More Than a Gut Feeling

Interest in the idea that the trillions of microbes inhabiting our intestines might influence how we think and feel has grown rapidly in recent years. Yet translating that intrigue into solid scientific understanding remains challenging. As discussed in the first article in this four-part series, cells in a dish are poor substitutes for humans living in the real world, where mental health conditions frequently overlap with other diseases.

“People with functional gastrointestinal disorders such as irritable bowel syndrome have higher rates of anxiety and depression,” notes Associate Professor Sunny Wong, a clinician-scientist at Nanyang Technological University specialising in gastroenterology and genomic medicine.

However, Wong cautions that while these observations are compelling, they remain more suggestive than conclusive. “At this stage, most studies show association rather than causation” he explains. Scientists still do not fully understand the biology underlying these interactions, nor whether findings derived predominantly from Western populations apply in Asia, where genetics, diets, and lifestyles differ substantially.

“What we are trying to do with the Gut-Linked Outcomes in Wellbeing (GLOW) project is not only to provide rigorous evidence on how the gut and brain are linked, but also to translate these insights into novel clinical applications or interventions,” says Associate Professor Jimmy Lee, Group Chief Research and Innovation Officer, NHG Health, and a senior consultant psychiatrist at the Institute of Mental Health.

The aim is to move beyond anecdotes and intuition, replacing a “gut feeling” with concrete hypotheses that can be tested, validated, and ultimately put into practice.

The Complexity Challenge

The challenge, however, is two-fold. Firstly, the human gastrointestinal tract hosts trillions of microbes from thousands of species, many of which are still unknown to science. “The more we study, the more we realise that there is an entire new world inside each of us,” says Wong. “The human body contains trillions of microbial cells, comparable or even more in number to human cells. In that sense, we are more microbial than human.”

These microbes are not passive passengers. They respond dynamically to what we eat, making diet one of the most powerful forces shaping the composition and function of the gut microbiome. “They essentially eat what we eat, in doing so, they produce a wide range of chemical compounds—what we call metabolites—making the gut microbiome like a factory,” Wong continues. “These metabolites go to different parts of the body, affecting organs like the liver, kidney, skin—and yes, the brain, too.”

Secondly, compounding this biological complexity is the nature of psychiatric illness itself. Depression, anxiety, and schizophrenia each involve hundreds—sometimes thousands—of genetic variants, each exerting small but cumulative effects. Environmental influences—from early-life stress to diet and socioeconomic factors—layer additional variability on top.

“Further complicating the issue is that unlike other fields of medicine, psychiatry often lacks definitive laboratory or imaging tests that can confirm or exclude a diagnosis. We just don’t have such tools in psychiatry,” explains Lee. “Instead, we rely largely on the observation of behaviours and the practice rules around that.”

This variability makes both diagnosis and treatment of psychiatric conditions uniquely challenging. Antidepressants work for some patients but not others; even within a single patient, treatment responses may fluctuate over time. Large-scale genomic studies are beginning to map these differences, but understanding the underlying biology requires integrating multiple layers of data, from genetics and metabolism to brain imaging and, increasingly, the gut microbiome.

Tackling Complexity with Collaboration

The solution to this complexity, Lee and Wong argue, is to measure it more carefully and more comprehensively. On the human side, GLOW combines human genetic data with detailed mental health assessments that capture the participants’ mood, anxiety levels, quality of life, and specific experiences such as the loss of pleasure (anhedonia).

Complementing these self-reported symptoms, the team will also be doing “digital phenotyping”, using wearables and mobile applications to capture participants’ day-to-day lives. Indicators such as sleep patterns, heart rate, and activity levels—closely linked to stress, mood, and recovery—provide objective physiological context. Together, these data allow GLOW researchers to see whether changes in the gut microbiome are reflected in real-world behaviours and physiological responses over time, helping to bridge the gap between subjective experiences and biological measurements.

On the microbial side, stool samples allow researchers to analyse both the makeup of gut bacteria and the chemicals they produce. Rather than treating each microbe as an isolated island, the team focuses on patterns of interaction—how different microbes cluster together and change in mental health. Layered with other data streams, microbiome profiles may eventually function as biomarkers of specific mental health states or conditions.

“The beauty of the GLOW project is that we will be collecting multilayered data that allow us to examine the gut-brain relationship at a systems level, using genomics, metabolomics, digital phenotyping, and clinical assessments together” Wong says. “This systems level of data will give us a new perspective, one that looks at the body as an integrated system,” adds Lee. “This comprehensive approach is what makes GLOW unique, especially in Asia, where few studies of this scale and depth exist.”

Ultimately, GLOW does not merely aim to generate more associations, but to identify insights that can meaningful inform healthcare. One potential outcome is that the microbiome could serve as a biomarker, changing in measurable ways as psychological conditions change or inform disease trajectories with interventions. Diet, in particular, offers a tangible bridge between biology and daily life. “We already know that certain foods can influence mood,” says Wong. “Microbiome data may help us understand why that happens, and which components really matter.”

As mental health research enters an era of unprecedented complexity, the challenge is not only collecting data, but deciding where to focus attention. “There is a lot of interest in the microbiome, but what we need is deep science to understand the mechanisms, identifying what will work, and knowing why,” says Lee. By sharpening that focus, GLOW seeks to turn complexity into clarity, laying the groundwork for advances that are not only scientifically robust, but meaningful for the public, patients, and clinicians alike.