Salk scientists develop compound that reverses gut inflammation in mice

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

“The FexD drug developed by Salk offers a new way to restore balance to the digestive system and treat inflammatory diseases that are currently very difficult to manage,” says lead author and Salk professor Ronald Evans, lab director of Salk and March of Dimes gene expression. Chair of Molecular and Developmental Biology.

Inflammatory bowel disease (IBD), which includes both 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, which work primarily by suppressing the entire immune system or targeting individual cytokines, are only effective for some patients and come with a host of side effects.

For more than two decades, Evans’ lab has studied the Farnesoid X receptor (FXR), a master regulatory protein that senses bile acids delivered to the digestive system to help digest food and absorb nutrients. When FXR detects a change in bile acids at the start of a meal, it prepares the body for an influx of food by turning on and off dozens of cellular programs related to digestion, blood sugar, and fat metabolism.

In 2015, Evans and colleagues developed a pill called fexaramine that activates FXR in the gut. The pill, they initially showed, can stop weight gain and control blood sugar in mice. In 2019, they showed that FexD, an updated version of fexaramine, also prevented cancer-associated changes in bowel stem cells. Their work suggested that FXR also plays a role in regulating inflammation.

“Every time you eat, you cause small amounts of inflammation in your gut as your gut cells encounter new molecules. FXR ensures inflammation stays under control during normal eating,” says lead scientist Michael Downes, co-corresponding author of the new paper.

In the new work, Evans’ group discovered that activating FXR can be used to relieve symptoms of inflammatory diseases. When the researchers gave mice with IBD a daily dose of FexD by mouth, before or after the onset of intestinal inflammation, the drug prevented or treated the inflammation. By activating FXR, FexD reduced the infiltration of a class of highly inflammatory immune cells called innate lymphoid cells. In turn, levels of cytokines already implicated in IBD decreased to levels normally seen in healthy mice.

“When we turn on FXR, we re-establish the proper signaling pathways in the gut, bringing things back to a homeostatic level,” says Annette Atkins, senior research scientist, co-author of the study.

Since FXR acts more like a reset button than a switch for the immune system, cytokines are not completely blocked by FexD. This means that the immune system continues to function normally after a dose of FexD. The compound has yet to be optimized for use in humans and tested in clinical trials, but the researchers say their findings provide important insights into the complex links between gut health and inflammation and could eventually lead to therapy. against IBD.

“In people with IBD, our strategy could potentially be very effective in preventing flare-ups and as a long-term maintenance medication,” says first author Ting Fu, previously a postdoctoral fellow at Salk and now an assistant professor at the University. of Wisconsin. -Madison.

Other authors of the article include Yuwenbin Li, Tae Gyu Oh, Fritz Cayabyab, Nanhai He, Qin Tang, Morgan Truitt, Paul Medina, Mingxiao He, Ruth T. Yu, and Ye Zheng of Salk; and Sally Coulter and Christopher Liddle of the University of Sydney.

The 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 (2017PG-MED001), SWCRF Investigative Award, Hewitt Medical Foundation Fellowship, Salk Alumni Fellowship, Crohn’s & Colitis Foundation (CCFA) IBD Research Fellowship, Stand Up Fellowship To Cancer-Cancer Research UK-Lustgarten 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).

About the Salk Institute for Biological Studies:

Each cure has a starting point. The Salk Institute embodies Jonas Salk’s mission to dare to turn dreams into reality. Its internationally renowned and award-winning scientists explore the very foundations of life, seeking new knowledge in neuroscience, genetics, immunology, plant biology, and more. The Institute is an independent, non-profit organization and an architectural landmark: small by choice, intimate by nature, and fearless in the face of any challenge. Whether it’s cancer or Alzheimer’s disease, aging or diabetes, Salk is the starting point for cures. Learn more at: salk.edu.