A 24-hour fast could help keep intestinal stem cells young and active. MIT biologists have discovered the pathway that allows these stem cells to regenerate and have created a molecule that imitates the process so that an actual fast isn’t necessary.

Fasting Buddha. Image credits: Percy Brown.

Intestinal stem cells are the source for all new intestinal cells and are thus important in healing when there is an injury or infection. They maintain the lining of the intestine, which renews itself about every five days. As people get older, their stem cells decline and take longer to recover.

A 24-hour fast caused the stem cells of old and young mice to regenerate more. The researchers removed intestinal stem cells from the fasting mice and grew them in a culture to see if they would form organoids, which are like mini-intestines. If they have the ability to form organoids, then the stem cells are more capable of regeneration. The stem cells from the fasting mice had the twice the regenerative capacity of non-fasting mice.

“It was very obvious that fasting had this really immense effect on the ability of intestinal crypts to form more organoids, which is stem-cell-driven,” says Maria Mihaylova Whitehead Institute postdoc and lead co-author. “This was something that we saw in both the young mice and the aged mice, and we really wanted to understand the molecular mechanisms driving this.”

An intenstinal organoid. Imge credits: Meritxell Huch.

The mice that fasted switched from their normal metabolism, which burns carbs like sugars in order to metabolize fatty acids. Transcription factors called PPARs that become activated are responsible for the switch — when this pathway was switched off, fasting had no effect on stem cell regeneration.

“This study provided evidence that fasting induces a metabolic switch in the intestinal stem cells, from utilizing carbohydrates to burning fat,” says David Sabatini, an MIT professor of biology, member of the Whitehead Institute for Biomedical Research and a senior author of the paper. “Interestingly, switching these cells to fatty acid oxidation enhanced their function significantly. Pharmacological targeting of this pathway may provide a therapeutic opportunity to improve tissue homeostasis in age-associated pathologies.”

Using this pathway, the researchers created a molecule that imitates the effects of these transcription factors. This means that a drug could be developed for older patients that would help their intestines regenerate. This treatment could be particularly useful for older patients recovering from infections or cancer patients undergoing chemotherapy, as it would be much less strenuous than undergoing an actual 24-hour fast. The researchers now want to test the efficacy of these treatments and determine if fasting can have a beneficial effect on other stem cell types. The research is published today in Cell Stem Cell.

Maria Mihaylova, Chia-Wei Cheng et al. 2018. Cell Stem Cell.