In the gut, the immune system has to maintain tissue health and prevent infection,while also tolerating the presence of trillions of microorganisms in the gut microbiome. When we experience stress, it changes the composition of the gut microbiome, and brain function is disrupted. New research has shed light on how the immune system is involved in that phenomenon. This work, which has been reported in Nature Immunology, revealed that a specific type of immune cell in the intestine called gamma delta T cells (γδ T cells) could be causing stress-induced mental disorders like depression. It may also be possible to treat those mental health issues by targeting these cells, the researchers suggested.

This is the first study to highlight the importance of intestinal gamma delta (γδ) T cells in the modification of psychological stress responses. It has also revealed the significance of a immune cell receptor called dectin-1, which could be a target for treating stress-induced behaviors, suggested senior study author Atsushi Kamiya, MD, PhD, a professor at the Johns Hopkins University (JHU) School of Medicine.

When dectin-1 binds to its partner proteins, it activates immune cells in specific ways. In a mouse model, the dectin-1 receptor also seems to be related to the response to inflammation in the colon and alterations in the microbiome; this could indicate that dectin-1 is involved in γδ T cell stress responses in gut immunity.

Since previous research has found that inflammatory responses in the gut are connected to depression, the researchers focused on how imbalances in the gut microbiome could be triggered by stress.

In a rodent model of chronic social-defeat stress (CSDS), the researchers assessed changed in the gut microbiome. Mice were subjected to stress-inducing environments, and classified after each exposure as resilient to stress because the environment did not reduce social interactions, or susceptible to stress because the exposures increased social avoidance.

Fecal samples were collected to assess the composition of the gut microbiomes of these mice; this revealed that there was less diversity in the gut microbiomes of the susceptible mice. The susceptible mice also had fewer beneficial Lactobacillus johnsonii bacteria compared to resilient mice. Increases in microbial diversity in the gut microbiome are thought to indicate healthier microbiomes, and reduced diversity has been linked to less healthy microbiomes.

The researchers also revealed that there were stress-induced increases in γδ T cells, which seems to increase social avoidance.“However, when the stressed mice were given L. johnsonii, social avoidance decreased and the γδ T cells went to normal levels, suggesting that CSDS-induced social avoidance behavior may be the result of lower levels of the bacteria and γδ T cell changes," said lead study author Xiaolei Zhu, MD, PhD, an assistant professor at JHU School of Medicine.

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The investigators also assessed human samples in a small clinical investigation. There were 32 patients with major depressive disorder and 34 unaffected volunteers, and women and men made up about half of each group. Stool samples were used to analyze the composition of their gut microbiomes, and this showed that within the group of depression patients, as Lactobacillus levels decreased the likelihood of depression and anxiety increased.

Among people with major depressive disorder, Lactobacillus levels were found to be inversely related to higher depression and anxiety scores. There were no differences among the compositions of the gut microbiomes overall, however.

“Despite the differences of intestinal microbiota between mice and humans, the results of our study indicate that the amount of Lactobacillus in the gut may potentially influence stress responses and the onset of depression and anxiety,” said Kamiya.

The researchers also investigated a natural compound found in wild mushrooms called pachyman, which is an Eastern medicine depression and anxiety treatment. When mice were fed a diet that contained pachyman, the researchers found that dectin-1 could bind to the compound, which may show that pachyman inhibits the γδ17 T cell activity triggered by chronic social defeat stress, and could relieve social avoidance behaviors.

“These early-stage findings show that, in addition to probiotic supplements, targeting drugs to such types of receptors in the gut immune system may potentially yield novel approaches to prevent and treat stress-induced psychiatric symptoms such as depression,” said Kamiya.

Sources: Johns Hopkins University, Nature Immunology