, stroke, high blood pressure, diabetes, and also cancer: all kinds of cancers. But exactly HOW obesity increases your chances of getting cancer is not entirely clear.

So what if we could understand what aspects of obesity contribute to a specific cancer in order to prevent the development of cancer in obese individuals and treat obesity independently while learning something about our own biology?

The scientists of this paper wanted to understand if and how obesity contributes to cancer.

Their findings are published in their article titled “Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome”, published in Nature in July 2013 by the Ohtani lab at the Japanese Foundation for Cancer Research.

In order to do this, the scientists fed either obese mice a high fat diet or lean mice a normal diet, and examined the development of liver cancer. Diet alone was not sufficient to cause cancer but when this treatment was combined with a cancer-inducing chemical, 100% of obese mice fed a high fat diet developed cancer, compared to only 5% of lean mice fed a normal diet.

But the question is: Is this due to the fact that the mice were obese or o the fact that they were eating a high fat diet? 

To answer this question, the scientists looked at mice that were obese due to changes in their DNA sequence, but that ate a normal diet. These mice were also more likely to develop cancer with the cancer-causing chemical than non-obese mice. So this suggests that obesity can promote the development of liver cancer when a trigger, in this case a cancer-causing chemical, was provided. So what could explain this?

The scientists noticed that the cells around the tumor were producing lots of molecules that promote cancer. These cells were in a state of arrest that we call “senescence”. When the senescent cells or the molecules they secrete were removed, obesity did not cause mice to develop cancer in the presence of the cancer-causing chemical. So this suggests that obesity is somehow making the cells in the liver senescent and causing them to produce all kinds of pro-cancer compounds.

So the next question is, how can obesity affect the state of cells in the liver?

To answer this question, the scientists looked at the intestine. Our intestine is full of microbes, including bacteria that form communities that play important roles in our health. Some bacteria are important in promoting health of the intestine, while others can be detrimental.

The scientists found that obesity can greatly influence the types of bacteria that live in our intestine. Lets say for example that obese mice have more red bacteria in their intestine Than lean mice that have more green bacteria. So they wondered if the different bacterial communities in obese vs. lean mice could influence biology in the liver and explain the fact that obesity promotes liver cancer.

But how could something in the intestine influence the liver? 

Well it turns out that bacteria produce byproducts that leave the intestine, enter the circulation, and travel directly to the liver. So the scientists wondered if bacteria from obese mice produced different byproducts than bacteria from lean mice.

Well, it turns out that bacteria from obese mice produce lots of DCA, a compound that damages cells and can even cause colon and liver cancer! That’s a very interesting finding!! When the scientists reduced levels of DCA or removed the bacteria from the intestines of obese mice, these mice no longer formed tumors in the presence of the cancer-causing chemical.

So what did this study show?

First, this study shows that obesity can promote liver cancer development.

Second, the scientists take this a step further to describe a mechanism by which this can happen. It goes like this: Obesity alters the types of bacteria that reside in the intestine. Now, obese mice have more red bacteria and fewer green bacteria. These red bacteria produce lots of DCA, which enters the bloodstream and travels to the liver. In the liver, DCA causes liver cells to enter a state of arrest, or “senescence”.

These senescent cells in turn produce compounds which promote liver cancer development in the presence of a trigger, in this case the cancer-causing chemical given to the mice. So the scientists have come full circle starting from their interesting discovery in the liver that took them all the way to the intestine and back to provide a theory that explains how obesity could promote liver cancer.

So what does this mean for you? 

This study shows that obesity can influence liver cancer and has broader implications than initially thought. Of course, it still remains to be seen if this result stands in humans. I’d also like to find out if DCA produced by intestinal bacteria could be causing cancer directly without acting through senescent cells in the liver.

It would also be interesting to find out HOW the microbiome changes over time as one becomes obese, and why? Is it because of the food that we eat? Is it because of a general state of body-wide inflammation? 

Overall we should take away that it’s important to live healthy lives. What we eat and how we treat ourselves influences biology all over our bodies. So as you can tell, scientists are studying cancer not only at the organ level but at the organism level. By trying to understand how biology in one organ can influence biology in another, we are developing powerful tools to understand our complex physiology and tackle these resilient diseases. Credited: You Reka Science

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