Colorectal cancer (CRC) is a leading cause of cancer-related illness and death
worldwide. While genetics contribute, lifestyle factors—particularly diet and gut
microbiota—play a major role. Among these, bile acids (BAs), cholesterol-derived
molecules essential for fat digestion, are increasingly recognized as key modulators of
colorectal carcinogenesis. Disruptions in bile acid metabolism and signaling can drive
both CRC initiation and progression.
Bile acids are synthesized in the liver as primary bile acids (cholic and
chenodeoxycholic acids) and secreted into the intestine. In the colon, gut bacteria
convert them into secondary bile acids such as deoxycholic (DCA) and lithocholic
(LCA) acids. These secondary bile acids are reabsorbed through the
enterohepatic system, influencing metabolic and signaling pathways.
Diet strongly affects bile acid metabolism. High-fat, high-meat diets increase bile
acid secretion and elevate colonic secondary bile acids, which correlates with
higher CRC incidence. In contrast, fiber-rich diets lower bile acid levels by
promoting excretion and supporting protective gut microbes.
Metabolic (gastric bypass) surgery, known for weight loss and improvement of
obesity-related conditions, also appears to reduce CRC risk, though the
mechanism has been unclear. The procedure creates a small stomach pouch and
reroutes the small intestine, limiting food contact with the stomach and upper
intestine and inducing early satiety.
To investigate the anti-cancer effect, Rebecca Kesselring and colleagues 1 at the
University of Freiburg studied mice fed a high-fat diet until they gained ~50%
of their body weight. Some underwent gastric bypass surgery, while others
received sham surgery. To separate the effects of surgery from weight loss,
the bypass group and half the sham group were placed on a diet that induced
~20% weight loss over six weeks.
After implanting colorectal cancer cells in the mice’s colons, researchers found
that six weeks later, tumors in the bypass group were two-thirds smaller than
in either control group. Liver metastases appeared in nearly all sham-operated
mice but in only one bypass mouse. Notably, weight loss alone did not explain
the protection—indicating a unique effect of the surgery.
The team suspected bile acids were involved. Bypass surgery alters the timing
and location of bile acid delivery, exposing them to a different microbial
environment. Mice with bypass surgery showed lower primary bile acid levels in
the colon and blood.
To confirm causality, the researchers performed an alternative surgery that
diverted bile acids to the distal small intestine without altering the stomach.
This also lowered primary bile acids and reduced tumor growth and spread,
mimicking the effects of gastric bypass. In lab experiments, primary bile acids
directly stimulated colorectal cancer cell growth.
These findings suggest that reducing primary bile acids may protect against CRC.
As Vance Albaugh of Louisiana State University notes, this could inspire oral drugs
that mimic the cancer-protective effects of gastric bypass without surgery.
