Metabolites Linked to Intestinal Stem Cell Function

Biologists at MIT’s Koch Institute of Integrative Cancer Research have shown that high levels of ketone bodies which are molecules produced through the breakdown of fat, help our intestines maintain a large pool of adult stem cells. These stem cells are critical for keeping the intestinal lining in our bodies healthy.

The team also found that intestinal stem cells also produce unusually high levels of ketone bodies in the absence of a high fat diet. The ketone bodies activate Notch, a well known signaling pathway. This pathway was previously shown to help regulate the differentiation of stem cells.

Ketone bodies are an example of how metabolites instruct stem cell fate within the intestines. Ketone bodies which are normally thought to perform a vital role in maintenance of energy during episodes of nutritional stress, engage the Notch pathway in order to enhance the function of stem cells. Changes in levels of ketone bodies in different diets or nutritional states enable stem cells to adapt to a variety of physiologies.

While studying mice, the team found that a ketogenic diet gave stem cells in the intestines a regenerative boost which enabled them to better recover from any damage to the lining of the intestine when compared to stem cells in the mice on a regular diet.

Adult stem cells can differentiate into a variety of different cell types and are found in tissues throughout the body. These particular stem cells are especially important in the intestine since the intestinal lining is replaced every few days. The lab had shown in previous studies that fasting will enhance stem cell function within aged mice. A high fat diet can stimulate a rapid growth of populations of stem cells in the intestine.

The team wanted to study the potential role of metabolism in the function of stem cells within the intestines. Through analyzing gene expression data, they discovered several enzymes that were involved in the production of ketone bodies to be more abundant in stem cells in the intestines than in other cell types.

When a very high fat diet was consumed, cells will use these enzymes to turn fat into ketone bodies which the body will use for fuel when carbohydrates are absent. However, these enzymes are so active in the stem cells within the intestines, they have unusually high ketone body levels even when a normal diet is consumed.

To the surprise of the team, they found the ketones stimulate the Notch signaling pathway. This is known to be critical for the regulation of stem cell functions such as damaged tissue regeneration.
Stem cells within the intestines can generate ketone bodies by themselves and then use them to sustain their own stemness by fine tuning a hardwired developmental pathway which controls stem cell fate and lineage.

By using mice, the team showed that a ketogenic diet would enhance this effect. The mice that were on this diet were better able to regenerate new tissue within the intestines. When the mice were fed a high sugar diet, they noted the opposite effect. Both stem cell function and ketone production declined.

This study helped the team answer some questions raised by previous work which showed that both a high fat diet and fasting enhance the function of intestinal stem cells. The newest findings suggest that by stimulating ketogenesis through any type of diet which limits carbohydrate intake helps promote the proliferation of stem cells.

During periods of food deprivation, ketone bodies will become highly induced within the intestine and therefore play a vital role in the process of enhancing and preserving the activity of stem cells. During times when food isn’t readily available, the intestine needs to preserve the function of stem cells so that when nutrients become replete, the body has a pool of very active stem cells which can then go on to repopulate the intestinal cells.

These findings suggest that a ketogenic diet which drives the production of ketone bodies in the intestine, could be helpful for damage repair in the lining of the intestines.

To view the original scientific study click below:

Study links certain metabolites to stem cell function in the intestine.