Dr. Charles Akle
Chief Medical Officer
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Our mycolicibacteria research
Mycobacterium vaccae is an environmental saprophytic bacterium with anti-inflammatory, immunoregulatory, and stress resilience properties. Previous (animal) studies have shown that whole, heat-killed preparations of M. vaccae prevent allergic airway inflammation.
Recent studies also demonstrate that immunization with M. vaccae prevents stress-induced anxiety-like defensive behavioral responses, amongst other things.
Furthermore, immunization with M. vaccae induces anti-inflammatory responses in the brain and prevents stress-induced exaggeration of microglial priming.
Inappropriate inflammation is emerging as a risk factor for anxiety disorders, affective disorders, and trauma-and stressor-related disorders, including posttraumatic stress disorder (PTSD). Traumatic experiences can lead to long-lasting fear memories and fear potentiation of the acoustic startle reflex.
Mycobacterium vaccae is a soil-derived bacterium with immunoregulatory and anti-inflammatory properties that has been demonstrated to enhance fear extinction in the fear-potentiated startle paradigm when given prior to fear conditioning.
However, M. vaccae-immunized rats showed enhanced fear extinction. Together with previous studies, these data are consistent with the hypothesis that immunoregulatory strategies, such as immunization with M. vaccae, have potential for both prevention and treatment of trauma- and stressor-related psychiatric disorders.
In this review, we provide evidence indicating that increases in immune (re)activity and inflammation, potentially promoted by a reduced exposure to immunoregulatory microorganisms (or “Old Friends”) in today’s modern society, may be causal factors in mediating the vulnerability to development and persistence of stress-related pathologies.
Moreover, we discuss strategies to increase immunoregulatory processes and attenuate inflammation. For example, contact with immunoregulatory Old Friends, which appears to be a promising strategy to promote stress resilience and to prevent and treat chronic stress-related disorders.
Urbanization is on the rise, and environments offering a narrow range of microbial exposures are linked to an increased prevalence of both physical and mental disorders.
Human and animal studies suggest that an overactive immune system not only accompanies stress-associated disorders but might even be causally involved in their pathogenesis.
Here, we compared young healthy human volunteers - half from urban upbringing in the absence of pets and half from rural upbringing in the presence of farm animals.
Our findings support the hypothesis that urban vs. rural upbringing in the absence or presence of animals, respectively, increases vulnerability to stress-associated physical and mental disorders by compromising adequate resolution of systemic immune activation following social stress and, in turn, aggravating stress-associated systemic immune activation.
In this study, we examined the effect of M. vaccae on neuroimmune regulation, stress-induced neuroinflammatory processes and anxiety-like behavior in adult male rats.
We explored the effects of M. vaccae on stress-induced hippocampal microglial priming and found that M. vaccae prevented stress-induced increases in anxiety-like behavior.
The present findings suggest that M. vaccae enhances immunomodulation and mitigates the neuroinflammatory and behavioral effects of stress, which may underpin its capacity to impart a stress resilient phenotype.
The hygiene hypothesis or "Old Friends" hypothesis proposes that inflammatory diseases are increasing in modern urban societies, due in part to reduced exposure to microorganisms that drive immunoregulatory circuits, and a failure to terminate inappropriate inflammatory responses.
Inappropriate inflammation is also emerging as a risk factor for trauma-related, anxiety, and affective disorders, including posttraumatic stress disorder (PTSD). Traumatic experiences can lead to long-lasting fear memories and exaggerated fear potentiation of the acoustic startle reflex.
Mycobacterium vaccae is a soil-derived bacterium with immunoregulatory and anti-inflammatory properties that has been demonstrated to confer stress resilience in mice. Our data is consistent with the hypothesis that immunoregulatory strategies, such as preimmunization with M. vaccae, have potential for prevention of stress- and trauma-related psychiatric disorders.
The hygiene, or “old friends,” hypothesis proposes that lack of exposure to immunoregulatory microorganisms in modern urban societies is resulting in an epidemic of inflammatory disease, as well as psychiatric disorders in which chronic, low-level inflammation is a risk factor.
An important determinant of immunoregulation is the microbial community occupying the host organism, collectively referred to as the microbiota.
Here we show that stress disrupts the homeostatic relationship between the microbiota and the host, resulting in exaggerated inflammation.
Treatment of mice with a heat-killed preparation of an immunoregulatory environmental microorganism, Mycobacterium vaccae, prevents stress-induced pathology. These data support a strategy of “reintroducing” humans to their old friends to promote optimal health and wellness.
Epidemiological studies suggest that living close to the natural environment is associated with long-term health benefits including reduced death rates, reduced cardiovascular disease, and reduced psychiatric problems. This is also often attributed to psychological mechanisms, boosted by exercise, social interactions, and sunlight.
Compared with urban environments, exposure to green spaces does indeed trigger rapid psychological, physiological, and endocrinological effects. However, there is little evidence that these rapid transient effects cause long-term health benefits or even that they are a specific property of natural environments.
Some Old Friends (such as helminths and infections picked up at birth) are almost eliminated from the urban environment. This increases our dependence on Old Friends derived from our mothers, other people, animals, and the environment.
It is suggested that the requirement for microbial input from the environment to drive immunoregulation is a major component of the beneficial effect of green space, and a neglected ecosystem service that is essential for our well-being.
Chronic inflammatory diseases (autoimmunity, allergy and inflammatory bowel diseases) are increasing in prevalence in urban communities in high-income countries.
One important factor is reduced exposure to immunoregulation-inducing macro- and microorganisms and microbiota that accompanied mammalian evolution (the hygiene hypothesis or 'Old Friends' mechanism). Reduced exposure to these organisms predisposes to poor regulation of inflammation.
But inflammation is equally relevant to psychiatric disorders. Inflammatory mediators modulate brain development, cognition and mood.
The risk of all these conditions (chronic inflammatory and psychiatric) is increased in urban versus rural communities, and increased in immigrants.
Diminished exposure to immunoregulation-inducing Old Friends in the perinatal period may enhance the consequences of psychosocial stressors, which induce increased levels of inflammatory mediators, modulate the microbiota and increase the risk for developing all known psychiatric conditions. In later life, the detrimental effects of psychosocial stressors may be exaggerated when the stress occurs against a background of reduced immunoregulation, so that more inflammation (and therefore more psychiatric symptoms) result from any given level of psychosocial stress.
This updated review examines the evidence for changed microbial exposure, or the lack of it, as a cause for allergy and the chronic inflammatory diseases that have increased in recent decades.
Newly important concepts such as the ‘Old Friends hypothesis’ and the related ‘Biodiversity hypothesis’ are examined, which suggest that microbial species beneficial for immune system development have become less common in the modern environment or have been replaced by other species, including invasive pathogens.
Peripheral immune activation can have profound physiological and behavioral effects including induction of fever and sickness behavior. One mechanism through which immune activation or immunomodulation may affect physiology and behavior is via actions on brainstem neuromodulatory systems, such as serotonergic systems.
Together with previous studies, this study also raises the possibility that immune stimulation activates a functionally and anatomically distinct subset of serotonergic neurons, different from the subset of serotonergic neurons activated by anxiogenic stimuli or uncontrollable stressors.
Increasing amounts of data suggest that inflammatory responses have an important role in the pathophysiology of depression.
Depressed patients have been found to have higher levels of proinflammatory cytokines, acute phase proteins, chemokines and cellular adhesion molecules.
In addition, therapeutic administration of the cytokine interferon-alpha leads to depression in up to 50% of patients.
Moreover, proinflammatory cytokines have been found to interact with many of the pathophysiological domains that characterize depression, including neurotransmitter metabolism, neuroendocrine function, synaptic plasticity and behavior.
Stress, which can precipitate depression, can also promote inflammatory responses through effects on sympathetic and parasympathetic nervous system pathways.
Finally, depression might be a behavioral byproduct of early adaptive advantages conferred by genes that promote inflammation.
These findings suggest that targeting proinflammatory cytokines and their signaling pathways might represent a novel strategy to treat depression.
Published 2021. This report verifies that Mycolicibacterium aurum Aogashima has been evaluated as safe for human consumption.
This report verifies that Mycolicibacterium aurum Aogashima has been evaluated as safe for human consumption.
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