Ketogenic diets may increase cancer risk in the small intestine

A high-fat, low-carbohydrate diet, also called a ketogenic diet, can help some people lose weight by forcing their bodies to burn fat for fuel instead of sugar. In recent years, scientists have been exploring how this type of diet might affect other aspects of health and disease, including cancer. While some research has shown that the diet may protect against the development of colon cancer, a new study by MIT researchers suggests that in the small intestine, a ketogenic diet may increase the risk of cancer.“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 study, which appears today in Nature. MIT postdocs Jessica Shay and Fangtao Chi are the lead authors of the paper. Researchers from the labs of Alex K. Shalek, director of MIT’s Institute for Medical Engineering and Science, and Matthew Vander Heiden, director of the Koch Institute, also contributed to the study.Diet and cancerKetogenic diets, originally developed in the 1920s as a way to treat epilepsy, have been adapted in the past few decades as a strategy to lose weight or increase lifespan. The diet comprises a high percentage of fat, low percentage of carbohydrates, and normal or reduced amounts of protein.This type of diet forces the body to burn fatty acids for energy in place of carbohydrates such as glucose. Burning these lipids produces ketone bodies — primarily β-hydroxybutyrate (BHB) and acetoacetate — as byproducts of fatty acid metabolism. These ketone bodies are also generated when people fast or follow very low-calorie diets, which force the body to burn its own fatty stores.A 2022 Nature study suggested that ketogenic diets have a protective effect against colon cancer and that BHB — the most abundant ketone body — is responsible for this effect. In the new Nature study, the MIT team wanted to explore whether ketogenic diets might have a similar protective effect in the small intestine.The researchers fed mice who were genetically predisposed to developing intestinal cancer either a ketogenic diet, a control diet, or a high fat/high calorie diet. They found that mice on a ketogenic diet were more likely to develop tumors of the small intestine than those on a control diet. While they did not become obese, mice on the ketogenic diet developed tumors at rates similar to or even higher than those of mice on an obesogenic high fat/high calorie diet. Additional studies revealed that ketone bodies did not play a role in tumor development. Instead, tumor growth was driven by how intestinal cells burn dietary fat for energy — a metabolic pathway called fatty acid oxidation. This pathway activates a family of proteins called PPARs, which signal stem cells to multiply more rapidly, increasing the chance that some become cancerous. This stem cell proliferation can be beneficial in certain situations, such as when the intestinal lining needs to be repaired after illness or injury. However, too much proliferation can tip cells toward becoming cancerous. “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.Opposite effectsSurprisingly, the same ketogenic diet that promoted tumors in the small intestine had the opposite effect in the colon. The researchers found, similar to the earlier Nature study back in 2022, that a ketogenic diet suppressed the development of colon tumors. However, the new findings suggest that ketone bodies are not responsible for this protective effect.“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 researchers now hope to further study why ketogenic diets have such different effects in the colon and the small intestine. As ketogenic diets continue to gain popularity, understanding these tissue-specific effects will be critical for guiding their use, the researchers say.“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.The findings carry practical implications. Because the diet’s effects — both the tumor acceleration in the small intestine and the protection in the colon — are driven entirely by fat metabolism rather than the ketones themselves, commercial ketone supplements or drinks would not be expected to mimic either the risks or the benefits discovered in this study. This may be especially relevant given that small intestinal tumors have been rising in incidence in recent decades, with the greatest impact on patients with inherited conditions that predispose them to intestinal cancer, such as 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.