MIT scientists find a hidden cancer risk of the keto diet

Scientists have increasingly studied whether this metabolic shift influences other areas of health, including cancer. Previous research has suggested that ketogenic diets may help protect against colon cancer. However, new research from MIT points to a very different outcome in the small intestine, where the same type of diet may increase cancer risk.

“Ketogenic diets have distinct effects on different tissues even within the gastrointestinal tract. I think the message here is that we need to be very careful in generalizing the effects that these diets can have, because what might be beneficial for one tissue may be detrimental for another tissue,” says Omer Yilmaz, director of the MIT Stem Cell Initiative, an associate professor of biology at MIT, and a member of MIT’s Koch Institute for Integrative Cancer Research.

Yilmaz is the senior author of the research, published in Nature. MIT postdoctoral researchers Jessica Shay and Fangtao Chi are the paper’s lead authors. Scientists from the laboratories of Alex K. Shalek, director of MIT’s Institute for Medical Engineering and Science, and Matthew Vander Heiden, director of the Koch Institute, also participated in the work.

How Keto Changes the Body’s Fuel Source

Ketogenic diets were first developed during the 1920s as a treatment for epilepsy. In more recent decades, they have also been adopted for weight loss and as a possible strategy for extending lifespan. These diets contain a large proportion of fat, very little carbohydrate, and normal or reduced amounts of protein.

With carbohydrates such as glucose in short supply, the body begins using fatty acids as a major energy source. Breaking down those fats generates compounds known as ketone bodies, including β-hydroxybutyrate (BHB) and acetoacetate. Ketone bodies also appear during fasting or very low-calorie diets, when the body must draw on stored fat for energy.

A 2022 study in Nature found evidence that a ketogenic diet could protect against colon cancer and proposed that BHB, the most abundant ketone body, played a central role in that benefit. The MIT researchers behind the new Nature study set out to determine whether keto might provide a similar protective effect in the small intestine.

Keto Increased Small Intestinal Tumors in Mice

To investigate, the researchers studied mice genetically predisposed to developing intestinal cancer. The animals were given either a ketogenic diet, a control diet, or a high fat/high calorie diet.

Mice eating the ketogenic diet developed small intestinal tumors more often than animals receiving the control diet. Although the keto-fed mice did not become obese, their tumor rates were similar to, and in some cases higher than, those seen in mice consuming the obesogenic high fat/high calorie diet.

Further experiments produced an unexpected result. Ketone bodies themselves did not appear to cause the increased tumor growth.

Instead, the effect was traced to fatty acid oxidation, the process intestinal cells use to burn dietary fat for energy. Increased activity in this pathway switches on a family of proteins called PPARs. Those proteins then encourage intestinal stem cells to divide more rapidly, creating more opportunities for some of the cells to become cancerous.

Having highly active stem cells is not always harmful. Rapid stem cell growth can help the intestinal lining recover after injury or illness. But excessive cell division can also increase the likelihood of tumor formation.

“Having more stem cells means that when you injure the small intestine, it can repair itself better, but the downside is that having more active stem cells can lead to tumor formation,” Yilmaz says.

The Colon Responded in the Opposite Way

The researchers found a striking contrast when they examined the colon. While the ketogenic diet promoted tumor development in the small intestine, it suppressed tumor formation in the colon.

That result was consistent with the earlier 2022 Nature study. However, the new experiments challenge the idea that ketone bodies are responsible for the protective effect in the colon.

“Given how much attention has been paid to ketone bodies like BHB, both as a commercial health trend and in recent high-profile studies suggesting BHB suppresses colon cancer, we fully expected them to be the direct drivers. Instead, our experiments in genetically engineered mice revealed that these molecules are essentially metabolic bystanders. The real surprise is that tumor acceleration is driven entirely by how stem cells process and burn the heavy influx of dietary fat itself,” Yilmaz says.

The team now wants to determine why a ketogenic diet can produce such different outcomes in two neighboring parts of the digestive tract. With ketogenic diets becoming increasingly popular, the researchers say it will be important to understand these tissue-specific effects before drawing broad conclusions about their health consequences.

“The deeper question is why the same diet has opposite consequences in two adjacent parts of the gut. That is what we are working to understand next,” Chi says.

What the Findings Could Mean for Ketone Supplements

The results also have implications for commercial ketone products. Because both the increased tumor growth in the small intestine and the reduced tumor development in the colon were linked to fat metabolism rather than ketones themselves, ketone supplements or drinks would not be expected to reproduce either effect identified in the study.

That distinction could be particularly important because the incidence of small intestinal tumors has risen in recent decades. The impact is especially significant for people with inherited disorders that increase their susceptibility to intestinal cancer, including familial adenomatous polyposis.

The research was funded, in part, by the National Institutes of Health, a Pew-Stewart Trust scholar award, the Kathy and Curt Marble cancer research award, a Koch Institute-Dana Farber/Harvard Cancer Center Bridge project grant, the American Federation for Aging Research, the MIT Stem Cell Initiative, a Damon Runyon Postdoctoral Research Fellowship, and the Koch Institute Support (core) grant from the National Cancer Institute.