Stress can induce anxiety and depression, which appears to be mediated in part by stress-induced neuroinflammatory processes.
The immunoregulatory bacterium Mycobacterium vaccae (M. vaccae) has anti-inflammatory and stress-resilient effects, but its impact on the brain is unclear.
A study discovered that M. vaccae immunization: induces anti-inflammatory and immunoregulatory processes in the hippocampus, blocks stress-induced neuroinflammation in this brain region, and prevents stress-induced anxiety-like behaviors in rats.
- M. vaccae increased expression of the anti-inflammatory cytokine interleukin-4 (IL-4) and markers of alternative macrophage activation in the hippocampus.
- M. vaccae prevented stress-induced decreases in CD200R1, a receptor involved in keeping microglia in a quiescent surveillant state.
- M. vaccae blocked stress-induced increases in HMGB1, an inflammatory alarmin protein released by damaged cells.
- M. vaccae prevented stress-induced priming of the microglial proinflammatory response to immune stimuli.
- M. vaccae blocked stress-induced anxiety-like behavior in a social exploration test.
Source: Brain, Behavior, and Immunity
Evaluating M. vaccae in Adult Sprague-Dawley Rats (Study Overview)
In this study, adult male Sprague-Dawley rats received repeated peripheral injections of heat-killed M. vaccae or a saline vehicle control.
M. vaccae’s effects on neuroinflammatory mediators were examined by measuring gene expression and protein levels of cytokines, microglial markers, and related signaling molecules in the hippocampus and amygdala.
To assess effects on microglial function, hippocampal microglia were isolated after stress exposure and challenged ex-vivo with lipopolysaccharide (LPS) to measure priming of proinflammatory responses.
Stress effects were examined by exposing rats to inescapable tail shocks, an acute stressor previously shown to induce neuroinflammation and anxiety-like behavior.
M. vaccae’s effects on behavior were assessed using the juvenile social exploration test, which measures time interacting with a juvenile rat and serves as a sensitive test of stress-induced anxiety-like behavior.
This multifaceted approach provided insight into how peripheral M. vaccae immunization affects neuroinflammation, microglial activity, and behavioral outcomes following exposure to an acute stressor.
The results shed light on mechanisms by which microbial exposures can modulate brain function and confer stress resilience.
M. vaccae Treatment Induces Anti-Inflammatory Mediators in the Hippocampus
M. vaccae has been found to increase peripheral anti-inflammatory cytokines including interleukin 10 (IL-10) and transforming growth factor beta (TGFβ1).
The researchers first examined whether M. vaccae could also induce an anti-inflammatory phenotype in the CNS.
They found that three injections of M. vaccae increased mRNA expression of the anti-inflammatory cytokine interleukin 4 (IL-4) in the hippocampus, as well as IL-4 protein levels.
However, M. vaccae did not affect expression of TGFβ1 or other anti-inflammatory cytokines like IL-10 and IL-13 in the hippocampus.
IL-4 can stimulate alternative activation of macrophages, which have anti-inflammatory properties.
The researchers found that M. vaccae also increased expression of markers of alternative macrophage activation in the hippocampus, including CD200 receptor 1 (Cd200r1) and the mannose receptor (Mrc1).
These effects mirror an alternative macrophage activation phenotype characterized by low inflammatory cytokine production and enhanced tissue repair.
To confirm the role of IL-4 in mediating these effects, the researchers administered recombinant IL-4 centrally.
This recapitulated the increase in Cd200r1 and Mrc1 expression induced by M. vaccae.
This suggests that the endogenous IL-4 induced by M. vaccae mediates its anti-inflammatory effects in the hippocampus.
M. vaccae Prevents Stress-Induced Changes in Neuroinflammatory Genes
Since IL-4 did not alter basal inflammatory cytokine levels but could prime microglia to immune stimuli, the researchers examined genes involved in neuroinflammatory processes.
Under basal conditions, M. vaccae did not affect hippocampal expression of the inflammatory cytokines IL-1β, IL-6, and TNF.
However, it reduced basal expression of Nlrp3 and Nfkbia, which are implicated in stress-induced microglial priming.
Microglial priming refers to sensitization of microglia to subsequent immune challenges, such that prior stress exposure potentiates the microglial proinflammatory response.
To examine priming, the researchers isolated hippocampal microglia after stress exposure in M. vaccae treated animals and challenged them ex vivo with LPS.
Stress exposure potentiated the LPS-induced microglial expression of Il1b and Nfkbia compared to unstressed controls, indicating microglial priming.
However, this priming effect was abrogated in stressed animals treated with M. vaccae.
This suggests that the anti-inflammatory effects of M. vaccae can prevent stress-induced microglial priming.
M. vaccae Blocks Stress-Induced Changes in CD200R1 and HMGB1
Prior studies found that stress exposure reduces hippocampal CD200R1 expression, disrupting CD200:CD200R1 signaling and leading to microglial priming.
Stress also increases levels of the alarmin HMGB1, which can prime microglia.
The researchers found that M. vaccae prevented stress-induced decreases in Cd200r1 expression in the hippocampus and isolated microglia.
It also blocked stress-induced increases in hippocampal HMGB1 levels.
This suggests that increased CD200R1 signaling and reduced HMGB1 induction could underlie the inhibitory effect of M. vaccae on stress-induced microglial priming.
M. vaccae Mitigates Anxiety-like Behavior Induced by Stress
Anti-inflammatory treatment can block the effects of stress on depressive-like behavior.
To determine if M. vaccae could mitigate stress-induced anxiety-like behavior, the researchers used the juvenile social exploration test.
Exposure to acute stress reduced social exploration, indicating anxiety-like behavior.
However, treatment with M. vaccae prevented this reduction, mitigating the anxiogenic effect of stress.
This demonstrates that in addition to its anti-inflammatory and antineuroinflammatory effects, M. vaccae can also block the behavioral impacts of stress.
Potential Translation to Human Therapeutics
The findings from the study on rats have significant implications for developing new treatments for stress-related disorders in humans.
The ability of Mycobacterium vaccae (M. vaccae) to induce an anti-inflammatory response in the brain and mitigate stress-induced neuroinflammation and anxiety-like behavior in rats suggests that similar mechanisms might be applicable in humans.
- Neuroinflammatory Disorders: Chronic stress and neuroinflammation are linked to various mental health conditions in humans, including depression, anxiety, and post-traumatic stress disorder (PTSD). The observed effects of M. vaccae in reducing neuroinflammation could lead to novel approaches for treating these conditions.
- Microbiome-Gut-Brain Axis: This research underscores the importance of the microbiome-gut-brain axis, a rapidly evolving area of study. M. vaccae, as a probiotic-like agent, could influence brain health through this axis, offering a less invasive and potentially more holistic treatment strategy compared to traditional pharmaceuticals.
- Stress Resilience: Enhancing stress resilience through microbial-based interventions could be a proactive strategy in mental health care. By strengthening the body’s natural defense mechanisms against the harmful effects of stress, it might be possible to prevent the onset of stress-related disorders.
Considerations for Human Application
- Safety and Efficacy: While the results in rats are promising, translating these findings to humans requires rigorous testing for safety and efficacy. Human immune systems and brain structures are more complex, and what works in rats may not directly apply to humans.
- Administration and Dosage: Determining the appropriate form (e.g., oral, injectable) and dosage for human use would require extensive research. Additionally, the frequency and duration of treatment would need to be optimized.
- Individual Variability: Humans have significant genetic and environmental variability, which can affect response to treatments. Personalized approaches may be necessary to achieve the best outcomes.
- Long-Term Effects: Understanding the long-term effects of manipulating the neuroimmune system is crucial. While short-term benefits may be evident, the long-term implications on brain health and immune function need thorough investigation.
- Ethical and Regulatory Considerations: Introducing live or attenuated bacteria for treatment purposes raises ethical and regulatory issues that must be navigated carefully.
Conclusion: M. vaccae, immunomodulation, and stress disorders
The application of M. vaccae and similar immunoregulatory microbes represents an exciting frontier in mental health treatment, potentially offering new, more naturalistic avenues for combating stress-related disorders.
However, translating these findings from rat models to human patients involves a complex process of clinical trials and regulatory approvals.
Ongoing research is essential to understand the broader implications, fine-tune treatment methodologies, and establish the safety and efficacy of such interventions in human populations.
- Paper: Immunization with Mycobacterium vaccae induces an anti-inflammatory milieu in the CNS: attenuation of stress-induced microglial priming, alarmins and anxiety-like behavior (2018)
- Authors: Matthew G. Frank et al.