Dietary regimens have become increasingly common, whether to prevent disease, avoid worsening existing health conditions, or simply for aesthetic reasons. Among the wide variety of dietary approaches, one has gained particular attention because it is characterized by a very low intake of carbohydrates and a high proportion of fats: the keto, or ketogenic, diet.

The goal of this diet is to reduce the availability of glucose in the body, causing it to rely on other sources, such as lipids, to obtain the energy required for normal functioning. This process occurs mainly in the liver, which produces ketone bodies—molecules such as beta-hydroxybutyrate (BHB)—that can serve as an alternative fuel for different tissues.

Because many tumor cells consume large amounts of glucose, it has been proposed that a ketogenic diet could make cancer growth more difficult. However, given the enormous diversity and heterogeneity of cancer, not all tumors depend on the same fuel. Some can adapt and use fats, amino acids, or other energy sources.

A recent experimental study published in Nature found that a very high-fat ketogenic diet accelerated tumor formation in the small intestine of genetically predisposed mice. Surprisingly, the effect was not caused by ketones, but by the ability of intestinal cells to use fatty acids as an energy source.

 

An Intestine That Constantly Renews Itself

The inner lining of the intestine, known as the intestinal epithelium, is one of the most rapidly renewing tissues in the body. Its cells are replaced approximately every four to five days. This renewal depends on intestinal stem cells, which are capable of dividing and producing the different cell types that make up the intestine.

These cells are essential for repairing tissue after injury. However, their strong proliferative capacity may also represent a risk when they lose the mechanisms that normally control their growth.

One of these mechanisms depends on the APC gene, a tumor suppressor gene. Tumor suppressor genes function like “brakes” that limit cell division. When APC is lost or inactivated, the Wnt–beta-catenin pathway may remain continuously active, promoting excessive and uncontrolled proliferation.

This alteration is especially important in familial adenomatous polyposis, or FAP, an inherited disorder caused by mutations in APC. People with FAP develop numerous polyps and have a very high risk of colorectal cancer.

An adenoma is an abnormal growth of glandular tissue that has not yet invaded surrounding tissues. Not all adenomas become cancerous, but some may accumulate additional alterations and progress into malignant lesions.

 

The Diet Increased Intestinal Stem Cell Activity

In the study, the researchers used a ketogenic diet containing approximately 80% fat. As expected, the animals developed elevated BHB levels and reduced circulating insulin.

However, the researchers also observed an expansion of intestinal stem cells and increased proliferation within the intestinal crypts. In healthy tissue, this activity may support repair. But in a cell that has lost APC, it may also increase the likelihood of tumor initiation.

Mice predisposed to developing adenomas formed more tumors, had a greater overall tumor burden, and experienced shorter survival when they were fed the ketogenic diet.

 

Ketones Were Not Responsible

To determine whether ketone bodies were causing this effect, the researchers manipulated several components of ketone metabolism.

The process of producing ketone bodies is called ketogenesis—hence the name of the diet. Although ketogenesis occurs mainly in the liver, intestinal cells can also produce small amounts of ketones.

When the researchers removed the enzyme required to produce ketone bodies in the intestine, local BHB production decreased. They also removed the corresponding enzyme in the liver to reduce systemic production, meaning the amount of ketones circulating throughout the body. Despite these reductions, the ketogenic diet continued to increase tumor formation. This indicated that ketones were not required for the effect.

The researchers then disrupted ketolysis, the process by which cells use ketone bodies to produce energy. To do so, they removed the enzymes responsible for this pathway.

Once again, blocking ketone utilization did not reduce tumor burden.

Finally, they performed the opposite experiment. They artificially increased BHB production in the intestines of animals that were not consuming a high-fat diet. Although ketone levels increased, tumor formation did not.

Taken together, these experiments showed that ketones were neither necessary nor sufficient to explain tumorigenesis.

So, what was driving the effect?

 

The Role of PPAR and Fat Oxidation

Gene expression analysis showed that the diet activated cellular programs involved in lipid transport and utilization. One of the main participants was the PPAR family of proteins.

PPAR proteins function as lipid sensors. When they detect a high availability of fats, they activate genes that help transport, store, or use those fats as an energy source.

The researchers deleted three members of this family—PPAR-alpha, PPAR-delta, and PPAR-gamma—from the intestinal epithelium. When they did so, the ketogenic diet lost much of its ability to increase crypt proliferation and expand the intestinal stem cell population.

They also identified a key enzyme called CPT1A.

CPT1A controls the entry of long-chain fatty acids into mitochondria, the structures where cells generate much of their energy.

Once inside the mitochondria, fatty acids undergo a process known as beta-oxidation, or fatty acid oxidation. During this process, fats are broken down to produce energy-generating molecules.

When the researchers deleted CPT1A from intestinal cells, animals fed the ketogenic diet developed fewer tumors, had a lower tumor burden, and survived longer.

This showed that fatty acid oxidation was not merely a feature associated with the tumors. It was required for excess dietary fat to promote adenoma formation in this model.

Figure 1. Relationship between a high-fat ketogenic diet, intestinal fat metabolism, and early tumor development in genetically predisposed tissue.

 

The Proposed Mechanism

The proposed mechanism can be summarized as follows:

Excess dietary fat → PPAR activation → increased CPT1A expression → enhanced fatty acid oxidation → expansion of intestinal stem cells → increased likelihood of tumor initiation after APC loss.

BHB appeared to be an associated metabolic product, but not the main driver of the process.

An important finding was that the diet did not have the same effect throughout the entire intestine. In the small intestine, it increased tumor formation. In the colon, by contrast, the researchers observed a reduction in tumor burden.

This difference may be related to the distinct functions of each intestinal segment. The small intestine absorbs most nutrients and is directly exposed to large amounts of fat after a meal.

The colon, on the other hand, has a closer relationship with the gut microbiome, absorbs water and electrolytes, and receives metabolites produced by intestinal bacteria.

There are also differences in immune composition and in the metabolic pathways used by cells in the small intestine and colon. For this reason, it is not accurate to broadly state that the ketogenic diet either “promotes” or “fights” intestinal cancer. Its effects may depend on the specific tissue involved.

 

Does This Mean the Ketogenic Diet Causes Cancer?

No. The study was conducted mainly in animal models that were genetically predisposed to developing intestinal tumors. The mice carried APC-related alterations, meaning they do not directly represent a healthy person without an inherited predisposition.

In addition, the experimental diet contained an extremely high proportion of fat and was carefully controlled. Not all ketogenic diets used by humans have the same composition.

However, it will be important to investigate whether these findings translate to humans and whether a high fat intake during a ketogenic diet could promote intestinal tumor development in people with a family history of cancer predisposition or hereditary syndromes such as familial adenomatous polyposis.

One of the study’s most important messages is that ketosis should not automatically be interpreted as an antitumor state. Although reductions in glucose or insulin may limit the activity of some tumor cells, others may be able to use fatty acids as an alternative energy source.

Main reference:

Shay, J. E. S., Chi, F., Tzouanas, C. N., Han, S., Zhang, X., Ten Hoeve, J., Williams, K. J., Neptun, S., Sever, T., Fuentes, I., Bhatia, S. N., Calibasi-Kocal, G., Vander Heiden, M. G., Shalek, A. K., & Yilmaz, Ö. H. (2026). Ketogenic diet mediates intestinal tumorigenesis through lipids not ketones. Nature, 10.1038/s41586-026-10779-y. Advance online publication. https://doi.org/10.1038/s41586-026-10779-y

Other references:

Mana, M. D., Hussey, A. M., Tzouanas, C. N., Imada, S., Barrera Millan, Y., Bahceci, D., Saiz, D. R., Webb, A. T., Lewis, C. A., Carmeliet, P., Mihaylova, M. M., Shalek, A. K., & Yilmaz, Ö. H. (2021). High-fat diet-activated fatty acid oxidation mediates intestinal stemness and tumorigenicity. Cell reports, 35(10), 109212. https://doi.org/10.1016/j.celrep.2021.109212

Beyaz, S., Mana, M. D., Roper, J., Kedrin, D., Saadatpour, A., Hong, S. J., Bauer-Rowe, K. E., Xifaras, M. E., Akkad, A., Arias, E., Pinello, L., Katz, Y., Shinagare, S., Abu-Remaileh, M., Mihaylova, M. M., Lamming, D. W., Dogum, R., Guo, G., Bell, G. W., Selig, M., … Yilmaz, Ö. H. (2016). High-fat diet enhances stemness and tumorigenicity of intestinal progenitors. Nature, 531(7592), 53–58. https://doi.org/10.1038/nature17173