ABOVE: Chronic stress alters the composition of viruses in the gut, which in turn, alters stress responses. ©istock, jonnysek

Over the past few years, researchers have found a link between the microbiome in the gut and psychiatric disorders connected to stress.1-3 However, most studies focus on the bacterial component of the microbiota, leaving the contribution of another microbial species unexplored.

In a recent paper, published in Nature Microbiology, researchers demonstrated that stress alters the gut virome, which in turn, affects behavior in mice.4 Understanding these interactions could help researchers better identify targets in dysregulated microbiomes of patients experiencing chronic stress to modulate their symptoms.

 “The trouble with the virome is that it’s a relatively new field,” said Stephen Collins, a gastroenterologist at McMaster University who was not involved in the study. He explained that the viral flora is not fully characterized, which introduces challenges for identifying important species.5

“We always think of viruses as something we want to get rid of and are negative,” said John Cryan, a stress neurobiologist at the University College Cork and coauthor of the study. “What this paper does is… turn that whole aspect on its head and say, ‘what if they’re good viruses?’”

To test their hypothesis, Cryan and his team first assessed the effect of stress on the bacterial and viral populations in mouse guts by intermittently housing one mouse with an aggressive mouse in an overcrowded cage over the course of three weeks. Using metagenomic or 16S ribosomal sequencing, the team analyzed the virome and bacteriome, respectively.

Stress altered the bacterial microbiome composition to a greater degree than the virome, but it did not change the species diversity in either the bacteriome or virome. However, the experimental housing modified the population density of 12 distinct viruses.

Corticosterone, a steroid hormone, regulates stress and immune responses, so the researchers assessed levels of this hormone as well as inflammatory cytokines produced from cells in the spleen.8 They showed that the adverse housing conditions increased circulating corticosterone and interleukin-6 production from splenocytes after stimulation with the antagonist concanavalin A (ConA).

To further explore the role of the virome in response to stress, the team collected fecal samples from mice prior to exposing them to an aggressive cage mate as a stressor. They isolated the viral component from these samples to generate a virome transplant that they administered to a group of mice housed under stressful conditions.

When the researchers assessed the mice for social, anxiety-like, and stress-coping behavior, they observed that stressed animals that didn’t receive a virome transplant exhibited increased stress and anxiety behaviors.  Meanwhile, mice that received the intervention during the stress experiment behaved comparably to normal mice that did not undergo the environmental stressor. “It was really remarkable that we could normalize it,” Cryan said. The viral transplantation also reversed the effect of stress on the animals’ production of inflammatory cytokines with and without ConA stimulation.

Finally, the researchers studied the role of the virome during stress by measuring gene expression using RNA sequencing in the hippocampus and amygdala, two brain regions that respond to stress. They showed that stress altered the expression of genes related to fear and stress responses, immune processes, viral activities like replication, and neurotransmitter levels. Transplanting mice with their virome returned the expression of these genes to normal levels.

“What this paper has done is added another level of complexity by introducing the fact that the viruses just don't sit there and handle the bacteria,” Collins said. “The virome control of the microbiota has consequences for behavior.”

References

  1. Bercik P, et al. The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice. Gastroenterology. 2011;141(2):599-609.e3
  2. Yang J, et al. Landscapes of bacterial and metabolic signatures and their interaction in major depressive disorders. Sci Adv. 2020;6(49):aba8555
  3. Neufeld KM, et al. Reduced anxiety-like behavior and central neurochemical change in germ-free mice. J Neurogastroenterol Motil. 2011;23(3):255-e119
  4. Ritz NL, et al. The gut virome is associated with stress-induced changes in behaviour and immune responses in mice. Nat Microbiol. 2024;9:359-376
  5. Shkoporov AN, Hill C. Bacteriophages of the human gut: The “known unknown” of the microbiome. Cell Host Microbe. 2019;25(2):195-209
  6. Fitzgerald CB, et al. Probing the “dark matter” of the human gut phageome: Culture assisted metagenomics enables rapid discovery and host-linking for novel bacteriophages. Front Immunol. 2021;11:616918
  7. Mayneris-Perxachs J, et al. Caudovirales bacteriophages are associated with improved executive function and memory in flies, mice, and humans. Cell Host Microbe. 2022;30(6):340-356.e8
  8. Dunphy-Doherty F, et al. Post-weaning social isolation of rats leads to long-term disruption of the gut microbiota-immune-brain axis. Brain Behav Immun. 2018;68:261-273