The big C’s: Bile acids as carcinogens in colon cancer

• Western countries with high-fat diets have the greatest incidence of colon cancer.
• In a recent review, Dr Carol Bernstein, a retired professor from the University of Arizona in the USA, brings together years of epidemiological, experimental, and cell culture research that collectively implicates increased bile acids due to a high-fat diet as a significant cause of colon cancer.
• DNA damage, mutations, and evading cell death are at the heart of this pathology.
• This improved understanding of the mechanisms involved helps reveal prevention strategies and provides insight into the carcinogenic role of bile acids in other gastrointestinal cancers.

We know eating a high-fat diet is not good for our health or waistline, but are you aware of the significantly heightened risk of colon cancer? When thinking of cancer-causing agents, well-known carcinogens such as tobacco smoke, UV radiation, or alcohol come to mind. But for our gastrointestinal tract, excessive bile acids are emerging as common culprits.

Bile acids play a crucial role in digesting fat and have biological functions. Still, excessive fat intake requires more primary bile acids for digestion. Elevated primary bile acids are acted upon by some bacteria to increase the levels of more toxic bile acids (secondary bile acids) that enhance intracellular reactive oxygen species (ROS), causing DNA damage and cancer.

In her latest publication, Dr Carol Bernstein, a retired professor from the University of Arizona in the USA, adopts an integrative approach to evaluate the mounting evidence from diverse studies. Her work shows that bile acids cause gastrointestinal cancers through underlying mechanisms of DNA damage and signalling pathways.

Fatty diets

In the last few years, figures reveal a global death toll of almost one million from colon cancer, with the prevalence of the disease a staggering twenty-five times greater in Western countries with high saturated fat diets. Native Alaskans with the greatest incidence have a diet much higher in fat content and lower in fibre compared to rural African populations with the lowest case rates. Red meat, processed meats, and dairy contain a lot of saturated fat – these are fatty acid chains that have no C=C double bonds but have chains of C-C single bonds.

Elevated bile acids, including the more toxic secondary bile acids, enhance intracellular reactive oxygen species, causing DNA damage and cancer.

The more fat you eat, the more bile acid is needed to digest it. The problem is that certain bacteria favour such high-fat environments. These species begin to dominate the gut, leading to an imbalance known as dysbiosis. Some gut bacteria convert primary bile acids into secondary bile acids such as deoxycholic acid (DOC), which are more toxic to cells. Evidence is growing that disruption to the gut microbiome elevates these secondary bile acids and leads to DNA damage and a predisposition to colon cancer.

Initially, epidemiological studies revealed a link between a high-fat diet and colon cancer. Subsequent observational studies suggested this is because of elevated bile acids, with a recent study showing that blood levels of secondary bile acids like DOC predict colon cancer risk in women years before diagnosis. Now, experimental and in vitro studies dig deeper to reveal the underlying cellular and molecular mechanisms.

Pathways to cancer

Mistakes happen! Damages in our DNA are common. Thankfully, we are equipped with repair mechanisms and have checkpoints in place to halt cell division so repairs can be done. If the damage is beyond repair, cell death is triggered so the damaged cell is not replicated. However, if these protective pathways are overwhelmed or compromised, damages may remain and mutations may occur when DNA is replicated past these damages. Mutated cells can multiply, and this may result in cancer.

In mice, DOC increases reactive oxygen species which can directly alter DNA, leading to mutations or indirectly causing epimutations. During DNA repair, epigenetic alterations are needed to silence genes. However, sometimes these silenced genes are not turned back on, resulting in epimutations. Such mutations or epimutations can give cells a reproductive advantage, meaning these mutated cells outgrow and outcompete their healthy neighbours. This growth advantage may be because a mutated cell is evading its inherent protective mechanism of programmed cell death (apoptosis). In fact, studies show cells exposed to DOC developed apoptosis resistance, allowing them to escape the mechanism that would otherwise ensure their termination when DNA damages are present.

These mutated or epimutated cells may rapidly duplicate and form field defects or patches that appear normal under the microscope because the eye cannot see mutations or epigenetic alterations. In addition to escaping apoptosis, studies suggest cells in these field defects have epigenetically repressed DNA repair genes meaning they are less able to repair damaged DNA and can replicate DNA without slowing down to repair DNA damages. Equipped with such replication advantages, they can now dominate the local tissue and grow to form a cancer. Colonic polyps can grow in such precancerous field defects, with one study finding the reoccurrence of polyps in a quarter of patients undergoing colonoscopies after having small colon cancers removed.

Another way bile acids can contribute to causing cancer is through their role as signalling molecules that orchestrate the expression of genes. For example, bile acids increase the level of the protein nuclear factor kappa B in the nucleus which, in turn, controls the expression of hundreds of genes with far-reaching functions such as inflammation, apoptosis, and cell proliferation. Thus, bile acids may act in at least two ways – through ROS-induced mutations and epimutations – and signalling pathways to induce colon cancer.

Research now implicates bile acids in the carcinogenesis of colon, stomach, pancreas, liver, and even oesophagus cancers.

After breaking down fat for absorption, bile acids, including the more toxic secondary bile acids, are reabsorbed by the gut and return to the liver and then the gall bladder to be used again when needed. Recirculation around the gastrointestinal tract can occur up to twelve times a day. This means that other organs in the system are exposed to carcinogenic secondary bile acids, increasing the risk of other types of cancer. Research now implicates bile acids in the carcinogenesis of colon, stomach, pancreas, liver, and even oesophagus cancers, among others.

Bernstein hopes that by integrating the evidence from studies worldwide implicating bile acids as carcinogens in the colon and gastrointestinal system, dietary changes will be promoted. Dietary changes could save thousands of lives a year, worldwide.