New therapeutic has the potential to treat inflammatory bowel disease by targeting a molecule that keeps order in the intestines.
Salk Institute scientists have developed a new drug that acts like a master reset switch in the gut. Called FexD, the compound has previously been found to burn fat, lower cholesterol, and ward off colorectal cancer in mice. Now, the team reports that FexD can also prevent and reverse intestinal inflammation in mouse models of inflammatory bowel disease. The study was published on December 12, 2022, in the journal Proceedings of the National Academy of Sciences.
“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,” says Salk Professor Ronald Evans, senior author of the study. Evans is also director of Salk’s Gene Expression Laboratory and March of Dimes Chair in Molecular and Developmental Biology.
Inflammatory bowel disease (IBD), which includes both Crohn’s disease and ulcerative colitis, is estimated by the CDC to affect approximately 1.3% of American adults (about 3 million people). It is a condition that is characterized by chronic inflammation of the gastrointestinal tract with an excess of immune cells and inflammatory signaling molecules known as cytokines in the gut. Existing treatments mostly work by either suppressing the entire immune system or by targeting individual cytokines. They are only effective for some patients and carry a large number of significant side effects.
Evans’ lab has studied Farnesoid X receptor (FXR) for more than two decades. FXR is a master regulator protein that senses the bile acids delivered to the digestive system to help digest food and absorb nutrients. When FXR detects a shift in bile acids at the beginning of a meal, it prepares the body for an influx of food by flipping on and off dozens of cellular programs related to digestion, blood sugar, and fat metabolism.
Evans and his colleagues developed a pill called fexaramine in 2015 that activates FXR in the gut. They initially showed the pill can stop weight gain and control blood sugar in mice. In 2019, they showed that an updated version of fexaramine—FexDan—also prevented cancer-associated changes to stem cells in the gut. Their work suggested that FXR also played a role in regulating inflammation.
“Every time you eat, you’re causing small amounts of inflammation in your gut as your intestinal cells encounter new molecules. FXR makes sure inflammation stays under control during normal feeding,” says Senior Staff Scientist Michael Downes, co-corresponding author of the new paper.
In the new work, Evans’ group discovered that activating FXR can be used to ease symptoms in inflammation-driven diseases. When the researchers gave mice with IBD a daily dose of oral FexD, either 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 activate FXR, we restore appropriate signaling pathways in the gut, bringing things back to a homeostatic level,” says Senior Research Scientist Annette Atkins, co-author of the study.
Cytokines are not completely blocked by FexD because FXR acts more like a reset button than an off switch for the immune system. This means that after a dose of FexD, the immune system continues functioning in a normal way. The compound still must be optimized for use in humans and tested in clinical trials, but the researchers say their findings provide important information about the complex links between gut health and inflammation and could eventually lead to an IBD therapeutic.
“In people with IBD, our strategy could potentially be very effective at preventing flare-ups and as a long-term maintenance drug,” says first author Ting Fu, previously a postdoctoral fellow at Salk and now an assistant professor at the University of Wisconsin-Madison.
Reference: “FXR mediates ILC-intrinsic responses to intestinal inflammation” by Ting Fu, Yuwenbin Li, Tae Gyu Oh, Fritz Cayabyab, Nanhai He, Qin Tang, Sally Coulter, Morgan Truitt, Paul Medina, Mingxiao He, Ruth T. Yu, Annette Atkins, Ye Zheng, Christopher Liddle, Michael Downes and Ronald M. Evans, 12 December 2022, Proceedings of the National Academy of Sciences.
Other authors of the paper 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), an SWCRF Investigator Award, a Hewitt Medical Foundation Fellowship, a Salk Alumni Fellowship, a Crohn’s & Colitis Foundation (CCFA) Visiting IBD Research Fellowship, a Stand Up To Cancer-Cancer Research UK-Lustgarten Foundation Pancreatic Cancer Dream Team Research Grant (SU2C-AACR-DT-20-16), the Howard Hughes Medical Institute, the NOMIS Foundation, and the National Institute of Environmental Health Sciences (P42ES010337).
Does this heal stomach erosion
I have suffered with gut issues for 10 years tried of prodeccedures that don’t work expensive medication interested in anything that would help it has changed my life for the worst
Just a bandaid. The cause is the bacteria that mimics the gluten protein. I’ve known quite a few who went on strict gf diet (no oats either) and completely reversed it. The medical industry makes more being drug dealers.
How long did it take to reverse? Mine started 6 yrs ago after I did a cleanse (detox) my digestive hasn’t been normal since.
I have suffered with gut issues most of my life. This medicine sounds like it could help with my inflamed GI tract. If it is open please consider me for it.
I would try anything that could provide a safe and effective treatment option. My entire retirement and life has been ruined by Crohn’s. I have been on a highly restrictive diet for the past four year and my condition is deteriorating which is why I would be over the moon to be offered a chance to try the FexD compound
Thank goodness for those who are working daily to find safe treatments for the appalling IBD conditions.
I’ve suffer from IBS for several years now and I found that a changed diet makes all the differences. Avoid gluten, dairy, coffee and spicy foods and you’re good to go.
I use dr gundry total restore with daily probiotics and it has given my life back.My issue is acid reflux and gerd which got so bad and Inflamed from taking antibiotics that messed up my gut flora.Antibiotics kill the good and bad😔
For the comments stating “I followed this or that diet and it worked” good for you. Not all of us are that lucky.
Diet is extremely important, but it’s not curing my disease.
Please let us know when it is accessible in Uganda.
I’ve been suffering from ibs/c before catching long covid in January 2022. When I recovered from covid (I still have long covid syndrome) that’s when the real problem started: as a result, I now have a very severely serious and aggressive form of ibs/c. I only eat a small handful of foods and can barely digest any form of protein. I’m bloated all the time and I managed to put the brakes on with losing weight after a 45 lb loss to which I haven’t gained back. Where can I purchase this drug/supplement that’s mentioned in the above article? At this point, my life depends upon it.
If anyone has any ideas please let me know 🙏
I hope this is accurate because every single day I go through digestive hell. I’ve been constipated since I was a little girl. It’s there but won’t come out unless I drink a glass of milk of Magnesia… which couldn’t be good for me.
Recently diagnosed with UC interested in whatever comes next
I bloat no matter what I eat?! Have tried every diet you get for IBS, stopped all gluten, starch, diary etc and yet if I touch any food whatsoever, I bloat.
I am beyond desperate!!!
I want to be considered as an experimental as I suffer from ibs since 5 years and no relief. Please consider me in the group.
FexD compound if this company is for real, and the product is not too expensive, I would be interested to know if the product is anything like the Gundry MD
I have had ibsd for 40 years and tried everything. Nothing helps for long. Many days I have hours of severe cramping and diarrhea. As I get older it gets worse and saps my energy. I’d give anything for help to have half a life.
This cannot come quick enough.
Hopefully it isn’t only used to treat IBS.
Dr. Douglas H Weinstein,MD (Gastroenterology at Capital Health in Pennington NJ) was the only doctor that listened and did a thorough history and was able to help get my family member back on track after becoming dangerously malnourished due to severe bloating, pain, diarhea,constipation, nausea. While waiting for appt, try to stay nourished with Kate Farms, high fat, protein, shakes. Sending good wishes for improvement, this was a devastating issue for too long.
Hi I suffer from ige milk allergy’s and also celiacs and ibs I would love to try this is it avalible in the USA?
Look into healing with honey mixed with water on an empty stomach
FexD I need this pill help
Re FexD. I have IBS-D. I’ve had it now 10 years.
Nothing works. I journal an keep track of everything I eat. It helps but life gets in the way!
If you get to clinical trials please consider me a candidate. This disease is debilitating. Nothing digests. Now my body is inflamed everywhere.
I have Diverticulosis and Sibo need restore my gut health ASAP can’t exist like that..
Let us please know when it will be available in UK 🤗🙏🏻
Don’t forget to eliminate alcohol. My aunt proclaimed IBS then my mom found out she does a bottle of wine each day.
I am suffering from Crohns Disease for over 40 years. 2 surgeries, and numeorous latest & greatest medications later and nothing is better. I live in Savannah, Ga. Will any of these clinical trials be done here?
Is there any of these clinical tests being done near Savannah, Ga? I have been battling Crohns Disease for over 40 years and have had 2 surgeries. Been through all the latest and greatest medications. I would be interested intaking part in this.