The ketogenic diet, widely promoted for weight loss and its potential health benefits, may influence cancer development in more complex ways than previously thought. New research in mice suggests that the same diet can both promote and suppress tumor growth, depending on where tumors develop within the intestine.
In a study published in Nature, researchers found that a high-fat, very low-carbohydrate ketogenic diet accelerated tumor growth in the small intestine of mice genetically predisposed to cancer. At the same time, the diet reduced tumor formation in the colon, highlighting that dietary effects can differ markedly within the same organ system.
Fat Metabolism, Not Ketones, Takes Center Stage
The research team, led by MIT biologist and pathologist Omer Yilmaz, set out to investigate the widely discussed hypothesis that ketone bodies produced during ketosis help protect against colorectal cancer. Mice genetically predisposed to developing intestinal tumors were assigned either a ketogenic diet, a standard control diet, or a high-fat, high-calorie diet commonly used to induce obesity.
Co-first author Fangtao Chi reported that altering ketone production did not significantly affect intestinal tumor growth. Instead, the tumor-promoting effects observed in the small intestine were linked to how intestinal cells metabolized dietary fat, challenging the assumption that ketone bodies themselves are the primary drivers of the ketogenic diet’s effects on cancer.
The researchers found that mice consuming the ketogenic diet developed small intestinal tumors at rates comparable to—or even higher than—those seen in mice fed the obesity-inducing diet, despite the ketogenic diet preventing obesity. In contrast, the same ketogenic diet reduced tumor formation in the colon, consistent with findings from some earlier studies suggesting potential protective effects against colon cancer.
Stem Cells and Cancer Development
Further investigation showed that when intestinal cells metabolized dietary fat through fatty acid oxidation, they activated proteins known as peroxisome proliferator-activated receptors (PPARs). Activation of these proteins increased both the activity and proliferation of intestinal stem cells, which are essential for repairing intestinal tissue but can also serve as the origin of cancer.
Yilmaz explained that greater stem cell activity can be beneficial following injury because it enhances the intestine’s ability to regenerate. However, increased stem cell proliferation may also raise the likelihood that some of these cells accumulate mutations that eventually lead to tumor formation.
Co-first author and MIT hepatologist Jessica Shay emphasized that the findings also highlight an important distinction between ketogenic diets and ketone supplements. Because the observed effects were driven primarily by fat metabolism rather than ketone molecules themselves, simply increasing ketone levels through supplements would not necessarily be expected to produce the same effects on cancer development.
Conflicting Evidence and Unanswered Questions
The new findings add complexity to earlier research, including a 2022 Nature study suggesting that ketone bodies such as beta-hydroxybutyrate might directly protect against colon cancer. In the current study, ketone bodies appeared to play a much smaller role, with dietary fat metabolism emerging as the dominant biological mechanism influencing tumor development.
The researchers emphasize that their experiments were conducted using a mouse model genetically predisposed to intestinal tumors, resembling certain inherited conditions such as familial adenomatous polyposis in humans. Consequently, the findings cannot be directly applied to the general population without additional studies in people.
Several important questions also remain unanswered. The researchers are continuing to investigate why the small intestine and colon respond so differently to the same ketogenic diet. Potential explanations include regional differences in cell populations, the intestinal microbiome, and local metabolic environments.
Experts caution that these findings should not prompt changes to cancer prevention strategies or treatment plans based solely on this animal research. Instead, the study adds to growing evidence that the relationship between diet, metabolism, and cancer is highly complex and may depend on factors including the affected organ, an individual’s genetic background, and broader lifestyle characteristics.
