When roundworms get a gut infection from disease-causing bacteria, signals from their gut teach them to avoid the same bacteria in the future.

Bacteria that cause disease may be microscopic, but animals can use senses other than sight to protect themselves from infection.

Some bacteria produce harmful toxins, which animals can instinctively recognize as being dangerous using their sense of smell or taste. This is called chemosensation, an innate ability that allows animals to react to chemical stimuli.

But animals can also ‘learn’ to avoid harmful bacteria, though it remains unclear how they do so. Now, Jogender Singh, Ph.D. (pictured above, left), postdoctoral fellow, and Alejandro Aballay, Ph.D.(pictured above, right), professor and chair of molecular microbiology and immunology, OHSU School of Medicine, have used roundworms as a model organism to study this phenomenon.

Their study, “Intestinal infection regulates behavior and learning via neuroendocrine signaling” published in eLife was selected as the School of Medicine’s Paper of the Month.

Sending signals

Roundworms feed on bacteria, so they need to be able to distinguish between disease-causing strains and harmless ones. However, they only start avoiding harmful bacteria after several hours of exposure, which would not necessarily be expected if they were using chemosensation.

This prompted Drs. Singh and Aballay to investigate whether another mechanism could be teaching the roundworms to avoid disease-causing bacteria, by comparing roundworms that had been exposed to harmful or benign strains.

As observed previously, the roundworms learned to avoid the harmful bacterium Pseudomonas aeruginosa. However, exposing the worms to certain chemicals produced by P. aeruginosa was not enough to teach them to avoid the bacterium.

Instead, the lab’s experiments showed that when roundworms ingested disease-causing bacteria, the infection caused intestinal bloating. The more toxic the bacteria, the more the intestine swelled, triggering a neural pathway associated with a preference for oxygen.

In a few hours, the worms learned to avoid the low oxygen environment associated with P. aeruginosa and developed a preference for high oxygen conditions surrounding harmless bacteria such as Escherichia coli.

These results show how an intestinal infection can send signals to the nervous system to modulate animal behavior. Moreover, Drs. Singh and Aballay have identified a neural pathway that stimulates a behavioral host response to defend against infection.

“It’s a fascinating example of the bi-directional interactions between brain and immune system,” said Mary Heinricher, Ph.D., associate dean for research, OHSU School of Medicine.

Next steps

The neural pathway that is triggered by intestinal bloating upon pathogen infection involves NPR-1, a G-protein coupled receptor (GPCR) similar to mammalian neuropeptide Y receptors (NPYr).

“In the future, it will be important to understand how intestinal bloating modulates the NPYr signaling,” said Dr. Singh. “NPYr are involved not only in the control of behavioral responses to infections but also a diverse set of other behavioral processes, including appetite, circadian rhythm, and anxiety. The identity and mode of action of the cues that are used by the intestine to activate the NPYr signaling may provide broad insights into the modulation of NPY-receptor-related behaviors such as appetite and anxiety.”

Added Dr. Aballay, “GPCRs are found on the surface of all cells of multicellular organisms and are both key mediators of host physiological processes and major targets for different drugs. Given the conserved nature of GPCR-mediated signaling and of innate immune responses, the studies provide a better understanding of the mechanisms by which microbial colonization and bloating of the intestine may be perceived as a danger signal that activates molecular and behavioral immune responses across metazoans.”

Summary by Drs. Alejandro Aballay, Jogender Singh, published in eLife.

Citation

Jogender Singh, Alejandro Aballay. “Intestinal infection regulates behavior and learning via neuroendocrine signaling.” eLife 2019;8:e50033 DOI: 10.7554/eLife.50033