Scientists have long suspected a link between obesity and colorectal cancer (CRC), but the mechanism has been unclear. In a paper published Jan. 16 in the journal Cell Reports, NIEHS researchers and their collaborators studied cells in the guts of obese mice. They found epigenetic changes that resemble those found in CRC, which is the third most common cancer worldwide.

Importantly, they found that the changes were reversed after long-term weight loss, but not after short-term weight loss. These findings could have profound implications for prevention and treatment of CRC, particularly among obese individuals.

Epigenetics holds the key

Wade is the deputy chief of the NIEHS Epigenetics and Stem Cell Laboratory. (Photo courtesy of Steve McCaw)

The new study, from Paul Wade, Ph.D., head of the Eukaryotic Transcriptional Regulation Group, and colleagues, follows an earlier project that explored the genetics of the obesity-CRC connection (see story).

In the current project, they looked at epigenetic markers in mice on different diets. Epigenetic markers are heritable changes that affect the function of genes without affecting the underlying DNA sequence.

The researchers fed one group of mice, who were equivalent in age to young adult humans, a high-fat diet for six months. At the end of that time, they looked at molecular features in the cells of the animals’ guts, including a type of epigenetic change known as DNA methylation.

“We found that the molecular features in the obese animals changed in a way that reflects increased potential for colorectal cancer,” Wade said.

“The obesity creates a landscape in the intestine that is prone to develop a cancer-like program,” he explained. “So if a mutation occurs that’s commonly associated with cancer, the likelihood that that mutated cell would develop into a clinically detectable tumor is much higher.”

Effects persist

When the young adult animals were removed from the high-fat diet and lost their excess weight, the cancer-conducive environment persisted for a period of time. Five weeks after the dietary change, twenty-five percent of the epigenetic effects remained. Interestingly, although colon epithelial cells normally turn over every five or six days, the effect was seen in cells that had never been exposed to the high-fat diet.

The results suggest that even when obese people lose substantial weight, their heightened risk of developing CRC may remain for months, or even years.

“Our study adds to momentum in the field that suggests that if an exposure, whether it’s diet, chemical, or endocrine disruption, has an impact on the epigenome, the impact can be much longer lasting than the duration of the initial exposure itself,” Wade added.

The good news that emerged from the study was that although the obesity-CRC connection persisted after short-term weight loss, DNA methylation and gene expression patterns eventually went back to normal after long-term weight loss.

The colon cell epigenetics of the animals who returned to the control diet after 20 weeks on the high-fat diet looked like the mice that had been given the control diet all along. This finding implies that to reduce CRC risk, it is important not only to lose excess weight, but to keep it off.

Implications for prevention and treatment

Wade explained that understanding molecular differences between an obese and a nonobese colon sheds light on the dominant molecular pathways involved, as well as the dominant changes in gene expression. “That provides clues as to what types of therapeutics might be useful in terms of prevention, and what might be useful in treatment of cancers found in obese people,” he said.

Next, Wade and his group will go beyond disease risk. Using a mouse model of CRC, they will explore molecular changes in the colons of obese animals that develop tumors versus those that do not.

Citation: Li R, Grimm SA, Mav D, Gu H, Djukovic D, Shah R, Merrick BA, Raftery D, Wade PA. 2018. Transcriptome and DNA methylation analysis in a mouse model of diet-induced obesity predicts increased risk of colorectal cancer. Cell Rep 22(3):624–637.

(Ernie Hood is a contractor for the NIEHS Office of Communications and Public Liaison.)