Potential Therapeutic Targets for Human Inflammatory Bowel Disease and Colitis Induced Colorectal Cancer

Intestinal inflammation can trigger a vicious cycle that disrupts the sensitive relationships between food, digestive acids, microorganisms, and the immune system, further promoting inflammation and sometimes even leading to tumor growth; Recently, a research report published in the journal JCI Insight titled "Farnesoid X receptor mediates macrophage-intrinsic responses to suppress colitis-induced colon cancer progression," scientists from institutions such as the University of Wisconsin Madison identified a promising new target for developing new therapies through their research, It may potentially help treat millions of patients worldwide suffering from inflammatory bowel disease and related colorectal cancer.

In the article, researchers uncovered a previously unknown function of a protein that is crucial for intestinal health and is involved in the development of colitis, a severe chronic inflammatory bowel disease. Colitis itself is a debilitating disease that is also associated with an increased risk of colorectal cancer. The findings of this study suggest that this protein may serve as a very promising target for the future development of colitis therapies.

This protein is called the farnesoid X receptor (FXR), which can help control the production of bile acids that digest lipids. FXR works in synergy with bile acids and plays multiple key roles in maintaining a healthy gut in the body; It can help balance the body's gut microbiota, promote healthy intestinal lining, and affect macrophages to patrol the digestive system, helping to resist potential pathogens in the food we consume.

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Researcher Xingchen Dong said that when FXR cannot function properly, this balance will be disrupted; In the article, researchers studied mice with chronic gastrointestinal inflammation, which promotes the growth of tumors in their colon, simulating the effects of colitis-related colon cancer in humans. The researchers found that FXR did not function properly in these mice, thus interfering with the protein's use to manage bile acid signaling. At the same time, researchers also noted the chemical changes in bile acids in the animal gastrointestinal tract, which can affect the host's bile acids (i.e. produced by mice themselves) and also affect microbial bile acids (products produced by gut microbiota metabolism of host bile acids).

In a series of negative effects, the altered bile acids can promote changes in the behavior of macrophages in the intestine and lead to a significant increase in cytokines that promote inflammation. This observation may provide convincing evidence to explain FXR dysfunction, such as worsening the behavior of intestinal macrophages and opening the inflammatory death cycle, which can promote colitis and ultimately lead to invasive cancer. From a scientific perspective, what excites researchers is that intestinal macrophages may be able to perceive the bile acids of hosts and microorganisms and produce different reactions to various bile acids, leading to changes in their state or activity.

In summary, the research results of this article reveal the unique regulatory role of FXR in intestinal macrophages, and it may be expected to serve as a therapeutic target to help develop new therapies for the treatment of inflammatory bowel disease and colitis-related colorectal cancer.

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Reference Xingchen Dong,Ming Qi,Chunmiao Cai, 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