A ketogenic diet accelerated the development of small intestinal tumors in genetically predisposed mice, even as it appeared to suppress tumors in the colon, according to new research from the Massachusetts Institute of Technology.
The animal study, published in Nature, does not show that ketogenic diets cause or prevent cancer in people. Instead, the findings demonstrate that the same experimental diet can produce sharply different effects in different parts of the intestine, complicating broad claims about ketogenic diets and cancer.
“Ketogenic diets have distinct effects on different tissues even within the gastrointestinal tract,” senior author Omer Yilmaz, director of the MIT Stem Cell Initiative and an associate professor of biology, said in a news release. “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.”
Ketogenic diets are high in fat and very low in carbohydrates, with normal or sometimes reduced amounts of protein. The pattern forces the body to rely more heavily on fat for energy, producing compounds known as ketone bodies.
The diets were originally developed in the 1920s to treat epilepsy. They have since gained popularity for weight loss and are sometimes promoted for longevity, metabolic health and cancer prevention, though evidence supporting many of those broader uses remains limited.
For the new study, researchers fed mice genetically predisposed to intestinal cancer either a ketogenic diet, a control diet or a high-fat, high-calorie diet designed to promote weight gain.
Mice eating the ketogenic diet developed more tumors in the small intestine than mice eating the control diet. Their tumor development was similar to, and in some experiments greater than, that of mice eating the high-fat, high-calorie diet.
The ketogenic-diet mice did not become obese, suggesting that the tumor effect was not simply a consequence of weight gain.
The researchers initially suspected that ketone bodies might explain the results. Previous animal research had linked beta-hydroxybutyrate, the primary ketone body produced during ketosis, to the suppression of colon tumors.
Instead, the new experiments indicated that ketone bodies were not driving tumor development in the small intestine. The effect came from how intestinal cells processed and burned the large amount of dietary fat.
That process, known as fatty acid oxidation, activated a group of proteins called peroxisome proliferator-activated receptors, or PPARs. Those signals encouraged intestinal stem cells to multiply more quickly.
Intestinal stem cells help replace damaged or aging cells in the intestinal lining. Increasing their activity can be useful when the intestine needs to repair itself after an injury or illness, but greater cell division also creates more opportunities for abnormal cells to develop.
“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.
The researchers found a markedly different response in the colon. In that part of the intestine, the ketogenic diet suppressed tumor development, consistent with findings from earlier mouse research.
However, the new study also challenged the proposed explanation for that protection. Ketone bodies did not appear to be directly responsible for the colon effect either.
“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 findings suggest that the dietary fat itself and the way cells use it may matter more than the presence of ketones. They also illustrate why effects observed in one organ or type of cancer cannot necessarily be applied to another.
The study does not establish whether the same biological responses occur in humans. The mice had genetic changes that made them particularly susceptible to intestinal tumors, and laboratory diets do not fully represent the many ways people construct ketogenic diets.
Real-world ketogenic eating patterns can differ in their total calories, fiber content, protein level and sources of fat. Those differences could influence how the diet affects the digestive system and overall health.
Small intestinal cancer is also uncommon in the general population. The findings may be especially relevant for future research involving people with inherited conditions that greatly increase their susceptibility to intestinal tumors, but the study did not evaluate patients with those conditions.
The results also do not mean that ketogenic diets have been shown to protect people against colon cancer. Both the apparent small intestinal risk and colon benefit were observed in experimental mouse models, not in studies tracking human cancer diagnoses.
Because the effects were linked to dietary fat metabolism rather than ketone bodies, the researchers said commercially sold ketone drinks or supplements would not be expected to reproduce either the tumor-promoting or tumor-suppressing effects seen in the mice.
The findings should not prompt people using a medically supervised ketogenic diet for epilepsy or another health condition to stop treatment. Decisions about therapeutic diets should be made with a qualified health professional who can consider an individual’s condition, medications and nutritional needs.
Researchers now plan to investigate why the small intestine and colon responded so differently to the same diet.
“The deeper question is why the same diet has opposite consequences in two adjacent parts of the gut,” lead author Fangtao Chi said. “That is what we are working to understand next.”
The research was supported by grants and awards from the National Institutes of Health, the National Cancer Institute, the Pew-Stewart Trust, the American Federation for Aging Research, the Damon Runyon Cancer Research Foundation, the American Gastroenterological Association, the MIT Stem Cell Initiative through Fondation MIT, the Koch Institute, the Kathy and Curt Marble cancer research award, the Koch Institute–Dana-Farber/Harvard Cancer Center Bridge Project and the Biswas Postdoctoral Fellows Program.