Study identifies promising target for treatment of colitis-induced inflammatory bowel disease and colorectal cancers

Inflammation in the gut can trigger a sort of doom loop. This disease disrupts the sensitive relationships between food, digestive acids, microbes and the immune system, which can promote increased inflammation and, sometimes, the possible growth of tumors.

Scientists at the University of Wisconsin-Madison have identified a promising new target for treatments that could help the millions of people worldwide who suffer from inflammatory bowel disease and related colorectal cancers. The work was published in the journal JCI Overview.

An essential regulator of intestinal health

Led by Ting Fu, assistant professor at the UW-Madison School of Pharmacy, researchers discovered a previously unknown function of a protein essential for intestinal health and involved in the development of colitis, a serious and serious form of colitis. chronic IBD. A debilitating disease in itself, colitis is also linked to an increased risk of colorectal cancer. The team’s findings suggest that the protein is a promising target for future treatments against colitis.

The protein is called farnesoid X receptor, or FXR. It helps control the production of bile acids that digest fats. Working in tandem, FXR and bile acids play several essential roles in maintaining a healthy gut. Together, they help balance gut bacteria, promote a healthy gut lining, and influence immune cells called macrophages that patrol the digestive system and fend off pathogens that sneak into the foods we eat.

“This balance can be disrupted when FXR is not functioning properly,” says Xingchen Dong, a postdoctoral researcher in Fu’s lab and lead author of the study.

Dong, Fu and their colleagues studied mice with chronic gastrointestinal inflammation leading to the growth of tumors in their colons. This mimics the effects of colitis-associated colon cancer in humans. They found that FXR didn’t work properly in these mice, disrupting the signals the protein sends to handle bile acids.

At the same time, they noted changes in the chemistry of bile acids in the animals’ gastrointestinal tracts. These changes affected both “host” bile acids, produced by the mice themselves, and microbial bile acids, which are the product of gut microbes metabolizing host bile acids.

In a cascade of negative effects, the change in bile acids caused changes in the behavior of intestinal macrophages, leading to a significant increase in certain proteins called cytokines that promote inflammation. This observation provided compelling new evidence on how FXR dysfunction alters the behavior of intestinal macrophages, triggering the catastrophic loop of inflammation that can cause colitis and eventually lead to aggressive cancers.

From a scientific perspective, “it is exciting to see that intestinal macrophages have the ability to sense both host bile acids and microbial bile acids and exhibit diverse responses to various bile acids, which that causes changes in their condition or activity,” Fu explains.

A promising treatment against colitis and associated cancers

FXR dysfunction is implicated in a number of gastrointestinal diseases, and Fu’s team studied whether existing drugs aimed at activating FXR, called FXR agonists, could prove effective treatments for colitis and associated colon cancers.

Mice treated with one of two FXR agonists (fexaramine D or FDA-approved obeticholic acid) saw a marked improvement in FXR function, with a stream of other positive effects including rebalancing of bile acids, improved macrophage function and reduced intestinal inflammation.

Colorectal tumors in the treated mice were also “profoundly reduced” in number and size, according to Fu. The median survival time of mice with colitis-associated cancer was twice as long in animals treated with these compounds compared to those that received no treatment.

“This study shows that FXR plays a crucial role in regulating macrophage behavior in the intestine,” explains Fu. “This could be very important for developing new treatments for cancers associated with IBD and colitis.”

Fu intends to continue exploring compounds that promote FXR function as potential treatments for colitis and related cancers, although any treatment strategies for human patients based on this research will require further exploration and confirmation. in-depth.