Genetic Switch turned on during Fasting helps stop Inflammation

Salk researchers uncover a fasting molecule, Crtc, which enhances immunity. The gastrointestinal tract of flies lacking Crtc, which is turned on during fasting (right panel), expresses more immune-related molecules compared with those of normal flies (left panel). These signs of inflammation mean that the gut barrier is compromised and more permeable to bacteria. Credit: Salk Institute

A molecular pathway activated in the brain during fasting helps halt the spread of GI bacteria into the bloodstream, according to a new study researchers at the Salk Institute. A molecular pathway by which the brain communicates with the GIT prevents unnecessary activation of the immune system during fasting by strengthening the barrier against gut microbes. The discovery of this brain-gut signal in fruit flies, which has many parallels to humans, could eventually inform the treatment of inflammatory bowel diseases, IBD in people.

“Fasting has a positive value that spills over not just into the metabolic system, but also inflammation and brain function,” says Prof Marc Montminy, Clayton Foundation Laboratories for Peptide Biology and holder of the J.W. Kieckhefer Foundation Chair. “Understanding how the gut maintains this barrier, and creating drugs to enhance that barrier, may have important benefits for people with inflammatory bowel disease.”

The new study aims to pin down the mechanisms that a genetic switch in the brain, Crtc uses to control energy balance. A constant network of communication–between our brains and the GI tract, as well as other tissues–helps our bodies keep tabs on our energy expenditure and stores. Crtc interacts with a molecule CREB, and fasting activates both proteins and boosts formation of long-term memories.

The Montminy and Thomas teams used fruit flies to study the Crtc switch, in part because flies express many of the same metabolism-related genes as humans do. Previous experiments by the two labs have shown that flies whose Crtc gene is deleted become sensitized to fasting–they only survive about half as long without food compared to flies with the Crtc gene. The researchers were aiming to understand why the deletion of Crtc caused flies to die sooner and had hypothesized it was because these mutant flies have fewer fat and sugar stores.

The guts of the flies without Crtc expressed several molecules indicating their immune system was keyed up. The new results suggest flies are more sensitive to starvation because the immune system is activated, which is energetically taxing. Without Crtc, bacteria leak from the gut into the fly’s circulation. The researchers found the normal role of Crtc is to fortify the barriers of the gut to prevent bacteria from entering the bloodstream and awakening the immune system.

While looking for molecular partners of Crtc, they uncovered a protein called short neuropeptide F (sNPF), also found in the brain and has an equivalent in humans (called neuropeptideY). This peptide is known to cause flies and mammals to search for food in response to hunger signals. Without sNPF in the brain, the flies showed signs of gut inflammation similar to those flies missing Crtc. What’s more, the normally tight seals along the gastrointestinal tract were broken down in the sNPF-lacking flies, letting bacteria out.

Conversely, flies expressing more than the normal amounts of Crtc or sNPF in their neurons were able to survive longer without food and showed less disruption to the tight junctions that maintain their gastrointestinal barriers. The researchers are conducting more experiments to understand how the neuropeptides activate the gut receptors that help protect it from bacterial invasion. http://www.salk.edu/news-release/genetic-switch-turned-on-during-fasting-helps-stop-inflammation/