Researchers have identified how Lactobacillus, a member of our guts’ microbiome community, affects a critical immune system protein, influencing stress levels and mental health. The findings could lead to new ways to prevent and treat depression and anxiety using specially formulated probiotic supplements.
The connection between the gut microbiome and the brain has emerged as an area of focus for research into psychological disorders. Studies have shown that disruption of the gut’s microbial community is associated with stress and mood disorders, with Lactobacillus found to be one of the primary bacterial families diminished in such disorders. Lactobacillus can be found in fermented foods, such as yogurt, fermented vegetables (olives, pickles, sauerkraut), salami, and sourdough bread.
Early attempts to manipulate gut microbes using beneficial bacteria – probiotics – produced mixed results, mostly due to the overwhelming complexity of the microbiome, which is estimated to include 39 trillion microorganisms. Using a technique that's not often used, researchers from the University of Virginia (UVA) have examined the mechanics underpinning how Lactobacillus affects mental health.
“We were aware from our prior research that Lactobacillus was beneficial in improving mood disorders and was lost following psychological stress, but the underlying reasons remained unclear, primarily due to the technical challenges associated with studying the microbiome,” said Alban Gaultier, one of the study’s corresponding authors.
To circumvent these technical challenges, the researchers used a gnotobiotic consortium of eight bacterial strains, including two strains of Lactobacillus, called Altered Schaedler Flora (ASF). Gnotobiotics is the study of organisms whose every germ is carefully controlled.
They exposed mice to two randomized mild stressors each day for three weeks, disrupting their microbiome and reducing levels of Lactobacillus. To determine whether the disrupted microbiome was a marker of or a contributor to anxiety- and depression-like behaviors, the researchers transferred the microbiota from the stressed mice to germ-free mice with no microorganisms living on or in them. They found that the behaviors were transferred along with the microbiota, indicating that bacterial transfer is sufficient to drive behaviors associated with mood disorders and environmental stress exposure.
To understand how this happened, the researchers performed metabolomics on the serum of the mice that received the stressed microbiome. The only cytokine, a protein secreted by immune system cells, that was significantly changed was interferon-gamma, which was reduced in these mice. Interferon-gamma is critical for innate and adaptive immunity against viral and some bacterial infections.
Using unchanged ASF or ASF with the two Lactobacillus strains removed, the researchers created mice with and without the bacteria to explore whether it was responsible for altering interferon-gamma production. Both groups of mice were exposed to stressors, and their brains were subsequently analyzed. Overall, Lactobacillus-negative mice had an increased neuronal activation in brain regions associated with fear and anxiety compared to Lactobacillus-positive mice.
Fresh groups of Lactobacillus-positive and -negative mice were subjected to stress by restraining them for two hours a day for seven days. Only mice without Lactobacillus were found to be more susceptible to stress. Measurements taken pre- and post-stress showed that Lactobacillus-negative mice had a lower concentration of interferon-gamma than positive mice, demonstrating that in the absence of the protein, mice are more susceptible to environmental stress. And mice given an interferon-gamma neutralizing antibody appeared to have heightened responses to acute stress.
The researchers say their findings provide a novel framework for understanding the roles of the gut microbiome and the immune system in mood disorders.
“With these results in hand, we have new tools to optimize the development of probiotics, which should speed up discoveries for novel therapies,” said Andrea Merchak, lead and corresponding author of the study. “Most importantly, we can now explore how maintaining a healthy level of Lactobacillus and/or interferon-gamma could be investigated to prevent and treat anxiety and depression.”
The study was published in the journal Brain, Behavior, and Immunity.
Source: University of Virginia