AsianScientist (Mar. 21, 2025) – Feeling anxious is a natural stress response that help us prepare for potential dangers. However, prolonged stress can overactivate the brain’s stress regulation systems, disrupting hormone balance leading to some lasting behavioural changes seen in anxiety disorders.
Now, new research shows that regulating anxiety isn’t all up to the brain. Scientists from Duke-NUS Medical School at National University of Singapore (NUS) and the National Neuroscience Institute in Singapore have uncovered how gut microbes and their chemical byproducts influence brain activity linked to anxiety-related behaviors. Their findings published in EMBO Molecular Medicine suggest that probiotics could offer a new avenue for improving mental health.
Patients with anxiety often experience digestive issues. In fact, previous studies in mice found that the gut microbiome plays a role in modulating brain chemistry and anxiety responses. However, the exact biological pathways connecting these resident microorganisms to anxiety-related brain changes remained unclear.
To investigate this connection, the scientists studied germ-free (GF) mice—mice raised without any exposure to microbes. They tested the animals’ anxiety levels using the open field and elevated zero maze behavioural test, which tracks a mouse’s willingness to explore open, elevated areas versus staying in enclosed spaces. Compared to their controls, the GF mice displayed more anxious behaviours and avoided open spaces more often.
Electrophysiological recordings also revealed a surge in the activity of the basolateral amygdala (BLA), a brain region key for processing fear and anxiety. At the cellular level, this overexcitability of BLA neurons was traced to a decline in the function of calcium dependent SK2 channels, which are specialised proteins that keep neuronal firing in check.
“Essentially, the lack of these microbes disrupted the way their brains functioned, particularly in areas that control fear and anxiety, leading to anxious behaviour,” said Hyunsoo Shawn Je, an associate professor from Duke-NUS’ Neuroscience and Behavioural Disorders Programme and one of the lead authors.
The researchers then introduced live microbes or supplemented GF mice with indoles—a key microbial compound that helps the brain recognize when a fearful situation is no longer a threat. Both interventions restored normal BLA activity and reduced anxiety-like behaviours.
This opens new possibilities for targeting the gut-brain axis or introducing indole-producing microbes as probiotics to help manage anxiety disorders and other mental health conditions.
“In other words, it opens for tailor-made therapies in line with 21st-century precision medicine,” said Sven Petterson, a professor at the Department of Research at the National Neuroscience Institute of Singapore and another lead author. “Studies such as this illustrate the close hereditary relationship that exists between our indigenous microbes and the higher complexity of life.”
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Source: Duke-NUS Medical School ; Image: Shutterstock
The article can be found at Microbial metabolites tune amygdala neuronal hyperexcitability and anxiety-linked behaviors.
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