Researchers studying mice at Massachusetts Institute of Technology have made a surprising discovery about ketogenic or fat-rich diets. They found that the ketone bodies produced when fats are broken down in the intestine trigger the proliferation of adult stem cells, which are needed to maintain a healthy intestinal lining.
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Compared with mice that were fed a regular diet, a ketogenic diet gave adult stem cells in the intestine a regenerative boost that improved their ability to recover from damage to the intestinal lining. The team also found that the stem cells produce especially high levels of ketone bodies in the absence of a high-fat diet.
Ketone bodies can determine cell fate in the intestine
Study author Omer Yilmaz says ketone bodies are one of the first examples of how a metabolite instructs stem cell fate in the intestine. They activate the Notch signaling pathway, which is a key regulator of the cell-to-cell communication needed for stem cells to differentiate.
These ketone bodies, which are normally thought to play a critical role in energy maintenance during times of nutritional stress, engage the Notch pathway to enhance stem cell function. Changes in ketone body levels in different nutritional states or diets enable stem cells to adapt to different physiologies.”
Dr. Omer Yilmaz, Senior Author
Stem cells particularly important in the gut
Adult stem cells, which can differentiate into any type of cell, are found throughout the body. However, they play a particularly important role in the intestine, since the gut lining is completely replaced every few days.
Yilmaz and colleagues have previously conducted studies showing that fasting improves intestinal stem cell function in aged mice and that a fat-rich diet can cause rapid proliferation of intestinal stem cell populations.
Stem cells can utilize ketones for maintenance and growth
In the current study, the researchers analyzed gene expression data to explore the role that metabolism may play in maintaining intestinal stem cell function.
This showed that certain enzymes involved in the generation of ketone bodies were more abundant in intestinal stem cells than in other cell types.
When fat-rich foods are eaten, these enzymes break the fat down into ketone bodies, which can be used as an alternative source of fuel in the absence of carbohydrates. The enzymes are particularly active in intestinal stem cells, which have very high levels of ketone bodies even when a regular diet is followed.
The researchers were surprised to find that the ketones induced the Notch signaling pathway, a crucial regulator of stem cell functions, including the regeneration of damaged tissue.
Intestinal stem cells can generate ketone bodies by themselves, and use them to sustain their own stemness through fine-tuning a hardwired developmental pathway that controls cell lineage and fate.”
Dr. Chia-Wei Cheng, Lead Author
As reported in the journal Cell, this effect was enhanced among mice that were fed a ketogenic diet and the animals were more able to generate new intestinal tissue, compared with when mice were fed a regular diet. When mice were fed a diet that was high in sugar, the opposite effect occurred, with both ketone production and stem cell function declining.
The findings answer important questions
The research helps to explain some of Yilmaz’s previous findings showing that both a fasting and a high-fat diet improve the function of intestinal stem cells. It suggests that any kind of diet where carbohydrate intake is limited stimulates ketogenesis and promotes the growth of stem cells.
"Ketone bodies become highly induced in the intestine during periods of food deprivation and play an important role in the process of preserving and enhancing stem cell activity," says Yilmaz.
"When food isn't readily available, it might be that the intestine needs to preserve stem cell function so that when nutrients become replete, you have a pool of very active stem cells that can go on to repopulate the cells of the intestine."
Can the ketogenic diet repair the intestinal barrier?
The study suggests that following a ketogenic diet, which would increase levels of ketones in the intestine, may help to repair damaged intestinal lining. Such damage can occur when people receive radiotherapy or chemotherapy.
Next, Yilmaz and team want to explore adult stem cells in other tissues that rely on ketone bodies to maintain their function.
Another important question the researchers want to answer is whether the increased stem cell activity that results from ketone production may be linked to cancer, since some tumors are known to arise from stem cells:
That's something we want to understand. What role do these ketone bodies play in the early steps of tumor formation, and can driving this pathway too much, either through diet or small molecule mimetics, impact cancer formation? We just don't know the answer to those questions.”
Dr. Omer Yilmaz, Senior Author
Cheng, C-W., et al. (2019). Ketone Body Signaling Mediates Intestinal Stem Cell Homeostasis and Adaptation to Diet. Cell. https://doi.org/10.1016/j.cell.2019.07.048.