A surprising gut-brain discovery suggests that anxiety could one day be treated with specially designed probiotics.
Could anxiety be shaped, at least in part, by tiny organisms living in the gut? Research from Duke-NUS Medical School and the National Neuroscience Institute of Singapore points to a striking connection between gut microbes and anxiety-related behavior. The findings suggest that certain compounds made by gut bacteria, especially molecules called indoles, can influence brain activity involved in fear, stress, and emotional balance.
The study, published in EMBO Molecular Medicine, adds to a growing body of research showing that mental health is not controlled by the brain alone. Instead, the gut and brain appear to be in constant communication, with microbes helping to shape some of the chemical signals that affect mood and stress responses.
Anxiety and the Gut-Brain Connection
Mental health disorders have become increasingly common. In Singapore, the latest nationwide study found that 1 in 7 people has experienced a mental health disorder, including depressive and anxiety disorders.[1] In 2019, mental health disorders ranked among the top four causes of disease burden in Singapore.[2]
Against this backdrop, the research team investigated whether gut microbes could affect anxious behavior. In preclinical experiments, they studied mice raised in a germ-free environment, meaning the animals had not been exposed to live microbes. These mice showed significantly more anxiety-related behavior than mice with a typical community of resident gut microbes.
The difference was not only behavioral. The germ-free mice also showed heightened activity in the basolateral amygdala (BLA), a brain region involved in processing fear and anxiety.
How Missing Microbes Changed the Brain
Further analysis revealed that the anxiety-like behavior was linked to changes in specialized proteins in brain cells called calcium-dependent SK2 channels. These channels help regulate how easily neurons become excited and how often they fire.
When the body and brain are exposed to metabolites produced by live microbes, the SK2 channels appear to act like a clutch. They help keep neurons from becoming overly active. Without those microbial signals, neurons in the BLA became more excitable, a pattern associated with increased anxiety-related behavior.
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 links 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.”
Gut Microbes Helped Calm Anxiety Signals
To test whether microbes could reverse these effects, the researchers introduced live microbes into germ-free mice.[3] After the microbes were restored, activity in the basolateral amygdala fell, SK2 channel activity improved, and the animals showed much less anxiety-related behavior. Their emotional responses became more similar to those of mice that had been exposed to microbes all along.
The team then tested indoles, which are metabolites produced by certain gut microbes. When germ-free mice received indoles, their basolateral amygdala activity decreased, and their anxiety-related behavior was reduced. This finding suggests that compounds made by native gut microbes may directly help maintain emotional 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 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.” 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.”
A Possible Path Toward Probiotic Therapies
The findings point to a possible way to target the gut-brain axis in anxiety-related disorders. One approach could involve restoring a healthier microbial balance through dietary strategies, indole-based supplements, or probiotics that contain indole-producing microbes.
For now, these possibilities remain experimental. The work was done in mice, and researchers still need clinical trials to determine whether indole-based probiotics or supplements can safely and effectively reduce anxiety in people.
“In other words, it opens [the door] 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.”
What Later Research Adds
Since this 2025 study, related work has continued to explore whether probiotics and other microbiome-focused strategies can influence mood, anxiety, and sleep in humans. The picture is promising, but not settled.
One later placebo-controlled study (npj Mental Health Research) in healthy adults found that a multispecies probiotic was associated with reduced negative mood in daily reports after about two weeks. However, standard mental health questionnaires did not show the same clear effect, highlighting how difficult it can be to measure subtle shifts in mood.
Broader reviews of clinical trials have also suggested that probiotics, prebiotics, and synbiotics may have potential for symptoms related to anxiety, depression, and sleep. At the same time, researchers continue to emphasize that effects can vary by strain, dose, study population, and baseline gut microbiome. In other words, a generic probiotic is unlikely to work the same way for everyone.
That makes the Duke-NUS and National Neuroscience Institute findings especially important. Rather than simply linking gut bacteria to anxiety, the study points to a specific biological route involving indoles, SK2 channels, and the basolateral amygdala. This gives scientists a clearer target as they investigate future microbiome-based mental health therapies.
The team hopes to explore clinical trials to determine whether indole-based probiotics or supplements can be used in humans as a natural approach to anxiety treatment. If successful, the research could help open a new era of mental health care, one in which gut microbes are not just bystanders, but active partners in keeping the mind at ease.
Notes
- 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
- 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
- The study was conducted according to the National Advisory Committee for Laboratory Animal Research (NACLAR) guidelines.
References:
“Microbial metabolites tune amygdala neuronal hyperexcitability and anxiety-linked behaviors” by Weonjin Yu, Yixin Xiao, Anusha Jayaraman, Yi-Chun Yen, Hae Ung Lee, Sven Pettersson and H Shawn Je, 5 February 2025, EMBO Molecular Medicine.
DOI: 10.1038/s44321-024-00179-y
“Probiotics reduce negative mood over time: the value of daily self-reports in detecting effects” by Katerina V.-A. Johnson, and Laura Steenbergen, 9 April 2025, npj Mental Health Research.
DOI: 10.1038/s44184-025-00123-z
“The efficacy of probiotics, prebiotics, and synbiotics on anxiety, depression, and sleep: a systematic review and meta-analysis of randomized controlled trials” by Jialin Zhang, Linqing Zhu, Qing Meng, Zuxing Wang and Hongru Zhu, 27 November 2025, BMC Psychiatry.
DOI: 10.1186/s12888-025-07644-z
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