by Will Cushman, University of Wisconsin-Madison
This image shows the effect of pro-inflammatory cytokines on the growth of a mouse intestinal organoid. Intestinal stem cells (red) are indicative of inflammation and Ki67 proteins (green) are associated with tumors. Credit: Ting Fu
Inflammation in the gut can trigger a doom loop of sorts. The condition messes with the sensitive relationships between food, digestive acids, microbes and the immune system in ways that can promote further inflammation and, sometimes, the eventual 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 has been published in the journal JCI Insight.
An essential regulator of gut health
Under the guidance of Ting Fu, an assistant professor in the UW–Madison School of Pharmacy, researchers uncovered a previously unknown function of a protein that is central to gut health and implicated in the development of colitis, a severe and chronic form of IBD. A debilitating condition in and of itself, colitis is also linked to an increased risk for colorectal cancer. The team’s findings suggest that the protein is a promising target for future colitis treatments.
The protein is called the 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 critical roles in maintaining a healthy gut. Together, they help balance gut bacteria, promote a healthy intestinal lining, and influence immune cells called macrophages that patrol the digestive system and ward off pathogens that sneak in with the food we eat.
“This balance can be thrown off when FXR isn’t functioning properly,” says Xingchen Dong, a postdoctoral researcher in Fu’s lab and the study’s lead author.
Dong, Fu and their colleagues studied mice with chronic gastrointestinal inflammation that led to the growth of tumors in their colons. This mimicked the effects of colitis-associated colon cancer in humans. They found that FXR was not functioning properly in these mice, messing with the signals the protein sends to manage bile acids.
At the same time, they noted shifts in the chemistry of bile acids within 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 altered bile acids prompted changes in the behavior of gut macrophages, leading to a large increase in certain proteins called cytokines that promote inflammation. This observation provided compelling new evidence for how FXR dysfunction changes the behavior of gut macrophages, initiating the inflammation doom loop that can cause colitis and eventually lead to aggressive cancers.
From a scientific perspective, “it is exciting to see that gut macrophages have the capability to sense both host and microbial bile acids and exhibit diverse responses to various bile acids, which leads to changes in their state or activity,” says Fu.
More information: Xingchen Dong et al, Farnesoid X receptor mediates macrophage-intrinsic responses to suppress colitis-induced colon cancer progression, JCI Insight (2024). DOI: 10.1172/jci.insight.170428
Journal information: JCI Insight
Provided by University of Wisconsin-Madison
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