PNAS: A compound that reverses intestinal inflammation in mice

A drug developed by researchers at the Salk Institute acts like a master reset switch
in the gut.
The compound, known as FexD, has previously been found to lower cholesterol, burn fat, and prevent colorectal cancer
in mice.
Now, the team reports in the December 12, 2022 issue of the Proceedings of the National Academy of Sciences that FexD can also prevent and reverse intestinal inflammation
in mouse models of inflammatory bowel disease.

"The drug FexD developed by Salk offers a new way to restore digestive balance and treat inflammatory diseases that are currently very difficult to control," said senior author and Salk Professor Ronald Evans, director of the Salk Gene Expression Laboratory and Chair
of the March of Dimes in Molecular and Developmental Biology.

Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is characterized by an excess
of immune cells and inflammatory signaling molecules called cytokines in the gut.
Existing treatments, mostly by suppressing the entire immune system or targeting individual cytokines, are only effective for some patients, and have many side effects
.

For more than two decades, Evans' lab has been studying the Farnesol X receptor (FXR), a major regulatory protein that senses bile acids delivered to the digestive system to help digest food and absorb nutrients
.
When FXR detects changes in bile acids at the beginning of a meal, it prepares the body for
a high intake of food by initiating and shutting down dozens of cellular programs related to digestion, blood sugar, and fat metabolism.

In 2015, Evans and his colleagues developed a pill called fexaramine that activates FXR
in the gut.
They initially demonstrated that the pill could stop the mice from gaining weight and control blood sugar
.
In 2019, they found that FexD (an updated version of fexaramine) also protects against cancer-related changes
in intestinal stem cells.
Their study showed that FXR also plays a role
in regulating inflammation.

"Every time you eat, your intestinal cells encounter new molecules that cause a small amount of inflammation
in the gut.
FXR ensures that inflammation is controlled during normal feeding," said
senior scientist Michael Downs, co-corresponding author of the new paper.

In the new study, Evans' team found that activating FXR could be used to alleviate symptoms
of inflammation-driven disease.
When the researchers gave daily oral FexD to mice with IBD, the drug prevented or treated inflammation, both before and after the onset of intestinal inflammation
.
By activating FXR, FexD reduces the infiltration
of a class of highly inflammatory immune cells known as innate lymphoid cells.
In turn, cytokine levels already involved in IBD dropped to normal levels
in healthy mice.

Senior research scientist Annette Atkins, co-author of the study, said: "When we activate FXR, we restore the proper signaling pathways in the gut to bring things back to homeostasis
.
"

Since FXR acts more like a reset button than an immune system shutdown switch, cytokines are not completely blocked
by FexD.
This means that after taking one dose of FexD, the immune system continues to function
in a normal manner.
The compound still has to be optimized before it can be used in humans and tested in clinical trials, but the researchers say their findings provide important information about the complex link between gut health and inflammation that could eventually lead to treatments
for IBD.

"In IBD patients, our strategy may be very effective in preventing attacks and acting as a long-term maintenance drug," said first author Ting Fu, a former postdoc at Salk who is now an assistant professor
at the University of Wisconsin-Madison.

This work was supported in part by the National Institutes of Health (DK057978, HL105278 and HL088093), the National Cancer Institute (CA014195), the National Health and Medical Research Council of Australia (grant 1087297), the Leona M.
and Harry B.
Helmsley Charitable Trust (2017pgmed001), the SWCRF Fellow Award, the Hewitt Medical Foundation Fellowship, Salk Alumni Scholarship, Crohn's Disease and Colitis Foundation (CCFA) Visiting IBD Research Fellowship, Luce Garton Foundation Pancreatic Cancer Dream Team Research Grant (SU2C-AACR-DT-20-16), Howard Hughes Medical Institute, NOMIS Foundation and National Institute of Environmental Health Sciences (P42ES010337).

Journal Reference:

1. Ting Fu et al.
   FXR mediates ILC-intrinsic responses to intestinal inflammation.
   PNAS, 2022 DOI: 10.
   1073/pnas.
   2213041119