A keto diet drove more small-intestine tumors in mice, even without making them obese, MIT found

Mice fed a ketogenic diet developed small-intestine tumors at rates similar to, and in some comparisons higher than, mice on a high-fat, high-calorie diet, yet the keto animals never became obese. The result comes from the laboratory of Omer Yilmaz at the Massachusetts Institute of Technology and was published in Nature on July 15, 2026. It also separates two assumed culprits, because the ketones that define the diet turned out to be bystanders.

Yilmaz, an associate professor of biology, directs the MIT Stem Cell Initiative; Jessica Shay and Fangtao Chi, both postdoctoral researchers, are the lead authors. The paper appears in Nature volume 656.

Fatty acid oxidation and PPAR signaling

The mice were genetically predisposed to intestinal cancer, and the work compared three feeding regimens: a ketogenic diet, a control diet and a high-fat, high-calorie diet. According to MIT News, keto-fed mice were more likely to develop small-intestinal tumors than controls. The release gives no tumor counts, sample sizes or strain name, so those details sit in the paper itself. The comparison to the high-fat group is the telling one: keto-fed mice matched or exceeded its tumor rates without becoming obese. Ketogenic diets were developed in the 1920s to treat epilepsy, and the diet’s reach has since extended well beyond neurology clinics.

The mechanism the team traced runs through fat burning. Intestinal cells oxidize dietary fat, and heavier activity in that pathway switches on PPAR proteins, which push intestinal stem cells to divide faster. Active stem cells are not a flaw in themselves: MIT notes they also help the lining repair itself after injury, and excess proliferation is what can tip into cancer.

The Nature abstract adds the genetic tests behind that chain. In the mouse models of spontaneous intestinal adenoma, the diet increased tumor burden and shortened survival, and the authors report the effect occurred independent of ketone metabolites. Raising or lowering HMGCS2, the enzyme that makes ketones, or blocking ketone breakdown, did not change tumor formation. Removing PPAR alpha, delta and gamma together in the intestine blunted the diet-driven stem cell expansion and proliferation, and knocking out CPT1A, which fat oxidation requires, limited adenoma formation specifically under the ketogenic diet. Yilmaz described ketones as “essentially metabolic bystanders,” which matters because the 2022 work had pointed toward ketones as the protective agent in the colon. A ketone-centered explanation would have predicted that boosting or blocking ketone production changes the outcome, and in these experiments it did not.

Colon protection, small-intestine risk

The same diet did the opposite one segment downstream. MIT reports that it suppressed colon tumors, consistent with a 2022 Nature study that implicated the ketone beta-hydroxybutyrate, though the new work found ketones drive neither the colon protection nor the small-intestine risk. Chi framed the puzzle as “why the same diet has opposite consequences in two adjacent parts of the gut.”

Yilmaz drew a narrower lesson for the public, cautioning against generalizing a diet’s effects from one tissue to another, since a regimen that appears protective in the colon can carry the opposite risk a short distance away in the same organ system. Because the effects trace to fat metabolism rather than ketones, MIT notes, commercial ketone supplements and drinks would not be expected to reproduce either the risk or the benefit.

Inherited polyposis and what a mouse cannot say

Small-intestinal tumors have become more common in recent decades, MIT notes, and the greatest impact falls on people with inherited conditions that predispose them to intestinal cancer, such as familial adenomatous polyposis. The National Cancer Institute describes cancer of the small intestine as rarer than colon or stomach cancer and says it usually begins in the duodenum, the first segment of the small bowel.

The same NCI prevention summary lists familial adenomatous polyposis among inherited colorectal risks and says it is not known whether a low-fat, high-fiber diet lowers colorectal cancer risk, with some studies linking high-fat, high-meat diets to higher risk and others finding no link. A mouse bred for intestinal cancer is a model of susceptibility, not of the general population, and the diet question for people with polyposis syndromes remains untested by these experiments.

The experiments establish a pathway in animals and do not establish the same effect in humans. Funding came from the National Institutes of Health, a Pew-Stewart Trust scholar award, the Kathy and Curt Marble cancer research award, the American Federation for Aging Research, the MIT Stem Cell Initiative, a Damon Runyon fellowship and the Koch Institute’s core grant from the National Cancer Institute, as a later syndicated summary lists. Nature’s record names the laboratories of Alex Shalek and Matthew Vander Heiden among the contributors, and MIT quotes Chi saying the group is now working out why the adjacent tissues respond so differently, a question the paper leaves open.

This article was produced with the assistance of AI and reviewed by Morning Overview editors prior to publication.

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