Genetic Process Activated by Fasting May Reduce Gut Inflammation

A molecular pathway activated in the brain during fasting, which communicates with the gastrointestinal (GI) tract, was found to help stop the spread of intestinal bacteria into the bloodstream.

A study published in the Proceedings of the National Academy of Sciences found that in fruit flies, the molecular pathway was able to stop unnecessary activation of the immune system during fasting by strengthening the barrier against gut microbes.

“Fasting has a positive value that spills over not just into the metabolic system, but also inflammation and brain function,” said lead study investigator Marc Montminy. “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 study is part of an ongoing collaborative effort to find the exact mechanisms that the genetic switch in the brain called Crtc uses to control energy balance. When Crtc interacts with the molecule CREB, fasting activates both of the proteins and boosts the formation of long-term memories.

Prior studies that fruit flies without the Crtc became sensitized to fasting and only survived about half as long without food compared to flies with the Crtc gene.

Researchers hypothesized that this process occurred because the flies had fewer areas of fat and sugar storage. However, the current study had unexpected results, revealing that flies without Crtc expressed several molecules indicating their immune system was activated.

The findings suggest that when the immune system is activated, the flies become more sensitive to starvation, and the amped-up immune response may cause bacteria to leak from the gut into circulation in flies without Crtc.

Researchers found that Crtc typically fortifies gut barriers to prevent the bacteria from traveling into the bloodstream, which jump starts the immune system. When Crtc is deleted, the connections between the cells that line the gut become disrupted, which results in bacteria leakage, activation of the immune response, and depleted energy reserves.

Upon further examination, the protein short neuropeptide F (sNPF) in the brain, which is equivalent to the neuropeptide Y in humans, was found to be a molecular partner to Crtc, the study noted.

The peptide causes flies and mammals to hunt for food in response to hunger signals, so without sNPF the flies had signs of gut inflammation, similar to that in the flies without Crtc.

The flies that expressed more amounts of Crtc or sNPF in their neurons than normal survived longer without food and had less of a disruption to the tight junctions that maintain gut barriers.

Researchers are currently conducting experiments to learn how neuropeptides are able to activate gut receptors.