'Keto' molecule may be useful in preventing and treating colorectal
cancer, study suggests

Date:
April 27, 2022
Source:
University of Pennsylvania School of Medicine
Summary:
Beta-hydroxybutyrate, an alternative-energy molecule produced by
the body in response to starvation or low-carb diets, strongly
suppresses the growth of colorectal tumors in lab experiments,
according to a new study.



FULL STORY ==========================================================================
A molecule produced in the liver in response to low-carb "ketogenic"
diets has a powerful effect in suppressing colorectal tumor growth and
may be useful as a preventive and treatment of such cancers, according
to a new study from researchers at the Perelman School of Medicine at
the University of Pennsylvania.


==========================================================================
In the study, published in Nature, researchers initially found that
mice on low-carb, high-fat ketogenic diets have a striking resistance
to colorectal tumor development and growth. The scientists then traced
this effect to beta- hydroxybutyrate (BHB), a small organic molecule
produced in the liver in response to keto diets or starvation.

"Our findings suggest that this natural molecule, BHB, could someday
become a standard part of colorectal cancer care and prevention,"
said study co-senior author Maayan Levy, PhD, an assistant professor of Microbiology at Penn Medicine, whose laboratory collaborated with the lab
of Christoph Thaiss, PhD, also an assistant professor of Microbiology. The study's first author was Oxana Dmitrieva-Posocco, PhD, a postdoctoral researcher in Levy's lab.

Colorectal cancer is one of the most common cancer types and kills more
than 50,000 Americans annually, making it the country's third leading
cause of cancer mortality. Alcohol use, obesity, red meat, and low-fiber
and high-sugar diets have all been linked to greater colorectal cancer
risk.

In the study, Levy, Thaiss and their teams set out to determine, with experiments in mice, whether different types of diet could inhibit
colorectal cancer development and growth. They put six groups of mice
on diets that had varying fat-to-carb ratios, and then used a standard
chemical technique that normally induces colorectal tumors.

They found that the two most ketogenic diets, with 90 percent fat-to-carb ratios -- one used lard (pig fat), the other Crisco (mostly soybean oil)
- - prevented colorectal tumor development in most of the animals on
those diets.

By contrast, all the animals on the other diets, including low-fat,
high-carb diets, developed tumors. Even when the researchers started
the mice on these diets after colorectal tumors had started growing,
the diets showed a "treatment effect" by markedly slowing further tumor
growth and proliferation.



==========================================================================
In subsequent experiments, the scientists determined that this tumor suppression is associated with a slower production, by stem cells,
of new epithelial cells lining the colon. Ultimately, they traced this
gut-cell growth slowdown to BHB -- normally produced by the liver as part
of a "starvation response," and triggered in this case by the low-carb
keto diets.

BHB is known to work as an alternative fuel source for key organs in
low-carb conditions. However, the researchers showed that it is not
only a fuel source but also a potent growth-slowing signal, at least
for gut-lining cells. They were able to reproduce the tumor-suppressing
effects of the keto diets simply by giving the mice BHB, either in
their water or via an infusion mimicking the liver's natural secretion
of the molecule.

The team showed that BHB exerts its gut-cell growth-slowing effect by activating a surface receptor called Hcar2. This in turn stimulates the expression of a growth-slowing gene, Hopx.

Experiments with gut-lining cells from humans provided evidence that
BHB has the same growth-slowing effect on these cells, via the human
versions of Hcar2 and Hopx.Colorectal tumor cells that don't express
these two genes were not responsive to BHB treatment, suggesting their
utility as possible predictors of treatment efficiency.

"Clinical trials of BHB supplementation are needed before any
recommendation can be made about its use in prevention or treatment,"
Thaiss said.

The researchers are now setting up just such a clinical trial of BHB
-- which is widely available as a dieting supplement -- in colorectal
cancer patients.

They are also continuing to study BHB's potential anticancer effects
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, P30-AR-069589, P30-DK-019525), the BSF US-Israel
Foundation, the Searle Scholar program, the Pew Charitable Trust,
the Edward Mallinckrodt, Jr. Foundation, the Abramson Cancer Center,
the Borrelli Family, the Global Probiotics Council, the National Mouse Metabolic Phenotyping Centers, the IDSA Foundation, and the Thyssen
Foundation.


========================================================================== Story Source: Materials provided by University_of_Pennsylvania_School_of_Medicine. Note: Content may be
edited for style and length.


========================================================================== Journal Reference:
1. Oxana Dmitrieva-Posocco, Andrea C. Wong, Patrick Lundgren,
Aleksandra M.

Golos, He'le`ne C. Descamps, Lenka Dohnalova', Zvi Cramer, Yuhua
Tian, Brian Yueh, Onur Eskiocak, Gabor Egervari, Yemin Lan, Jinping
Liu, Jiaxin Fan, Jihee Kim, Bhoomi Madhu, Kai Markus Schneider,
Svetlana Khoziainova, Natalia Andreeva, Qiaohong Wang, Ning Li,
Emma E. Furth, Will Bailis, Judith R. Kelsen, Kathryn E. Hamilton,
Klaus H. Kaestner, Shelley L.

Berger, Jonathan A. Epstein, Rajan Jain, Mingyao Li, Semir Beyaz,
Christopher J. Lengner, Bryson W. Katona, Sergei I. Grivennikov,
Christoph A. Thaiss, Maayan Levy. b-Hydroxybutyrate suppresses
colorectal cancer. Nature, 2022; DOI: 10.1038/s41586-022-04649-6 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/04/220427115716.htm

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