Research by Salk Institute
A medication created by Salk Institute researchers functions in the intestines like a master reset switch. The compound, known as FexD, has been shown in the past to reduce cholesterol, burn fat, and prevent colorectal cancer in mice.
Now, the team reports that FexD can also reverse or eliminate intestinal inflammation in mouse models of inflammatory bowel disease in Proceedings of the National Academy of Sciences on December 12, 2022.
According to senior author and Salk Professor Ronald Evans, director of Salk’s Gene Expression Laboratory and March of Dimes Chair in Molecular and Developmental Biology, “the Salk-developed drug FexD provides a new way to restore balance to the digestive system and treat inflammatory diseases that are currently very difficult to manage.”
Crohn’s disease and ulcerative colitis are both examples of inflammatory bowel disease (IBD), which is characterized by an overabundance of immune cells and inflammatory signaling chemicals known as cytokines in the gut.
Existing therapies only work for some people and come with a range of side effects. They often suppress the immune system as a whole or specifically target specific cytokines.
How does the drug work?
The Farnesoid X receptor (FXR), a master regulator protein that monitors the bile acids given to the digestive system to aid in food digestion and nutrient absorption, has been the focus of research at Evans’ lab for more than 20 years.
The body gets ready for an influx of food by turning on and off dozens of cellular programs involved in digestion, blood sugar regulation, and fat metabolism when FXR notices a change in bile acids at the start of a meal.
Fexaramine is a pill that Evans and his coworkers created in 2015 to activate FXR in the gut. They first demonstrated that the tablet can prevent weight gain and regulate blood sugar in mice.
They demonstrated in 2019 that FexD, an improved form of fexaramine, also protected changes to the gut’s stem cells caused by cancer. Their research revealed that FXR was involved in the control of inflammation.
Every time you eat, your intestinal cells come into contact with new substances, generating little amounts of inflammation in your gut. Senior Staff Scientist Michael Downes, a co-corresponding author of the current paper, claims that FXR ensures that inflammation is kept in check throughout regular feeding.
In the latest research, Evans’ team found that activating FXR can be utilized to reduce symptoms in disorders caused by inflammation. The medicine prevented or treated intestinal inflammation in IBD-affected mice when the researchers administered oral FexD daily, either before or after the beginning of intestinal inflammation.
Annette Atkins, a senior research scientist and a co-author of the paper, explains that activating FXR restores appropriate signaling pathways in the gut and returns things to a homeostatic state.
Cytokines are partially prevented by FexD because FXR functions more like a reset switch for the immune system than an off switch. This indicates that following a dose of FexD, the immune system continues to operate normally.
The molecule still needs to be refined for use in people and put through clinical trials, but the researchers claim their findings offer crucial insight into the intricate relationships between gut health and inflammation and may one day result in an IBD treatment.
First author Ting Fu, formerly a postdoctoral fellow at Salk and currently an assistant professor at the University of Wisconsin-Madison, says, “In people with IBD, our strategy could potentially be very effective at preventing flare-ups and as a long-term maintenance drug.”
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