Heat-killed environmental bacteria may improve stress responses in mice [PreClinical]

1. Repeated injection with heat-inactivated Mycobacterium (M.) vaccae enhanced the ability for mice to cope in response to psychosocial stress.

2. Vaccination with M. vaccae also reduced the development of stress-induced colitis through the activation of regulatory T cells.

Evidence Rating Level: 2 (Good)

Study Rundown: Immunoregulatory treatments, such as using probiotics to modulate host microbial communities, have been effective in alleviating chromic inflammatory diseases. However, it is unclear as to whether they can also prevent stress-induced psychiatric disorders that are associated with risk factors like poor immunoregulation and low-grade inflammation. In this work, the authors tested the potential of heat-killed M. vaccae environmental bacteria in diminishing the impact of stress on mental and physical health.

Mice that were immunized with multiple doses of a heat-killed preparation of M. vaccae were evaluated for their ability to cope with stress induced by being housed with a dominant male. As compared to the control group, immunized mice showed a reduction in the number of submissive and avoidance behaviors. Treated mice also showed reduced aversion to unconfined spaces, as demonstrated by an increase in the time spent in the open areas of an elevated maze.  In addition to improving psychosocial responses to stress, treatment with M. vaccae prevented the onset of colitis, which is typically associated with the stress of being housed with a dominant aggressor. This effect was lost when mice were pretreated with an antibody to deplete regulatory T cells.

While future studies will be needed to determine the more long-term effects of M. vaccae vaccination on stress-related behaviors and physiology, this work demonstrates the potential of using microbiome-based approaches to alleviate negative responses to stress.

Click to read the study in PNAS

Relevant Reading: The ‘hygiene hypothesis’ for autoimmune and allergic diseases: an update

In-Depth [animal study]: Male C57BL/6NCrl mice received three subcutaneous injections with heat-killed M. vaccae or the vehicle control. They were then tested for stress responses in a chronic subordinate colony (CSC) housing setting, where they were housed with a dominant male. Vaccinated mice demonstrated significantly fewer displays of submission, especially on the first day of CSC exposure, for up to one week after the start of CSC housing. To test the fear-reducing effects of M. vaccae vaccination, mice were placed in an elevated plus-maze (EPM) 19 days after being subjected to CSC housing. When a two-week time interval was used between the final vaccination and beginning of CSC exposure, mice with M. vaccae treatment increased the amount of time spent in the open arms of the maze as compared to the control group (p<0.01), suggesting that vaccination reduced anxiety associated with exposure in unconfined areas. Histological examination of the colon after 20 days of CSC exposure revealed that treatment with M. vaccae significantly diminished spontaneous tissue damage (p<0.001).

When mice were intraperitoneally injected with an anti-CD25 antibody to inhibit regulatory T cells before being moved to CSC housing, positive effects of M. vaccae treatment were reduced. While stress coping behaviors were unaffected, anti-CD25 pretreatment led to diminished time spent in the open arms of the EPM as compared to control antibody treatment (p<0.001). Similarly, these pretreated mice also presented with significantly higher levels of spontaneous damage to the colon (p<0.001).

Image: PD

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