A new study has revealed the pathway that enables intermittent fasting to boost the ability of gut stem cells to regenerate, which is activated once food is returned after fasting. The study also reveals a dark side to this regeneration: when cancerous mutations occur during the regeneration period, early-stage intestinal tumors can develop.
When Intermittent Fasting Is on Our Side
Studies have shown that low-calorie diets and intermittent fasting have many health benefits. They can delay the onset of some age-related diseases and increase life expectancy, not only in humans, but in many other organisms.
There are many complex mechanisms behind these benefits, and previous research from MIT has shown that one way fasting enhances its positive effects is by enhancing the regenerative capabilities of gut stem cells, helping the gut recover from injury or inflammation.
“Increasing stem cell activity is good for regeneration, but increasing it too much may have less positive long-term consequences,” says Omer Yilmaz, an associate professor of biology at MIT, a member of the MIT Koch Institute for Integrative Cancer Research, and lead author of the new study in mice.
Yilmaz added that more studies are needed before any conclusions can be reached about whether fasting has a similar effect in humans.
“We still have a lot to learn, but it is interesting that being in a fasted or re-fed state when exposed to a mutagenic substance can have a significant impact on the likelihood of cancer development in mouse models,” he said.
Stimulate renewal
Yilmaz’s lab has been studying how fasting and low-calorie diets affect gut health for years. In a 2018 study, the team found that stem cells in the gut begin using fat for energy instead of carbohydrates during fasting, and that fasting significantly increased the stem cells’ ability to regenerate.
However, some questions remain unanswered: How does fasting stimulate this increase in regenerative capacity? And when does regeneration begin?
“Since then, we have focused on understanding what drives regeneration during fasting,” says Yilmaz. “Is it the fasting itself that drives regeneration or the eating after fasting?”
In their new study, published in Nature on August 21, the researchers found that stem cell regeneration is suppressed during fasting but ramps up during the refeeding period. The researchers followed three groups of mice: one that fasted for 24 hours, another that fasted for 24 hours and then had the opportunity to eat freely during a 24-hour refeeding period, and a control group that ate freely throughout the experiment.
The researchers analyzed the stem cells’ ability to proliferate at different time points, and found that the stem cells showed the highest levels of proliferation at the end of the 24-hour period of their return to food. These cells were also more able to proliferate than cells from mice that had not fasted at all.
“We think that fasting and refeeding represent two different states,” said Shinya Imada, a researcher in the Department of Biology, Koch Institute for Integrative Cancer Research at MIT and the study’s first author. “In the fasting state, cells were able to use fat and fatty acids as an energy source, which helped them survive when nutrients were scarce. Then, it was the refeeding state after fasting that stimulated regeneration. When nutrients were available, these stem cells and progenitor cells activated programs that allowed them to build cell mass and regenerate the intestinal lining.”
When Intermittent Fasting Is on the Enemy’s Side
The researchers also found that when stem cells are in this highly regenerative state, they are more likely to turn into cancer cells. Stem cells in the intestine are some of the most prolific dividing cells in the body, helping to regenerate the lining of the intestine every 5 to 10 days. Because they divide so frequently, these stem cells are the most common source of precancerous cells in the intestine.
In this study, the researchers found that if they turned on a cancer-causing gene in mice during the refeeding phase, they were more likely to develop precancerous tumors than if they turned on the gene during the fasting state. Cancer-related mutations that occurred during the refeeding state were more likely to produce tumors than mutations that occurred in mice that did not undergo the fasting-refeeding cycle.
“I would like to emphasize that all this was done in mice, using well-defined cancer mutations,” Yilmaz says, according to EurekAlert. “In humans, the situation would be much more complicated, but it leads us to the following idea: Fasting is very beneficial, but if you are unlucky when you return to food after fasting and are exposed to a mutagenic substance, such as a burnt steak, you may actually increase your chances of developing a lesion that could turn into cancer.”
Yilmaz also noted that the regenerative benefits of fasting may be significant for people undergoing radiation therapy, which can damage the intestinal lining, or other injuries to the intestines.