Gut microbes have an unexpected link to anxiety

Anxiety is a common mental health disorder that affects millions of people all over the world. It has long been the subject of intense scientific study.

Recently, researchers have stumbled upon an unexpected ally in the fight against this prevalent condition – the humble gut microbe.

It appears that gut microbes, in their natural habitat, produce compounds known as indoles, which are crucial for regulating the brain activity associated with anxiety.

Tiny microbes, big impacts

The researchers, who were based at Duke-NUS Medical School and the National Neuroscience Institute, set out to investigate the role that gut microbes play in regulating anxious behavior.

The findings are truly eye-opening. Not only do microbes in the gut influence brain activity, they may also hold the key to potential treatments for mental health issues such as anxiety and depression.

Gut microbes and anxiety

Mental health disorders are becoming increasingly prevalent in today’s world. In Singapore, for instance, 1 in 7 people has experienced a mental health issue.

The most common conditions include depression and anxiety, which contribute significantly to the disease burden in many countries.

The research team set out to explore how the presence of microbes affects the anxious behavior of mice.

In germ-free mice that had not been exposed to any living microbes, observable anxiety-related behavior increased significantly compared to the behavior of mice that had been exposed to microbes.

From the gut to the brain

Upon further study, the researchers linked this increased anxiety to heightened activity in the basolateral amygdala (BLA) – a part of the brain responsible for processing emotions such as fear and anxiety.

More specifically, the team identified the role of specialized proteins within brain cells, referred to as calcium-dependent SK2 channels, which regulate anxiety behavior.

“Our findings reveal the specific and intricate neural process that links microbes to mental health,” said co-lead author Professor Shawn Je.

“Those without any live microbes showed higher levels of anxious behavior than those with live bacteria. Essentially, the lack of these microbes disrupted the way their brains functioned, particularly in areas that control fear and anxiety, leading to anxious behavior.”

Gut microbes and mental balance

The researchers extended their investigation by introducing live microbes to germ-free mice.

With live microbes reintroduced, the heightened neuronal activity in the basolateral amygdala was significantly reduced, and the rodents showed less anxiety-related behavior.

Additionally, treating these germ-free mice with indoles – metabolites produced by certain microbes – resulted in similar effects, confirming a direct link between the gut microbiota and mental balance.

“Establishing hunger signals and controlling hunger is an evolutionarily conserved defense mechanism. The physiological switch at birth, can therefore, be viewed as a first major wave of anxiety exposure for the newborn, which simply says, ‘If you don’t eat, you will die,'” explained co-lead author Professor Sven Pettersson.

“Additionally, birth is associated with exposure to breast milk, known to contain microbes that can produce molecules known as indoles.”

“Indoles are known to be secreted in plants when they are exposed to stress or malnutrition (drought) and in this paper we report a similar mechanism in which indoles can regulate anxiety levels in mammals.”

A new era of anxiety treatments

This breakthrough suggests that targeting the gut-brain axis could pave the way for new anxiety treatments, either through dietary indole supplementation or introduction of indole-producing microbes as probiotics.

Professor Patrick Tan, Senior Vice-Dean for Research at Duke-NUS said that the findings underscore the deep evolutionary links between microbes, nutrition, and brain function.

“This has huge potential for people suffering from stress-related conditions, such as sleep disorders or those unable to tolerate standard psychiatric medications. It’s a reminder that mental health is not just in the brain – it’s in the gut too,” said Professor Tan.

Next, the researchers will test their findings in clinical trials and examine the efficacy of indole-based probiotics or supplements as a natural anxiety treatment in humans.

If these trials are successful, we may be on the brink of a new era in mental health care, where gut microbes play a pivotal role in maintaining mental health balance.

The full study was published in the journal EMBO Molecular Medicine.

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