By Ann Trafton | MIT News
A high-fat, low-carbohydrate diet, also called a ketogenic diet, can help some people lose weight by forcing their bodies to burn fat for fuel instead of sugar.
In recent years, scientists have been exploring how such diets may affect other aspects of health and disease, including cancer. While some studies have shown that the diet may protect against the development of colon cancer, a new study by MIT researchers suggests that in the small intestine, a ketogenic diet may increase the risk of cancer.
“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 about the effects that these diets can have, because what may be beneficial for one tissue may be harmful for another,” said Omar Yilmaz, director of MIT Cytology at the Institute of Intestinology Stem as Stem. MIT, and is a member of MIT’s Koch Institute for Integrative Cancer Research.
Yilmaz is senior author of the study, which appeared today the nature. MIT postdocs Jessica Shaw and Fangtao Chi are lead authors of the paper. MIT’s Institute for Medical Engineering and Science Director Alex K. Researchers in Schalke’s lab and Koch Institute director Matthew Vander Heyden also contributed to the study.
Diet and Cancer
The ketogenic diet, originally developed in the 1920s as a way to treat epilepsy, has been adapted in recent decades as a strategy for weight loss or life extension. The diet has a high percentage of fat, a low percentage of carbohydrates, and a normal or low amount of protein.
This type of diet forces the body to burn fatty acids for energy instead of carbohydrates like glucose. Burning these lipids produces ketone bodies — primarily β-hydroxybutyrate (BHB) and acetoacetate — as byproducts of fatty acid metabolism. These ketone bodies also form when people fast or follow a very low-calorie diet, which forces the body to burn its own fatty stores.
A 2022 the nature Studies have suggested that the ketogenic diet has a protective effect against colon cancer and that BHB – the most abundant ketone body – is responsible for this effect. in the new the nature In the study, the MIT team wanted to explore whether ketogenic diets could have similar protective effects on the small intestine.
The researchers fed mice that were genetically predisposed to develop colon cancer a ketogenic diet, a control diet, or a high-fat/high-calorie diet. They found that mice on a ketogenic diet were more likely to develop small bowel tumors than those on a control diet. Although they did not become obese, mice on the ketogenic diet developed tumors at the same or greater rate than mice on the obese high-fat/high-calorie diet.
Additional studies have shown that ketone bodies do not play a role in tumor development. Instead, tumor growth was driven by how intestinal cells burn dietary fat for energy — a metabolic pathway called fatty acid oxidation. This pathway activates a family of proteins called PPARs, which signal stem cells to multiply more rapidly, making certain cancers more likely.
The proliferation of these stem cells may be beneficial in some situations, such as when the intestinal lining needs to be repaired after illness or injury. However, excessive proliferation can cause cells to become cancerous.
“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,” says Yilmaz.
opposite effect
Surprisingly, the same ketogenic diet that promoted tumors in the small intestine had the opposite effect in the colon. Researchers found, as before the nature In a 2022 study, a ketogenic diet suppresses the development of colon tumors. However, new findings suggest that ketone bodies are not responsible for this protective effect.
“Given how much attention has been given to ketone bodies like BHB, Both as a commercial health trend and recent high-profile studies suggesting BHB suppresses colon cancer, we expect them to be direct drivers. Instead, our experiments in genetically engineered mice revealed that these molecules are essentially metabolic pathways. The real surprise is that tumor acceleration is completely driven by how stem cells process and burn dietary fat,” says Yilmaz.
The researchers now hope to further study why ketogenic diets have such different effects on the colon and small intestine. As ketogenic diets continue to gain popularity, understanding these tissue-specific effects will be important for guiding their use, the researchers said.
“The deeper question is why the same diet has opposite consequences in two adjacent parts of the gut. That’s what we’re working to understand next,” Chi said.
The findings carry practical implications. Because the diet’s effects — tumor acceleration in the small intestine and protection in the colon — are both driven entirely by fat metabolism rather than ketones, commercial ketone supplements or drinks are not expected to mimic the risks or benefits discovered in this study. This may be particularly relevant given that the incidence of small bowel tumors has been increasing in recent decades, with the greatest impact on patients with inherited conditions that predispose them to bowel cancer, such as familial adenomatous polyposis.
The research was funded in part by the National Institutes of Health, a Pew-Stewart Trust Scholar Award, a Kathy and Kurt Marble Cancer Research Award, a Koch Institute-Dana Farber/Harvard Cancer Center Bridge Project grant, the American Federation for Aging Research, the MIT Stem Cell Initiative, a Damon Runyon Postdoctoral Institute, and the Koch Institute. From the National Cancer Institute.
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Reprinted with permission MIT News
Image: splash
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