Could the key to easing anxiety be hidden in our gut? Scientists from Duke-NUS Medical School and the National Neuroscience Institute have discovered a crucial connection between gut microbes and anxiety-related behaviour. Their research, published today in EMBO Molecular Medicine , suggests that microbial metabolites– specifically indoles–play a direct role in regulating brain activity linked to anxiety. This finding opens up exciting possibilities for new probiotic-based therapies to improve mental health.
The prevalence of mental health disorders has been rising over the years. According to the latest nationwide study, 1 in 7 people in Singapore has experienced a mental health disorder, which includes depressive and anxiety disorders [1] . In 2019, mental health disorders were one of the top four leading causes of disease burden in Singapore [2] .
The research team thus set out to investigate the role microbes play in anxious behaviour. In pre-clinical studies, the scientists observed that in a germ-free environment, those 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 dependent 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.
Associate Professor Shawn Je from Duke-NUS' Neuroscience and Behavioural Disorders Programme and one of the lead authors, explained:
"Our findings reveal the specific and intricate neural process that link microbes to mental health. 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."
To better understand the role of microbes in this process, the researchers introduced live microbes into germ-free mice [3] . 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 behavior—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.
Professor Sven Pettersson from the Department of Research, National Neuroscience Institute of Singapore, who is also a lead author of the study, said:
"Establishing hunger signals and controlling hunger is an evolutionarily conserved defence 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." 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 (draught) 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 implications of these observations are multiple: for example, it opens for the therapeutic potential of targeting the gut-brain axis to treat anxiety-related disorders by restoring the microbe composition through dietary supplementation with indoles or by introducing indole-producing gut microbes as probiotics. "In other words, it opens for tailor-made therapies in line with 21st-century precision medicine. Studies such as this illustrate the close hereditary relationship that exists between our indigenous microbes and the higher complexity of life," concludes Pettersson.
Professor Patrick Tan , Senior Vice-Dean for Research at Duke-NUS, said:
"Our 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."
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 keep our minds at ease.
[1] Institute of Mental Health, Singapore Mental Health study https://www.imh.com.sg/Newsroom/News-Releases/Documents/SMHS%202016_Media%20Release_FINAL_web%20upload.pdf
[2] Ministry of Health 28 October 2020 Global Burden of Disease 2019 Study Findings https://www.moh.gov.sg/news-highlights/details/global-burden- of-disease-2019-study-findings
[3] The study was conducted according to the National Advisory Committee for Laboratory Animal Research (NACLAR) guidelines.
