Ketogenic diet linked to small intestine cancer risk
The Decades-Old Puzzle of Diet and Cancer Growth
For nearly a century, scientists have known that what we eat can influence the growth of cancer, but the precise mechanisms remained stubbornly unclear. The ketogenic diet, first developed in the 1920s to treat epilepsy, forces the body into a metabolic state called ketosis. In this state, blood sugar and insulin levels drop, and the liver converts dietary fat into molecules known as ketone bodies — primarily beta-hydroxybutyrate (BHB) and acetoacetate. These ketone bodies then become a major fuel source for tissues throughout the body.
Cancer cells consume sugar with remarkable avidity, a phenomenon known as the Warburg effect. Because ketogenic diets drastically reduce carbohydrate intake, researchers reasoned that starving tumors of their preferred fuel might slow or stop their growth. This logic seemed so sound that the diet gained widespread attention as a potential anti-cancer strategy, both in popular culture and in scientific laboratories. Yet the evidence remained mixed, with some studies showing protective effects and others showing no benefit at all.
The gastrointestinal tract presented a particularly confusing picture. A 2022 study in Nature suggested that ketogenic diets protect against colon cancer, with BHB identified as the key protective agent But the small intestine, despite being part of the same digestive system, appeared to respond differently. No one could explain why the same diet would protect one part of the gut while potentially harming another.
Researchers at the Massachusetts Institute of Technology (MIT), led by Omer Yilmaz, PhD, director of the MIT Stem Cell Initiative and a member of the Koch Institute for Integrative Cancer Research, decided to investigate whether the ketogenic diet’s protective effects extended to the small intestine or whether the earlier colon findings were tissue-specific. What they found would upend the prevailing understanding of how dietary fat interacts with cancer risk.
The Timeline to Understanding: Fat Metabolism, Not Ketones
The researchers designed a careful experiment using mice genetically predisposed to developing intestinal cancer. They fed these mice one of three diets: a standard ketogenic diet, a control diet, or a high-fat, high-calorie diet known to promote obesity and tumor growth. The results were striking and immediate. Mice on the ketogenic diet developed significantly more tumors in the small intestine than those on the control diet. Remarkably, these mice did not become obese, yet their tumor rates matched or even exceeded those of mice on the obesogenic high-fat, high-calorie diet.
The first surprise came when the team tested whether ketone bodies were responsible. They genetically engineered mice that could not produce BHB or acetoacetate, then fed them the same ketogenic diet. The tumors still appeared. “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,” Yilmaz said. “Instead, our experiments in genetically engineered mice revealed that these molecules are essentially metabolic bystanders.”
The real driver, the team discovered, was fatty acid oxidation — the process by which cells burn dietary fat for energy. When the small intestine was flooded with fat from the ketogenic diet, its stem cells began processing this fat through a pathway that activates a family of proteins called PPAR. These PPAR proteins then signal the stem cells to multiply more rapidly. The faster the stem cells divide, the greater the chance that some will acquire mutations and become cancerous.
This finding resolves a puzzle that had persisted for decades. Previous studies had focused on ketone bodies as the active agents, but they were looking at the wrong molecule. The accelerating effect is driven entirely by how stem cells process and burn the heavy influx of dietary fat itself. The timeline for this effect in the mouse model was measurable within weeks of starting the diet, though in humans, the consequences might take years or decades to manifest.
The Closing Finding: Opposite Effects in the Colon
The most surprising result came when the researchers examined the colon. The same ketogenic diet that promoted tumors in the small intestine had the opposite effect in the colon. Mice on the ketogenic diet developed fewer colon tumors than those on the control diet. This confirmed the 2022 study’s finding that ketogenic diets protect against colon cancer, but with a critical twist: the new study showed that ketone bodies are not responsible for this protective effect either.
The team found that the protective mechanism in the colon also involves fatty acid metabolism, but through a different pathway than in the small intestine. The colon’s stem cells process dietary fat in a way that suppresses rather than accelerates their division. This explains why the same diet can have opposite effects on different parts of the same organ system. “Ketogenic diets have distinct effects on different tissues even within the gastrointestinal tract,” Yilmaz explained. “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.”
Sources
1. DOI: 10.1038/d41586-026-02039-w