, researchers initially found that mice fed a low-carb, high-fat ketogenic diet were resistant to colorectal tumor growth and development. The scientists then traced this effect to beta-hydroxybutyrate (BHB), a small organic molecule produced in the liver in response to a keto or starvation diet.
“Our findings suggest that this natural molecule, BHB, may one day become a standard part of colorectal cancer care and prevention,” said Maayan Levy, PhD, deputy Professor of microbiology at Penn Medicine, whose lab works in partnership with Christoph Thaiss’ lab. PhD and Associate Professor of Microbiology.
Colorectal cancer and the Keto molecule
Colorectal cancer is one of the most common cancers and kills more than 50,000 Americans annually, making it the third leading cause of cancer death in the country. Alcohol use, obesity, red meat, and diets low in fiber and high in sugar are all associated with colorectal cancer risk.
In the study, Levy, Thaiss and their teams set out to determine, with experiments in mice, whether different dietary patterns could inhibit colorectal cancer growth and development. . They put six groups of mice on diets with different fat-to-carb ratios, and then used a standard chemical technique that commonly induces colorectal tumors.
They found that the two most ketogenic diets, with a 90% fat-to-carb ratio, one using lard (lard lard), the other Crisco (mainly soybean oil), suppressed growth. growth of colorectal tumors in most animals on that diet. In contrast, all animals on other diets, including the low-fat, high-carb diets, developed tumors. Even when the researchers fed these diets to mice after colorectal tumors began to grow, the diets showed a “therapeutic effect” by markedly slowing down tumor growth and proliferation.
In further experiments, the scientists determined that this tumor suppression was associated with a slower production of stem cells of new epithelial cells lining the colon. Finally, they tracked this gut cell retardation—BHB—usually produced by the liver as part of the “hunger response,” and triggered in this case by the low-carb keto diet.
BHB is known as an alternative fuel source for vital organs in low-carb conditions. However, researchers have shown that it is not only a fuel source but also a strong growth-retarding signal, at least for the cells lining the gut. They were able to replicate the tumor-suppressing effects of the keto diet simply by giving mice BHB, either in their own water, or through an infusion that mimicked the liver’s natural secretion of the molecule.
The team showed that BHB exerts its effects on slowing the growth of intestinal cells by activating a surface receptor called Hcar2. This in turn stimulates the expression of a growth-retarding gene, Hopx.
Experiments with human intestinal mucosal cells have provided evidence that BHB has the same growth-retarding effect on these cells, through its human versions of Hcar2 and Hopx. Colorectal tumor cells that do not express these two genes do not respond to BHB treatment, suggesting their utility as predictors of treatment efficacy.
“Clinical trials of BHB supplementation are needed before any recommendations can be made for its use in prevention or treatment,” Thaiss said.
Researchers are now setting up a clinical trial of BHB, widely available as a dietary supplement, in colorectal cancer patients. They are also continuing to study the potential anticancer effects of BHB in other parts of the body, and are investigating the effects of other molecules produced under ketogenic conditions.
Source: Eurekalert
