



Stress can lead to anxiety and symptoms of depression, which are caused, in part, by neuroinflammatory processes. Studies in mice by a team at the University of Colorado Boulder have now shown how injections of the bacterium Mycobacterium vaccae can prevent these stress-related inflammatory responses in the brain and reduce stress-induced anxiety behavior.

Reporting in their findings Brain, Behavior, and Immunity, the researchers suggest that if similar results could be generated in humans, they could lead to the development of probiotic-based immunizations that help to protect against or treat disorders such as posttraumatic stress disorder, anxiety, or depression. “If you look at the field of probiotics generally, they have been shown to have strong effects in the domains of cognitive function, anxiety, and fear,” comments senior author Christopher Lowry, Ph.D., an associate professor of integrative physiology at CU Boulder. “This paper helps make sense of that by suggesting that these beneficial microbes, or signals derived from these microbes, somehow make their way to the hippocampus, inducing an anti-inflammatory state.”

The CU Boulder team's published paper is entitled “Immunization with Mycobacterium vaccae Induces an Anti-Inflammatory Milieu in the CNS: Attenuation of Stress-Induced Microglial Priming, Alarmins and Anxiety-Like Behavior.”

An estimated 25% of people will at some point in their lives suffer from anxiety or trauma-related disorders and other stress-related conditions, which can also lead to major depression. Collective evidence indicates that enhanced stress-induced inflammatory immune activation and reduced immunoregulation may play a causal role in the development of anxiety and trauma- and stress-related disorders. Research has, for example, suggested that chronic inflammation may impact mood-linked neurotransmitters, such as norepinephrine or dopamine. Studies have also shown that patients with anxiety- and trauma-related conditions have reduced numbers of regulatory T cells (Tregs, while research also suggests that trauma, illness, or surgery can sensitize certain regions of the brain to mount an inflammatory response to subsequent stressors, which can lead to mood disorders.

“There is a robust literature that shows if you induce an inflammatory immune response in people, they quickly show signs of depression and anxiety,” says lead author Matthew Frank, Ph.D., a senior research associate in the department of psychology and neuroscience. “Just think about how you feel when you get the flu.”

“Given the evidence for reduced immunoregulation and chronic low-grade inflammation in anxiety and trauma-related disorders, microbial interventions that increase Treg, promote immunoregulation, and increase anti-inflammatory signaling may have value in the prevention or treatment of these disorders,” the authors suggest.

M. vaccae has previously been shown to increase induction of Treg production and anti-inflammatory cytokines. A previous study by CU Boulder scientists showed that mice given injections of a heat-killed M. vaccae preparation and then placed in housing with an aggressive male exhibited less anxiety-like behavior and were less likely to suffer colitis or peripheral inflammation than control animals. These findings suggest that immunoregulatory and anti-inflammatory treatments can “buffer against the proinflammatory effects of stress,” the researchers point out. What hasn’t been studied before is whether M. vaccae has a direct impact on stress-induced neuroinflammation.

Interestingly, prior studies have demonstrated that exposure to stress induces proinflammatory cytokines in the central nervous system (CNS) and sensitizes inflammatory processes to subsequent immune challenges. Research has linked such neuroinflammatory processes with stress-related depressive and anxiogenic effects. “For example, a number of studies have found that prior exposure to either acute or chronic stressors potentiates the neuroinflammatory and microglial proinflammatory response to subsequent immune challenges,” the team writes.

Mounting evidence of M. vaccae’s beneficial effects on peripheral anti-inflammatory processes and anxiety prompted the team to take their research further and examine the effects of immunizing male mice with a heat-killed preparation of M. vaccae on inflammatory responses in the central nervous system, as well as on stress-induced microglial sensitization, in the context of stress-induced anxiety.

Their results showed that animals given three separate weekly M. vaccae immunizations demonstrated marked anti-inflammatory immune responses in the hippocampus, including increased levels of hippocampal interleukin-4 (IL-4) expression. M. vaccae immunization also blocked priming of the microglia response to immune challenge and prevented stress-induced increases in anxiety-like behaviors. The immunized animals showed lower levels of a stress-induced protein, or alarmin, called HMGB1, and higher expression of CD200R1, a receptor for keeping glial cells in an anti-inflammatory state. “Alarmins are host biomolecules that can initiate and perpetuate a noninfectious inflammatory response, often in response to cell or tissue damage, or immune activation,” the researchers explain. “Particularly noteworthy is the effect of M. vaccae on Cd200r1, which plays a prominent role in microglial immunomodulation.” Treating the animals directly with IL-4 recapitulated the effects of M. vaccae on the expression of specific genes in the hippocampus, a region of the brain that modulates cognitive function, anxiety, and fear.

“We found that in rodents this particular bacterium, M. vaccae, actually shifts the environment in the brain toward an anti-inflammatory state,” comments Dr. Frank. “We found that M. vaccae blocked those sensitizing effects of stress too, creating a lasting stress-resilient phenotype in the brain.…If you could do that in people, it could have broad implications for a number of neuroinflammaory diseases.”

M. vaccae was first isolated from mud on the shores of Lake Kyoga in Uganda. Dr. Lowry can envisage that it may one day be possible to administer the bacterium to people, including military personnel and emergency room staff, as a way of helping to buffer the effects of stress on the brain. He is also working with a team at the University of Colorado Denver on a study exploring whether veterans with PTSD might benefit from an oral probiotic that includes a different bacterial strain, Lactobacillus reuteri. “More research is necessary, but its possible that other strains of beneficial bacteria or probiotics may have a similar effect on the brain,” he says.



























