Science has only just started to tease out a fascinating relationship between bacteria, inflammation and mood over the last few years. Not only are some conditions, such as depression, being hypothesized to be caused by brain inflammation, but it's possible brain inflammation could be modulated by bacteria in our microbiome.

Intriguing new research from the University of Colorado Boulder suggests that one particular bacteria could have beneficial anti-inflammatory effects on the brain. Early studies in rodent models have found that through injections of the bacteria the animals can be essentially "immunized" against displaying anxious responses to stressful situations.

"We found that in rodents this particular bacterium, Mycobacterium vaccae, actually shifts the environment in the brain toward an anti-inflammatory state," says Matthew Frank, lead author of the new study.

Mycobacterium vaccae was first discovered in the 1990s in soil near the shores of Lake Kyoga in Uganda. It turned out the bacterium was from the same genus as that which causes tuberculosis. Interestingly, scientists noticed that people living in the vicinity of the lake in Uganda tended to respond to tuberculosis vaccines better than others. Since then, research into this mysterious bacterium has been booming.

Initially, researchers were studying Mycobacterium vaccae for its immune-modulating properties. In 2004, a trial using the bacterium as an adjunct to chemotherapy in lung cancer patients failed to improve survival rates but it did deliver a curious side effect. Patients receiving the bacterium displayed a significantly improved mood, leading researchers to begin exploring its cognitive effects.

A 2016 study led by the CU Boulder team found that mice injected with a heat-killed preparation of Mycobacterium vaccae displayed less anxiety and fear-based behavior when placed in proximity to a larger, aggressive mouse. Less systemic inflammation was also monitored in the animals over the course of the initial study.

This new study set out to try and understand exactly what the bacterium was doing in the brain to potentially be causing these behavioral and anti-inflammatory effects. The researchers again delivered injections of a heat-killed bacterium preparation, this time using a rat model. An "immunization" pattern was administered, with three injections across three weeks.

Eight days after the final dose, the rats were seen to have increased levels of interleukin-4 in the hippocampus. Interleukin-4 is an anti-inflammatory protein and it is thought that its increased presence in the hippocampus can help modulate moods like anxiety and fear. After being subjected to potential stresses, as in the first study, the animals showed lower levels of HMGB1, a stress-induced protein, and higher levels of CD200R1, a key receptor for helping keep the brain's immune cells in an anti-inflammatory state.

"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," says Christopher Lowry, who has been investigating the effects of Mycobacterium vaccae for 17 years and is senior author on this new study. "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."

There are some undeniably compelling recent studies finding correlations between gut bacteria and mental health. Two studies last year, one in mice and one in humans, found a probiotic formulation could reduce symptoms of anxiety and depression, while other 2017 studies found provocative connections between gut bacteria and both PTSD and Alzheimer's disease.

Underlying all these studies is the growing hypothesis that mental health could be significantly modulated by brain inflammation. As well as severe depression being linked with neuroinflammation, one paper even suggested suicidal thoughts could be directly connected to increased microglial activity in the brain. Microglia being the primary immune cell active in our brain and spinal cord.

"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 Frank. "Just think about how you feel when you get the flu."

It's still very early stages for much of this research but there are bold implications if these effects can be carried across into humans. Lowry suggests Mycobacterium vaccae holds promise as essentially a probiotic vaccine against stress. He imagines a potential future where it is given to people in high-stress occupations – soldiers or emergency room workers, for example – to reduce the effects of stress on the body and mind.

Unlike other probiotic delivery mechanisms that are more geared at being consumed orally, to enter the gut and alter one's microbiome, this technique operates more like a traditional vaccine – an injection of an inert compound that stimulates the body to produce its own beneficial response. In other words, a literal immunization against stress, depression and anxiety.

The new research was published in the journal Brain, Behavior and Immunity.


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