Research discoveries by Bali Pulendran (seated) and colleagues point to possible new treatment strategies for inflammatory bowel diseases and autoimmune diseases in humans. Credit: Image courtesy of Emory Health Sciences
Intestinal inflammation in mice can be dampened by subjecting them briefly to a diet restricted in amino acids. 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.
This protective effect was shown to be mediated by molecule 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.
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% vs 16% in a standard diet) or a diet without 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.”
Pulendran cautions that more research is needed before applying the findings to human inflammatory bowel diseases. For instance, a low protein diet is not advisable for long periods, although a low protein diet is sometimes recommended for people with kidney disease to postpone the need for dialysis. The duration or extent of a low protein diet needed to have the desired effect on intestinal inflammation in humans is not clear. http://news.emory.edu/stories/2016/03/pulendran_nature_intestinal_inflammation/index.html
http://www.nature.com/nature/journal/vaop/ncurrent/full/nature17186.html
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