Ketone Bodies Help Maintain a Large Pool of Adult Intestinal Stem Cells

What is the ketogenic diet?

An individual following a ketogenic diet will mainly consume foods that are high in fat, moderate in protein content and very little carbohydrates. The diet was first adopted in 1921 as a treatment option for epilepsy patients, however it has seen a resurgence recently in modern diet culture for rapid weight-loss.¹

When the body does not have sufficient glucose for energy, it burns stored fats instead – a metabolic process known as ketosis. The breakdown of fat produces molecules known as ketone bodies.

Researchers at MIT have discovered an unexpected finding of consuming a ketogenic diet. Ketone bodies are known to activate signaling pathways implicated in stem cell differentiation. In a mouse model, they have shown that high levels of ketone bodies help the intestine to maintain a large pool of adult stem cells. These stem cells contribute to keeping the lining of the intestine healthy.

The study is published in the journal Cell.  

A closer look at stem cells

In previous research, Yilmaz and team had shown that fasting enhances stem cell function in mice and that a high-fat diet stimulates a rapid growth of stem cells in the intestine. 

Adult stem cells are able to differentiate into the many different cells that constitute an organism. They serve several key physiological roles, particularly in the intestine, where the lining is replaced every few days.

In the mammalian intestine, the active cycling of these stem cells, known as Lgr5+ intestinal stem (ISCs) depends on the precise control of intrinsic mechanisms such as the Notch pathway, the Wnt pathway and the Bmp developmental signaling pathways.

It was already known that ISCs generate ketone bodies by themselves: "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," says postdoc Chia-Wei Cheng is the paper's lead author. However, in this study the researchers wanted to explore further the role of energetic metabolites in the executive control over Lgr5+ ISCs, by subjecting mice to a ketogenic diet.

The study results demonstrate that a ketogenic diet gave the ISCs a regenerative boost that made them better able to recover from cell damage to the intestinal lining when compared to control mice consuming a regular diet. When mice were fed a high-sugar diet, they saw that ketone production and stem cell function declined.

How is this mediated?

The researchers analyzed RNA-seq data to identify the metabolic pathways enriched in ISCs. They discovered that the expression of several enzymes involved in the production of ketone bodies, such as HMGCS2, were more enriched in ISCs when compared to other intestinal cells, such as crypt cells. The ketone bodies produced were found to stimulate the Notch signaling pathway.

"Ketone bodies are one of the first examples of how a metabolite instructs stem cell fate in the intestine," says Omer Yilmaz, the Eisen and Chang Career Development Associate Professor of Biology and a member of MIT's Koch Institute for Integrative Cancer Research. "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."

Yilmaz continues: "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. 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."

Translational to the clinic?

The study findings suggest that a ketogenic diet, which enhances natural ketone body production in the intestine, may be helpful for the repair of damaged intestinal lining. Cancer patients that receive radiation or chemotherapy treatments can experience such damage, demonstrating clinical value of the results. However, it must be considered that this study was executed in an animal model.

To take the study further, the researchers will next explore whether adult stem cells in other types of tissue also use ketone bodies to regulate their function.

A second question also emerges from this research: is ketone-induced stem cell activity linked to cancer development? This is based on the knowledge that tumors in the intestines can arise from stem cells.

"If an intervention drives stem cell proliferation, a population of cells that serve as the origin of some tumors, could such an intervention possibly elevate cancer risk? That's something we want to understand," Yilmaz says. "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."

Reference:

1.    Masood W, Uppaluri KR. Ketogenic Diet. 2019. StatPearls. Available from: https://www.ncbi.nlm.nih.gov/books/NBK499830/

2. Cheng et al. 2019. Ketone Body Signaling Mediates Intestinal Stem Cell Homeostasis and Adaptation to Diet. Cell. DOI: https://doi.org/10.1016/j.cell.2019.07.048