A molecule produced in the liver in response to low-carbohydrate ketogenic diets has a powerful effect in suppressing colorectal tumor growth and may be useful in preventing and treating these cancers, according to a new study by researchers of Perelman. University of Pennsylvania School of Medicine.
In the study, published in Nature, researchers initially found that mice on low-carbohydrate, high-fat ketogenic diets have a surprising resistance to the development and growth of colorectal tumor. Scientists then traced this effect to beta-hydroxybutyrate (BHB), a small organic molecule produced in the liver in response to ketogenic diets or hunger.
“Our results suggest that this natural molecule, BHB, could one day become a standard part of colorectal cancer treatment and prevention,” said study co-author Maayan Levy, PhD, adjunct professor. of Microbiology at Penn Medicine, whose lab collaborated with the lab of Christoph Thaiss, PhD, also an Assistant Professor of Microbiology. The first author of the study was Oxana Dmitrieva-Posocco, PhD, a postdoctoral researcher in Levy’s lab.
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 mortality in the country. Alcohol consumption, obesity, red meat, and low-fiber, high-sugar diets have been linked to an increased risk of colorectal cancer.
In the study, Levy, Thaiss, and their team set out to determine, with experiments in mice, whether different types of diet could inhibit the development and growth of colorectal cancer. They put six groups of mice on diets that had different proportions of fat to carbohydrates and then used a standard chemical technique that usually induces colorectal tumors.
They found that the two most ketogenic diets, with 90 percent fat-to-carbohydrate proportions, one used with lard (lard), the other Crisco (especially soybean oil), prevented the development of colorectal tumor. in most animals with these diets. In contrast, all animals on other diets, including low-fat and high-carbohydrate diets, developed tumors. Even when the researchers started the mice with these diets after the colorectal tumors had started to grow, the diets showed a “treatment effect” by significantly delaying tumor growth and proliferation.
In later experiments, scientists determined that this suppression of the tumor was associated with a slower production by stem cells of new epithelial cells lining the colon. Ultimately, they tracked this slowdown in intestinal cell growth to BHB, which is usually caused by the liver as part of a “hunger response” and triggered in this case by low-carb keto diets.
BHB is known to function as an alternative fuel source for key organs in low-carbohydrate conditions. However, researchers have shown that it is not only a source of fuel, but also a powerful signal of growth retardation, at least for the cells lining the gut. They were able to reproduce the tumor suppressing effects of ketogenic diets simply by giving BHB mice either in their water or by infusion mimicking the natural secretion of the liver molecule.
The team showed that BHB exerts its effect of slowing down the growth of intestinal cells by activating a surface receptor called Hcar2. This in turn stimulates the expression of a growth retardant gene, Hopx.
Experiments with human cells lining the gut provided evidence that BHB has the same effect of slowing growth in these cells, using human versions of Hcar2 and Hopx. Colorectal tumor cells that do not express these two genes did not respond to BHB treatment, suggesting their usefulness as possible predictors of treatment efficiency.
“Clinical trials of BHB supplements are needed before any recommendation can be made about their use in prevention or treatment,” Thaiss said.
Researchers are now preparing a clinical trial of this type of BHB, which is widely available as a dietary supplement, in patients with colorectal cancer. They are also continuing to study the possible anticancer effects of BHB in other parts of the body and are investigating the effects of other molecules produced under ketogenic conditions.
The study was funded by the National Institutes of Health (R01 CA218133, R01 CA227629, P30 CA-006927, DP2AG067511, P30 ES013508, DP2AG067492, P30-DK-050306, P630-DK-050306, P630-DK). DK-050306, P630-DK-050306, P630-DK-050306, P630-DK-067492). The U.S.-Israel Foundation, the Searle Scholar Program, the Pew Charitable Trust, the Edward Mallinckrodt Foundation, Jr., the Abramson Cancer Center, the Borrelli Family, the Global Probiotics Council, the National Mouse Metabolic Phenotyping Centers, the IDSA Foundation, and the Thyssen Foundation.