How fasting helps and harms the gut

Intermittent fasting can delay the onset of some age-related diseases and lengthen lifespan. In part, MIT researchers have found, that’s because it boosts intestinal stem cells’ ability to regenerate, which helps the intestine recover from injuries or inflammation. A new mouse study by the same researchers now sheds further light on how this mechanism works, suggesting that the regeneration happens not when the animals are actually fasting, but when they begin eating again. Yet the research also points to an unsettling downside.

The researchers followed one group of mice as they fasted for 24 hours and another group as they fasted for 24 hours and then ate as much as they wanted for 24 hours. A control group did not fast at all. When they analyzed the intestinal stem cells’ ability to proliferate at different points in time (including at the end of a fast and 24 hours after refeeding) they found that fasting itself reduces proliferation but refeeding after fasting increases proliferation. 

In addition, the researchers found that the regeneration was due in part to activation of a cellular signaling pathway known as mTOR, which causes cells to produce more protein; this protein synthesis is essential for stem cells to proliferate. And they showed that mTOR activation led to production of large quantities of polyamines, small molecules that help cells grow and divide.

Another finding, though, was that if a cancer-causing gene was turned on during the refeeding stage, the mice were much more likely to develop precancerous polyps than if the gene was turned on during the fast. Cancer-linked mutations that occurred during refeeding were also much more likely to produce polyps than mutations that occurred in mice that did not undergo the cycle of fasting and refeeding. “Having more stem-cell activity is good for regeneration, but too much of a good thing over time can have less favorable consequences,” says Omer Yilmaz, an associate professor of biology and the senior author of the study.

The effects of fasting are much more complex in humans than in mice, Yilmaz says, but the work does suggest that “if you’re unlucky and you’re refeeding after a fasting, and you get exposed to a mutagen, like a charred steak or something, you might actually be increasing your chances of developing a lesion that can go on to give rise to cancer.”

Still, Yilmaz says the regenerative benefits of fasting could be significant for people who undergo radiation treatment, which can damage the intestinal lining, or for those with other types of intestinal injury. His lab is now studying whether polyamine supplements could help stimulate this kind of regeneration, without the need to fast.