How stressed-out gut bacteria may trigger autoimmune response

Summary: Chronic social stress in mice induces the expression of virulent genes in the gut microbiota. The altered microbiota increases the presence of effector T helper cells in the lymph nodes and induces myelin autoreactive cells. Exposure to chronic stress, therefore, may increase the risk of developing autoimmune diseases for some individuals with a susceptibility.

Source: ASM

Stressful life events most likely contribute to autoimmune diseases, but scientists don’t have a deep understanding of the underlying chain of events. A study on mice published this week in mSystems suggests that the gut microbiota may play a significant role in that connection. Researchers found that the onset of stress caused changes in the intestinal bacteria that, in turn, stimulated the activity of immune cells in a way that increased the likelihood that the body would attack itself.

The factors behind autoimmune diseases, conditions in which the body’s immune defense attacks its own tissues and systems, can be difficult to pin down. That’s partly because these diseases vary in severity and presentation. They include multiple sclerosis, lupus, rheumatoid arthritis, juvenile diabetes, scleroderma, and pulmonary fibrosis. The National Institutes of Health estimates that more than 20 million people in the United States have autoimmune diseases, the vast majority of whom are women.

Although researchers have identified some inherited risks, autoimmune diseases are believed to arise from the complex interplay of genetic and environmental factors. In the study published in mSystems, immunologist Orly Avni, PhD, at Bar Ilan University, worked with graduate student Michal Werbner and other collaborators to investigate environmental risks, like psychological and social stress, because those offer opportunities for potential treatment.

“We know that there’s strong crosstalk between the immune system and the microbiota,” Avni said. An important step in understanding how stress may lead to autoimmune conditions, she said, is to identify the genetic responses of bacteria. Her group’s study showed that social stress changed both the composition and transcriptional patterns in the microbiota. “And the consequent immune response to that threat jeopardized the tolerance to self,” she said.

The researchers studied two groups of mice. One was exposed to stress in the form of daily, threatening encounters with other dominant and aggressive mouse. The other group was left alone. After 10 days, the researchers analyzed the gut microbiome of each group and found that the stressed mice had higher levels of some bacteria. Those included Bilophila and Dehalobacterium microbes, genera that have been observed at unusually high abundance in patients with multiple sclerosis.

However, Avni says she’s as interested in bacterial behavioral as she is in composition. The study showed that stress led to the activation of bacterial genes related to potentially violent traits — including growth, motility, and signals sent between a pathogen and a host. Microbes with these traits can travel to other parts of the body, including lymph nodes, and elicit an immune response.

This shows slides from the study

Histological analysis (hematoxylin and eosin) of optic nerves sections and immunostaining (4′,6-diamidino-2-phenylindole [DAPI], blue; anti-CD3ε, red) from control (I to III) and SD (IV to VI) 2D2 mice. The image is credited to Orly Avni et al.

When the researchers analyzed the lymph nodes of stressed mice, they found an increased abundance of several known pathogenic bacterial species. They also found a higher percentage of effector T cells known to play a role in autoimmunity. These findings suggest that stress causes changes in the activity of the gut microbes, which in turn influence the immune response in a way that can eventually trigger an attack of the body.

The study shows that gut bacteria can sense and respond to social stress, but Avni notes that researchers need to better understand how that long-lasting interaction works between bacteria and their hosts.

“It’s not enough to study the composition or the increase or decrease of a species,” she said. “We also have to understand how the microbiota senses us, and how they change their ‘behavior’ accordingly.” That knowledge, she added, could potentially lead to tailored microbial interventions that could dampen autoimmunity and additional stress-inducible illness.

About this neuroscience research article

Source:
ASM
Media Contacts:
Aleea Khan – ASM
Image Source:
The image is credited to Orly Avni et al.

Original Research: Open access
“Social-Stress-Responsive Microbiota Induces Stimulation of Self-Reactive Effector T Helper Cells” Michal Werbner, Yiftah Barsheshet, Nir Werbner, Mor Zigdon, Itamar Averbuch, Oren Ziv, Boris Brant, Evan Elliot, Shachaf Gelberg, Moran Titelbaum, Omry Koren, Orly Avni.
mSystems. doi:10.1128/mSystems.00292-18

Abstract

Social-Stress-Responsive Microbiota Induces Stimulation of Self-Reactive Effector T Helper Cells

Stressful life events are considered a risk factor for autoimmune disorders, though the mechanisms are unclear. Here we demonstrate that chronic social stress induces virulence-associated transcriptional patterns in the murine gut microbiota. The stress-influenced microbiota increased the presence of effector T helper cells in the mesenteric lymph nodes, including myelin-autoreactive cells. Inhibition of the bacterial quorum sensor QseC, which is also responsive to norepinephrine, diminished the presence of effector T helper cells and bacteria such as Acinetobacter in the mesenteric lymph nodes, without remarkably affecting the gut microbial composition. Together, our results delineate a model in which the immune reaction to stress-responsive microbiota may compromise tolerance to self and therefore may increase the risk for autoimmune diseases in susceptible individuals.

IMPORTANCE How do stressful life events increase the risk for autoimmune disorders? Here we show that chronic social stress in mice promotes the expression of virulent genes in the gut microbiota and alters the microbial translocation into the mesenteric lymph nodes. Our results also suggest that the consequent immune response to the stress-affected microbiota may endanger the tolerance for self. The presence of specific translocated bacteria and the immune response in the mesenteric lymph nodes can be diminished using an inhibitor of the bacterial communication system without drastically affecting the gut microbial composition as antibiotics do.

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