Ketogenic diets, originally developed in the 1920s to treat epilepsy, have been adapted in the past few decades as a strategy to lose weight or increase lifespan. This type of diet (a high percentage of fat, low percentage of carbohydrates, and normal or reduced amounts of protein) 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. The impact of ketogenic diets on the gastrointestinal tract remains poorly understood.
In recent years, scientists investigated whether this type of diet might affect the development of cancer. While some research has shown that the diet may protect against the development of colon cancer, a new study suggests that in the small intestine, a ketogenic diet may increase the risk of cancer—with a mechanism through fatty acid oxidation rather than ketone metabolism
This work appears in Nature in the paper, “Ketogenic diet mediates intestinal tumorigenesis through lipids not ketones.”
“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, PhD, 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
A 2022 study in Nature 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 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 fatty acid oxidation. This pathway activates the PPAR family of proteins, which signal stem cells to multiply more rapidly, increasing the chance that some become cancerous
Surprisingly, 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 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 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.
NewsColon cancerDiet therapyGastrointestinal cancerMiceProteins
Previous articleModular Modeling Drives Smarter mRNA Manufacturing
Next articleIncreased Levels of Micro- and Nanoplastics Found in the Blood of Heart Attack Patients
