Starvation signals control intestinal inflammation in mice

Starvation signals control intestinal inflammation in mice

The findings, made by Bali Pulendran and colleagues at Emory University, highlight an ancient connection between cellular mechanisms to sense nutrient availability and control of inflammation. They also suggest that a low protein diet or drugs that mimic its effects on immune cells could be tools for the treatment of inflammatory bowel diseases, such as Crohn’s disease or ulcerative colitis.

Starvation signals control intestinal inflammation in mice
Starvation signals control intestinal inflammation in mice

This protective effect was shown to be mediated by a molecule known as GCN2, which is highly conserved from yeasts to man, and which is a critical sensor of amino acid starvation in cells. The finding grew out of the Emory team’s earlier discovery that GCN2 is pivotal for induction of immunity to the yellow fever vaccine.

“We reasoned that the intestine would be a site where the immune system is faced with dynamic changes in nutrient bioavailability,” says senior author Bali Pulendran, PhD. “So we wondered whether the amino acid sensing pathway involving GCN2 would impact immune homeostasis in the gut.”

Pulendran is Charles Howard Candler professor of pathology and laboratory medicine at Emory University School of Medicine, Emory Vaccine Center and Yerkes National Primate Research Center. The co-first authors of the paper are postdoctoral fellows Rajesh Ravindran, PhD, and Jens Loebbermann, PhD. Co-authors on the paper include Randal Kaufman, PhD, at the Sanford Burnham Prebys Medical Discovery Institute, and Jennifer Martinez, PhD, at the National Institute of Environmental Health Sciences.

The team discovered that mice lacking GCN2 are more sensitive to the chemical irritant DSS (dextran sodium sulfate), often used to model colitis in animals. In the absence of irritants, the intestines in mice lacking GCN2 looked normal.

Mice fed a low protein diet (2 percent, compared to 16 percent in a standard diet) or a diet lacking only the amino acid leucine were protected from signs of colitis, such as weight loss and bloody diarrhea. Mice lacking GCN2 were not protected from colitis when fed a low protein diet, which demonstrates that GCN2 is necessary for the protective effect.

The results could have implications for treatment of inflammatory bowel diseases, and autoimmune diseases such as rheumatoid arthritis and psoriasis. The researchers showed that responses of Th17 immune cells, which are important in several autoimmune diseases, are controlled by GCN2.

“It is well known that the immune system can detect and respond to pathogens, but these results highlight its capacity to sense and adapt to environmental changes, such as nutritional starvation, which cause cellular stress,” Pulendran says.

“It is interesting to ponder the evolutionary pressures that might have resulted in the coupling of this ancient amino acid starvation pathway with control of inflammation. Perhaps this coupling evolved as a sort of negative feedback mechanism to limit inflammation, by sensing depletion of amino acids that might occur in cells during the repair and regeneration of tissues, in response to cell death during inflammation.”

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OASIS clinical study

Ulcerative Colitis Adults Clinical Study

ROCKVILLE, Md., Jan. 12, 2016 /PRNewswire-USNewswire/ — Ulcerative Colitis (UC) is a chronic disease of the colon that causes the colon to become inflamed and forms ulcers. UC is a type of irritable bowel disease (IBD), which is a term that describes conditions with chronic or recurring inflammation of the gastrointestinal tract.

The number of patients diagnosed with IBD has increased significantly across the past 50 years, with 1.6 million people in the United States alone affected by IBD. The incidence of IBDs, including UC, is highest among people between the ages of 20 and 40, often affecting individuals during their healthiest and most productive years of life.

Managing the symptoms of UC is a constant challenge for patients with frequent bathroom trips, abdominal cramps, and diarrhea significantly affecting the day-to-day routines of people with the disease. The availability of an oral medication such as the one being studied in the OASIS clinical study could offer patients an additional, more convenient treatment for UC.

The OASIS clinical study is evaluating an investigational medication to learn if it may safely and effectively reduce the inflammation of the gut in patients with moderately to severely active UC. The medication is considered investigational because it is not approved by health authorities, including the U.S. Food and Drug Administration (FDA), for the treatment of UC.

Clinical studies are done to help determine if investigational medications are safe and are effective in treating diseases and conditions. People volunteer to participate in clinical studies and these studies play an important role in the development of medications. Many drugs, therapies, and devices that are used today are the result of past clinical studies.

The study is being conducted at more than 100 clinical centers worldwide, and about 240 adults aged 18 to 80 will participate in the OASIS clinical study. The study will last about 16 to 18 weeks and include 7 to 10 visits to the study clinic.

To learn more about the OASIS study, visit



Crohns Disease Treatments for Kids

WEDNESDAY, Oct. 14, 2015 (HealthDay News) Current therapies for children with Crohn’s disease don’t fully restore healthy bacteria and fungi populations in their digestive systems, a new study shows.

These findings suggest that treatments don’t have to bring bacteria and other microbe levels back to normal levels in the gut to be useful. This knowledge could lead to new approaches for diagnosing and treating inflammatory bowel disease, according to the Oct. 14 study in the journal Cell Host & Microbe.

“We show that microbes in the gut respond to treatment of inflammatory bowel disease in a much more complex way than has been previously appreciated,” co-principal investigator Gary Wu, from the University of Pennsylvania in Philadelphia, said in a journal news release.

“The results of our study provide information that could be used to track or predict disease, as well as new diet-based therapeutic strategies,” he added.

The study included 90 children with Crohn’s disease and 26 healthy kids. The kids with Crohn’s disease received either diet-based or anti-inflammatory treatments. None of the treatments fully restored the balance of gut microbes to that of a healthy child, the researchers said.

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