A ketogenic diet sped up small-intestine tumors in cancer-prone mice and slowed them in the colon

In mice bred to develop intestinal cancer, a ketogenic diet made tumors in the small intestine appear faster and shortened the animals’ lives. A few inches further along the gut, in the colon, the same diet held tumors back.

Both results come from a study at the Massachusetts Institute of Technology (MIT), published in Nature in July and described by the university this month. Everything in it was done in mice. No person was put on a diet, and the mice were not ordinary ones: they carried genetic changes that make intestinal tumors form without any outside trigger.

What the study offers is a mechanism and a warning against treating one result from one tissue as a rule for the whole body. Nothing in it is a basis for anyone to change how they eat.

What a ketogenic diet is

A ketogenic diet is very high in fat and very low in carbohydrate. Ketogenic diets were first developed during the 1920s as a treatment for epilepsy, and have since been taken up for weight loss. With little sugar coming in, the body switches to burning fat. Breaking down those fats generates compounds known as ketone bodies, which circulate in the blood as an alternative fuel.

The diet has attracted cancer researchers because it lowers insulin, a hormone that many tumors use as a growth signal. The MIT team describes ketogenic diets as ones which contain even higher lipid content but reduce circulating insulin and induce ketogenesis. Higher, that is, than an ordinary high-fat diet. Lipid means fat, and ketogenesis means the making of ketones.

That description holds the puzzle the study set out to solve. The same lab showed in 2016 that an ordinary high-fat diet, the kind that makes mice obese, drives the stem cells of the gut lining to multiply. Little is known about how pro-obesity diets regulate tissue stem and progenitor cell function, they wrote then, before reporting that such a diet alters not only the function of intestinal stem and progenitor cells, but also their capacity to initiate tumors. Stem cells are the cells that renew a tissue, progenitor cells are their immediate offspring, and most intestinal tumors begin in them.

A ketogenic diet has even more fat than that diet, but does not cause obesity and lowers insulin. Which way would it push?

What the ketogenic diet did to intestinal tumors in mice

The researchers combined dietary, genetic and metabolic manipulations in mouse models of spontaneous intestinal adenoma formation. An adenoma is a growth in the gut lining that can turn into cancer.

The animals were given either a ketogenic diet, a control diet, or a high fat/high calorie diet. Mice eating the ketogenic diet developed small intestinal tumors more often than animals receiving the control diet. According to the abstract, the diet increased the amount of tumor the animals carried and shortened survival, independent of ketone metabolites.

Weight did not explain it. Although the keto-fed mice did not become obese, their tumor rates were similar to, and in some cases higher than, those seen in mice consuming the obesogenic high fat/high calorie diet. Obesogenic means obesity-causing.

Why the diet fed tumors: fat burning, not ketones

The obvious suspect was ketones. They are what sets a ketogenic diet apart, and they are sold as supplements. So the team took them out of the picture and put them back.

By altering the gene for the enzyme that makes ketones in gut cells and in the body, they could raise or lower ketone levels at will. It made no difference. Neither blocking nor boosting that enzyme, nor disabling the cells’ ability to use ketones, altered tumor growth.

What did matter was the step before ketones are made, when cells burn fat for energy, a process called fatty acid oxidation. Disabling a gene that this process depends on reduced the number of adenomas, the early growths that tumors develop from, and it did so only in mice on the ketogenic diet. The authors conclude that dietary lipid content, through fatty acid oxidation rather than ketone metabolism, influences intestinal tumorigenesis, which is the formation of tumors.

The release describes the chain of events. Burning more fat switches on a family of proteins inside the stem cells, and those proteins tell the cells to divide faster. More dividing stem cells means more chances for one to go wrong.

Senior author Ömer Yilmaz pointed out that this is not purely a harm. “Having more stem cells means that when you injure the small intestine, it can repair itself better, but the downside is that having more active stem cells can lead to tumor formation,” Yilmaz said.

On ketones, Yilmaz was blunt. “Our experiments in genetically engineered mice revealed that these molecules are essentially metabolic bystanders,” Yilmaz said.

The release draws one inference from this. Because the effects ran through fat and not ketones, ketone supplements or drinks would not be expected to reproduce either effect identified in the study. No ketone product was tested, and an earlier study from another laboratory reached a different view of ketones in the colon.

The opposite result in the colon

The colon behaved differently. On the same diet, the release reports, the same animals showed the opposite in the large bowel, where the diet suppressed tumor formation in the colon.

That part agrees with earlier work from another institution. In 2022 a team at the University of Pennsylvania tested a range of diets in mice prone to colon cancer and found that ketogenic diets strongly inhibited tumors. They attributed the effect to one ketone in particular. These properties of ketogenic diets are recapitulated by the ketone body beta-hydroxybutyrate, they wrote, recapitulated meaning reproduced. They went on to suggest that oral or systemic interventions with a single metabolite may complement current prevention and treatment strategies for colon cancer, that is, giving the one compound by mouth or by injection.

The MIT study confirms the Pennsylvania team’s observation and disputes its explanation. The colon tumors were suppressed, but in the MIT experiments ketones were not the reason there either. Two laboratories now agree on what happens in the mouse colon and disagree on why.

Why neighboring stretches of gut respond in opposite ways is not known. “The deeper question is why the same diet has opposite consequences in two adjacent parts of the gut. That is what we are working to understand next,” said Fangtao Chi, one of the lead authors.

Yilmaz drew the general lesson. “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,” Yilmaz said.

Where this fits: ketogenic diets and cancer so far

Mouse studies of the diet have pointed in several directions. Besides the colon result, a 2018 study from Weill Cornell Medicine tested ways to stop the insulin surge that weakens one class of cancer drugs. The researchers evaluated two diabetes medicines as well as a ketogenic diet in their mouse models of cancer. They concluded that this insulin feedback can be prevented using dietary or pharmaceutical approaches. In that setting the diet helped a drug work.

The evidence in people is much thinner than the laboratory record. A German team searched for every study of the diet in cancer patients, as a treatment on its own or alongside standard care. In the end 46 publications concerning 39 studies with 770 patients were included in this systematic review. Most studies had a low quality, high risk of bias and were highly heterogeneous, meaning too different from one another to combine.

Their verdict cut both ways. There was no conclusive evidence for anti-tumor effects or improved OS, meaning overall survival. Nor did they report evidence that the diet made cancers worse. Adherence to the diet was rather low in most studies. Their conclusion was that clinical evidence for the effectiveness of ketogenic diets in cancer patients is still lacking.

None of those human studies looked at whether the diet changes the chance of developing cancer in the first place, which is the question the mouse work raises.

What the mouse study cannot say about people on a ketogenic diet

These were engineered animals. The mice carried mutations that guarantee intestinal tumors. A diet that speeds up a process already under way in such an animal may do nothing measurable in a gut without those mutations.

Mouse diets are not human diets. Laboratory ketogenic feed is a fixed formula eaten at every meal for the animal’s whole life. People who follow the diet eat varied foods, often for months, not for life.

The small intestine is an uncommon site for cancer in humans. Most intestinal cancer in people arises in the colon. The diet held tumors back there in these mice, and that too is untested in people.

The group for whom the authors think it could matter is small and specific. The work is particularly relevant for patients with familial adenomatous polyposis who face a high risk of small-intestinal tumors, they write. That is an inherited condition in which hundreds of growths form in the gut. The paper’s closing line calls for nuanced consideration of dietary strategies for cancer prevention in genetically susceptible populations.

In mice built to develop intestinal tumors, a ketogenic diet accelerated them in the small intestine by way of fat burning in stem cells, and restrained them in the colon for reasons not yet known, and whether either effect occurs in people has not been tested.