Could the solution to reducing anxiety be found in our digestive system? Recent studies have revealed an important link between gut bacteria and behaviors associated with anxiety. Research indicates that specific byproducts from these microbes—namely indoles—are directly involved in managing brain functions tied to anxiety. This groundbreaking discovery paves the way for innovative probiotic treatments aimed at enhancing mental well-being.
Could the solution to reducing anxiety be found in our digestive system? Researchers from Duke-NUS Medical School and the National Neuroscience Institute have identified a vital relationship between gut bacteria and anxiety-related behavior. Their recent findings, published in EMBO Molecular Medicine, highlight that microbial metabolites—particularly indoles—have a significant impact on brain activity associated with anxiety. This discovery presents thrilling prospects for the development of new probiotic therapies intended to bolster mental health.
The incidence of mental health disorders has been climbing in recent years. The latest national survey reveals that 1 in 7 individuals in Singapore has encountered some form of mental health issue, encompassing both depression and anxiety disorders[1]. In fact, in 2019, mental health conditions ranked among the top four contributors to disease burden in Singapore[2].
This prompted the research team to explore the influence of gut microbes on anxious behavior. Their pre-clinical studies demonstrated that mice raised in a germ-free environment—lacking exposure to any live microbes—exhibited considerably heightened anxiety behaviors compared to those with typical resident gut bacteria.
Further examination indicated that the increased anxiety levels were linked to heightened activity in the basolateral amygdala (BLA), a brain area involved in handling emotions like fear and anxiety. This was shown to involve specialized proteins within the brain cells called calcium-dependent SK2 channels, which are also related to anxiety behavior. When the body and brain are exposed to metabolites from live microbes, these SK2 channels function like a brake, preventing neurons from becoming overly active and firing too much.
Associate Professor Shawn Je from Duke-NUS’ Neuroscience and Behavioural Disorders Programme, and one of the study’s lead authors, elaborated:
“Our research uncovers the detailed neural mechanisms that link gut microbes to mental health. Mice with no live microbes exhibited greater anxiety behaviors compared to those with live bacterial presence. In essence, the absence of these microbes disrupted normal brain functions, especially in areas responsible for fear and anxiety, resulting in increased anxious behavior.”
To gain deeper insight into the role of microbes, researchers introduced live microbes to germ-free mice[3]. This intervention led to a decline in neuronal activity within the basolateral amygdala and a reduction in SK2 channel activity. Consequently, the mice demonstrated significantly less anxiety-related behavior, reflecting emotional responses similar to those exposed to live microbes.
The team also tested the effects of indoles, the microbial metabolites originating from specific gut bacteria. Upon administering indoles to germ-free mice, they observed diminished activity in the basolateral amygdala and less anxiety-related behavior. This highlighted a direct link between our gut microbiota and the maintenance of mental stability.
Professor Sven Pettersson from the Department of Research at the National Neuroscience Institute of Singapore, also a lead author of the study, remarked:
“The establishment of hunger cues and their regulation serves as an evolved defense mechanism. The physiological changes occurring at birth can actually be seen as an initial significant exposure to anxiety for the newborn, essentially conveying the message, ‘If you don’t eat, you’ll perish.’ Furthermore, birth exposes the infant to breast milk, rich in microbes that produce indoles. These metabolites are known to be released by plants under stress or malnutrition, and our study indicates a similar mechanism where indoles might help regulate anxiety levels in mammals. Variations in the levels of microbial indoles in the bloodstream could signify differences in one’s sensitivity to stress, thus influencing the risk of encountering anxiety-related situations.”
The implications of these findings are extensive: they suggest that restoring the balance of gut microbes may offer therapeutic opportunities for treating anxiety disorders through dietary intake of indoles or by reintroducing indole-producing gut bacteria as probiotics. This ultimately paves the path for customized therapies that align with the principles of 21st-century precision medicine. Studies like this reveal the significant evolutionary connection between our native microbes and the complex nature of life’s processes,” Pettersson concluded.
Professor Patrick Tan, Senior Vice-Dean for Research at Duke-NUS, added:
“Our discoveries highlight the profound evolutionary connections among microbes, nutrition, and brain functionality. This holds tremendous promise for individuals struggling with stress-related issues, including sleep disturbances or those who cannot tolerate conventional psychiatric medications. It serves as a reminder that mental well-being is not just rooted in the brain; it is also influenced by our gut health.”
The research team is now eager to conduct clinical trials to ascertain whether probiotics or supplements based on indoles can serve effectively as natural treatments for anxiety in humans. If these trials yield positive results, it could herald a new chapter in mental health management—one in which gut microbes play a role in maintaining a calm mind.
[1] Institute of Mental Health, Singapore Mental Health study
[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 adhered to the National Advisory Committee for Laboratory Animal Research (NACLAR) guidelines.
