Written by Annie Lennon — Fact checked by Anna Guildford, Ph.D.
Colorectal cancer (CRC) is the third most common cancer diagnosed in the United States. Studies have shown that the Western diet, high-sugar diets, and excessive consumption of animal protein — especially red meat — increase CRC risk.
Studies show that diets involving fasting and caloric restriction are protective against intestinal tumors in animal models. Whether they may translate over to humans remains unknown.
Understanding more about the mechanisms underlying the effects of various diets on tumor growth could help researchers develop treatments and preventative options for CRC.
Recently, researchers conducted a series of mouse studies investigating the underlying protective mechanisms behind a low-carb diet for CRC.
They found that beta-hydroxybutyrate (BHB) — an alternative-energy molecule produced in response to low carb diets — suppresses intestinal tumor growth.
“BHB is a small molecule produced in the liver in response to starvation or a ketogenic diet,” Dr. Anton Bilchik, surgical oncologist and chief of medicine at Saint John’s Cancer Institute at Providence Saint John’s Health Center in Santa Monica, CA, told Medical News Today.
“This [new study] demonstrates in a mice model that it prevents colorectal cancer by activating a growth slowing receptor Hcar2 which is found in the lining of the bowel. This receptor may play an important role in preventing cell growth within the intestine,” Dr. Bilchik added. He was not involved in the study.
The new study was published in Nature.
The researchers first sought to identify dietary interventions that affect intestinal tumor growth. To do so, they designed six diets with varying fat-to-carbohydrate ratios, including two ketogenic diets with 90% fat-to-carbohydrate ratios from plant or animal sources.
After beginning the diets, the researchers induced CRC in the mice via standard chemical procedures. In doing so, they noted tumor numbers and sizes reduced when fat-to-carbohydrate ratios increased.
They also found that mice on keto diets survived for longer, and keto diets inhibited tumor development in a genetic model of CRC.
The keto diet also suppressed tumor growth when started after triggering CRC.
Meanwhile, cessation of the keto diet led to tumor regrowth, even if the diet had previously reduced tumor size.
The researchers wrote that their findings indicate that keto diets potently suppress colorectal tumor growth in both prevention and treatment models of CRC.
The researchers next investigated the underlying mechanisms behind tumor suppression.
Through a series of experiments, they found that keto diets release BHB, which interacts with cells in the intestine to reduce and prevent tumor growth.
Dr. Maayan Levy, one of the study’s authors, told MNT:
“BHB inhibits the growth and proliferation of intestinal epithelial cells. It achieves this by activating the transcriptional regulator Hopx. Hopx, in turn, reduces the expression of genes involved in cell division. How exactly Hopx exerts its gene-regulatory effects is unknown; this is something we’re currently investigating.”
To see how BHB works in humans, the researchers observed its effects on human cell lines. In doing so, they noted that BHB reduced the growth of organoids in both healthy donors and CRC cell lines and elevated Hopx expression.
They found, however, that only cell lines with HCAR2-HOPX responded to BHB, and that others such as HCT116 and RKO did not.
Finally, the researchers collected blood samples from 41 patients with CRC to assess the link between blood levels of BHB and Hopx levels. They found that BHB levels correlated positively with Hopx levels and negatively with cell cycle progression.
This, they wrote, suggests that BHB might increase Hopx levels and reduce CRC tumor growth in people.
The researchers conclude that oral or systemic interventions such as BHB could complement current prevention and treatment strategies for CRC.
When asked about the study’s limitations, Dr. Bilchick said:
“While these studies are exciting and thought-provoking, little is known about how they will translate to human clinical efficacy. Positive clinical results could impact thousands of lives and reduce the development of colorectal cancer, particularly in young people where we are seeing a massive increase in incidence for unclear reasons.”
“One important aspect that our study has not yet addressed is the levels of circulating BHB and their duration that need to be achieved in order to observe a tumor-inhibitory effect,” added Dr. Levy.
“In other words, do BHB levels need to be elevated continuously? Is intermittent BHB supplementation effective? Are short bouts of BHB supplementation sufficient? If so, how frequent do these bouts need to be? We are actively investigating these important questions.”
While much remains unknown about BHB’s role in CRC, Dr. Levy explained that her team has initiated clinical trials to determine the effect of BHB on human colorectal cancer.
“What is encouraging is that in animal models, all the colorectal cancer types we have used to test the efficiency of BHB have responded to intervention,” she said. “Furthermore, intestinal organoids derived from colorectal cancer patients likewise respond to BHB treatment with reduced growth.”