Mental Health’s New Frontier: The Microbiome Within

Could the key to tackling rising mental health challenges lie in the microbiome? Researchers at GLOW are leading the charge to find out. 

Singapore’s healthcare priorities have evolved with the times—shifting from infectious diseases like tuberculosis to chronic conditions like cardiovascular disease and cancer. Now, attention is turning to a new frontier: mental health. Addressing this complex issue could be the country’s most ambitious healthcare goal to date. “This is a moonshot; it is uncharted territory and no one yet knows what we will be able to find,” says Professor John Chambers, Chief Scientific Officer of Singapore’s national precision health initiative, PRECISE. 

The statistics paint a compelling picture: 1 in 7 Singaporeans would have experienced a mental health condition such as depression over the course of their lifetimes. Beyond the profound personal toll, the economic impact of mental health conditions is substantial. In 2022, lost productivity due to anxiety and depression was estimated to cost S$15.7 billion, nearly 3% of Singapore’s GDP; highlighting the urgent need for innovative approaches to understand, prevent, and treat mental health conditions. 

While dedicated research has led to significant strides in how conditions like cancer are treated, studying mental health presents a unique set of challenges. The predominant research tools—cell lines and animal models—just aren’t able to capture the complexity of the human mind and behaviour. “Are brain cells in a dish or even a mouse brain a good model of the human brain? Particularly when it comes to behavioural responses to stress and so on, it is much more difficult to make that leap from research to the real world,” explains Professor Patrick Tan, Executive Director of PRECISE. Furthermore, obtaining patient samples from the brain is often considerably more difficult than skin or tumour tissue, he adds. 

A promising new approach: The microbiome 

How then can Singapore tackle the multifaceted challenge of mental health? “One way is to study the population and look at natural genetic variation in a sufficiently large number of people and see if specific variants affect these sorts of conditions,” says Tan, noting that this has been the goal of the National Precision Medicine (NPM) programme since its inception in 2017.  

While certain mental health conditions are known to have a strong genetic basis, genetics typically accounts for approximately 30% of susceptibility for most diseases, says Chambers. “That means the rest of the causes are non-genetic and there is still a lot more to be discovered. Those could be behavioural choices, diets or patterns of physical activity, but also exposures we encounter on a day-to-day basis—including the microbes that live within us,” he continues. 

The microbiome is a complex ecosystem comprising trillions of bacteria, viruses, fungi and other microorganisms that live in the body, collectively containing far more genetic information than their human hosts. In addition to conditions like inflammatory bowel disease and obesity, the dysregulation of the gut microbiome has also been linked to mental health disturbances. There are several plausible reasons for this: Firstly, the gut is directly linked to the brain through a dense network of nerves known as the gut-brain axis. Secondly, many gut bacteria are known to produce chemicals that can affect the brain, such as short chain fatty acids. Finally, damage to the gut barrier could also lead to inflammation that in turn affects brain function.  

“So there is some evidence to suggest that different gut microbiomes might be linked to differences in mental health or the enjoyment of life, but it is largely based on cross-sectional studies in a small number of settings, mostly in the northern hemisphere,” says Chambers. “There are some good hypotheses around generation of neuroactive peptides or neuroactive chemicals, but the evidence base is relatively weak and there’s a lot more to be discovered.”  

Furthermore, the microbiome is an appealing target for intervention: unlike genetics which are largely fixed upon conception, the microbiome can be altered—perhaps even easily and cost-effectively—offering a novel and accessible pathway for improving mental wellbeing, he says. 

GLOW: A mental health moonshot 

To better understand the connection between the microbiome and mental health, Singapore has launched a multi-institutional research initiative called Gut-Linked Outcomes in Wellbeing or GLOW. A pioneering initiative and largest of its kind in Asia, GLOW brings together academic institutions such as the National University of Singapore (NUS) and the Genome Institute of Singapore, medical institutions like Duke-NUS and the Lee Kong Chian Medical School and hospital partners Institute of Mental Health (IMH), Tan Tock Seng Hospital (TTSH) and NHG Polyclinics. The initiative extends the capabilities of the first two phases of the NPM, encompassing both human and microbial genetics. 

The study aims to involve some 6,000 participants, building a database of each person’s microbiome and juxtaposing it with their own genetic data as well as non-genetic information. “GLOW is substantially different from what we have done previously as it allows us to characterise the stool microbiome, which has not been done before at scale in Singapore,” Chambers says.  

“It will also give us a substantial amount of information decoding each individual’s mental state, including a more extensive range of subjective measures about self-perceived wellness but also objective techniques, in particular digital platforms for assessing metrics that are indicative of mental wellbeing.” Called “digital phenotyping” these metrics include data from wearables, such as heart rate variability and activity levels, which could give a more comprehensive view of a person’s mental state. 

In the next few years, the goal is for GLOW to raise the profile of mental health and microbiome research, building local capabilities in both fields and establishing Singapore as a well-regarded place to conduct globally significant research, Tan says. “We hope to catalyse interest and get a community of people collaborating, starting with the investigators in the programme but expanding out to the wider institutions to increase interest in this line of research,” he shares. Looking further to the horizon, the second goal is to get from insights to potential interventions, having validated the functional links between the gut and the brain. 

“Our ultimate goal, however, is to bring the results back to Singaporean patients,” Tan says. “For this we have to be balanced between speed and responsibility, in terms of introducing interventions only after they have been sufficiently validated but also deemed to be cost-effective. This is where our partnerships with hospitals are particularly important, as we work together to design what can be done in this space on a national scale.” 

The good news is that GLOW is not starting from ground zero, but builds on a solid foundation laid during the earlier stages of the NPM programme. “For instance, we can bring in the sequencing capabilities and data sharing frameworks developed for NPM Phase I and II. We also have experience with national-scale rollouts, with the launch of the familial hypercholesterolemia screening programme,” Tan says. “So while GLOW is not exactly the same, we can use some of the lessons learnt as a ‘pathfinder’ for the way forward.” 

“I’m really excited not only to address mental health as an issue particularly relevant to the next generation, but also discovering potentially groundbreaking solutions,” Chambers adds.  

Next feature coming soon - stay tuned for the next GLOW release! 

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