Fats, Not Ketones, Shape How Keto Diets Influence Cancer Risk

Ketogenic, or “keto”, diets were initially designed to help treat epilepsy but have risen in popularity as a strategy for weight-loss. 

However, new research indicates that keto diets may increase the risk of cancer in the small intestine, and illustrates that this is “surprisingly” due to dietary fat, rather than an increase in ketones.

Diet and intestinal cancers 

For decades, scientists have suspected that what we eat has an important influence on our risk of developing cancer, but identifying how dietary factors shape cancer risk has proved challenging. 

“The gut is where diet and cancer meet most directly,” Dr. Ömer Yilmaz, a professor of biology at the Massachusetts Institute of Technology and senior author of the new study, told Technology Networks. 

Stem cells in intestinal crypts—small glands in the epithelial lining of the small and large intestines—are responsible for renewing the gut lining, with complete renewal happening every few days. “The same adaptations that help the gut regenerate and repair itself can, if the timing is wrong or a cancer-predisposing mutation is present, tip a cell toward forming a tumor,” explained Yilmaz. 

Intestinal crypt stem cells are “exquisitely sensitive” to what we eat, he said. Dietary factors, including fasting, caloric restriction, and high fat intake, can reprogram cellular homeostasis and influence cancer risk. 

“The trade-off between regeneration and cancer is what drew me in [to study the relationship between dietary interventions and cancer], and ketogenic diets were a natural question because they're both popular and poorly understood in this context,” Yilmaz said. 

Keto diets influence cellular metabolism 

A keto diet is characterized by a very high intake of fat, a very low intake of carbohydrates, and normal or reduced protein intake.  

“Starved of sugar, the body shifts to burning fat for fuel, and in the process the liver makes ketones, an alternative energy source,” explained Yilmaz. “The keto diet changes cellular metabolism on two fronts at once: it floods the body with fat to burn, and it raises ketones. Both of these have been claimed to matter for cancer, often in opposite directions.” 

Ketone bodies, primarily β-hydroxybutyrate (BHB) and acetoacetate, are produced as a byproduct of fatty acid metabolism. BHB has been found to play both a cancer-suppressive and a cancer-promoting role, depending on the context. For example, BHB and its metabolic signaling pathway were found to suppress colorectal cancer risk by reducing crypt cell regeneration, but they have also been linked to increased metastasis in pancreatic cancer. 

Dietary fats may influence cancer development through inflammatory, lipid metabolism, and oxidative stress pathways. However, the type of dietary fat is also an important factor, with saturated fats broadly seen to increase cancer risk and mono- and poly-unsaturated fats shown to have a potentially protective effect. 

“If you want to know whether a diet helps or harms in cancer, you have to separate these effects rather than lumping them together as ‘keto’.” — Dr. Ömer Yilmaz.

“That separation turned out to be the crux of our study,” Yilmaz noted.

Exploring the paradox of ketogenic diets in cancer 

Yilmaz and his colleagues fed mice engineered to have a higher predisposition to developing intestinal cancer either a ketogenic diet, a normal diet, or a high-fat/high-calorie obesogenic diet. 

“The obesogenic high-fat diet was essential as a comparison,” Yilmaz said. “A ketogenic diet is high in fat and produces ketones and lowers insulin—three things bundled together. An obesogenic high-fat diet is also high in fat, but it doesn't drive the body into ketosis the same way, so putting the two side by side lets us ask the following: is it the fat, or is it the ketosis?” 

The researchers tracked tumor formation and survival in the mice and performed single-cell RNA (scRNA) sequencing to characterize how diet modulated the biology of intestinal cells. 

They found that mice on the obesogenic diet gained weight and were more likely to develop tumors in the small intestine than those on a control diet, and while they didn’t gain weight, mice on the ketogenic diet also developed tumors at a similar rate to those on the obesogenic diet. 

“When both diets produced similar effects in a given tissue, that told us the fat—not the ketones—was the common driver,” said Yilmaz. 

Increased dietary fat influences intestinal tumor formation 

To use the large amounts of dietary fat in a ketogenic diet for energy, cells in the small intestine increase fatty acid oxidation. “This fat-burning powers the gut’s cells to divide more, and when they've taken a cancerous hit, to form tumors more readily,” Yilmaz explained. 

When the team genetically blocked fatty acid oxidation, mice on the ketogenic diet showed prolonged survival, fewer tumors, and a lower tumor burden. 

 

Further analysis pinpointed PPAR signaling as a critical upstream effector. PPAR proteins are activated by fatty acid oxidation and can trigger cells to divide more rapidly. When PPAR signaling was knocked out and the mice were fed a ketogenic diet, intestinal crypt cells showed reduced proliferation. 

“The surprising part was what didn't matter: the ketones,” said Yilmaz. 

As ketones had previously been identified as an important factor linking the keto diet and cancer, the researchers directly tested their effects.  

“We switched their production off, forced it on, blocked the gut's ability to use them. In every case, the tumors were unchanged,” Yilmaz explained. 

“Ketones had been cast as the important players... But the molecule everyone was watching turned out to be a bystander; the fat was doing the work.” — Dr. Ömer Yilmaz. 

These findings indicate that increased fatty acid oxidation—not increased ketone production—caused by a ketogenic diet triggers increased cellular proliferation in intestinal crypts, which can tip cells toward becoming cancerous. 

Ketogenic diets have opposite effects in the small intestine and the colon 

While a ketogenic diet increased cancer risk in the small intestine, it appeared to have a protective effect in the colon.  

“They handled the diet's fat very differently,” noted Yilmaz. “The small intestine took up and processed far more of it; the colon's fat profile changed much less.” 

The differing roles of the small intestine and the colon may help to explain the opposing effects—the small intestine is the primary site of nutrient absorption, whereas the colon plays a greater role in water balance and interacting with the gut microbiome. 

“I suspect the answer involves more than the lining cells themselves—the local immune environment and the gut microbiome are strong candidates, since the colon is where those systems are most active,” said Yilmaz. “Untangling which of those is doing the protecting is a major direction for us.” 

Implications for the use of ketogenic diets and ketone supplements 

Keto diets and ketone supplements are being increasingly explored as therapeutic strategies for neurological disorders, metabolic diseases, and cancer.  

The new study illustrates the context-dependent relationship between keto diets and cancer risk, highlighting that dietary strategies are not one-size-fits-all.  

Yilmaz noted that: “Blanket claims that keto is good or bad for cancer are too crude. For someone with an inherited risk of small-intestinal cancer, our data are a reason for genuine caution and a conversation with their doctor; for a healthy person, they're not cause for alarm.” 

“There's growing interest in taking ketones directly, as pills or drinks, to capture keto's supposed benefits without the diet,” he continued. “Our work is a caution there.” 

In their research, the reduced risk of colon cancer associated with a ketogenic diet was due to the dietary fat, not the ketones. Yilmaz warned: “You shouldn't assume a ketone supplement reproduces what a ketogenic diet does; biologically, they may be quite different things.” 

Reference: Shay JES, Chi F, Tzouanas CN, et al. Ketogenic diet mediates intestinal tumorigenesis through lipids not ketones. Nature. 2026. doi: 10.1038/s41586-026-10779-y

About the interviewee: 

Dr. Ömer H. Yilmaz, MD, is a professor of biology and director of the MIT Stem Cell Initiative, as well as a pathologist and director of Translational Pathology at the Beth Israel Deaconess Medical Center, Harvard Medical School. He received his PhD and MD from the University of Michigan Medical School and conducted postdoctoral work at the Whitehead Institute for Biomedical Research before establishing his lab in 2014.

His research focuses on understanding how intestinal stem cells and their microenvironment adapt to diverse diets in the context of tissue regeneration, aging, and cancer initiation and progression.

His achievements, to date, have been recognized with a Harold Weintraub Award (2007), a V Scholar Award (2015), a Pew-Stewart Trust Fellowship (2016), a Sidney Kimmel Fellowship (2016), a Sabri Ulker International Science Prize (2018), a AAAS Martin and Rose Wachtel Cancer Research Prize (2018), a Glenn Foundation for Medical Research Breakthroughs in Gerontology (BIG) Award (2022), a Crohn’s & Colitis Foundation Senior Research Award (2023), and a Kenneth Rainin Foundation Innovator Award (2023).