Gut microbes appear to regulate anxiety

Scientists from Duke-NUS Medical School and Singapore’s National Neuroscience Institute have discovered a crucial connection between gut microbes (or lack thereof) and anxiety-related behaviour. Their findings, published in EMBO Molecular Medicine, open up exciting possibilities for new probiotic-based therapies to improve mental health.

With the prevalence of mental health disorders having risen over the years, the research team set out to study the role microbes play in anxious behaviour. In preclinical studies, they observed that in a germ-free environment, mice which were not exposed to live microbes showed significantly more anxiety-related behaviour than those with typical resident live microbes.

Further investigation revealed that the increased anxiety was associated with heightened activity in a brain region involved in processing emotions such as fear and anxiety, the basolateral amygdala (BLA). This was further identified to be related to specialised proteins within brain cells known as the calcium-activated potassium (SK2) channels, associated with anxiety behaviour. In conditions when the body and brain are exposed to live microbe metabolites, the SK2 channels act like a clutch, thus preventing neurons from becoming overly excited and firing too frequently.

“Our findings reveal the specific and intricate neural process that links microbes to mental health,” said co-lead author Associate Professor Shawn Je, from Duke-NUS. “Those without any live microbes showed higher levels of anxious behaviour 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 behaviour.”

To better understand the role of microbes in this process, the researchers introduced live microbes into germ-free mice. This reduced the elevated neuronal activity in the basolateral amygdala and thus SK2 channel activity. As a result, the mice showed significantly less anxiety-related behaviour —their emotional responses became like those exposed to microbes.

The researchers also tried treatment with indoles — microbial metabolites produced by certain microbes. When the germ-free mice were given indoles, they showed reduced activity in the basolateral amygdala and displayed less anxiety-related behaviour. This demonstrated that our indigenous microbes produce metabolites, which suggest a direct link between our microbiota and maintaining mental balance.

“Birth is associated with exposure to breast milk, known to contain microbes that can produce … indoles,” said co-lead author Professor Sven Pettersson, from National Neuroscience Institute. “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. That is, different levels of circulating microbial plasma indoles in the blood may reflect different sensitivity and vulnerability to stressful situations and therefore variable risk of experiencing anxiety-related situations.”

The team now hopes to explore clinical trials to determine whether indole-based probiotics or supplements can be effectively used in humans as a natural anxiety treatment. If successful, this could mark the beginning of a new era in mental health care — one where gut microbes help to keep our minds at ease.

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

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