Researchers from Duke-NUS and the National Neuroscience Institute of Singapore plan to develop an indole-based supplement to stimulate gut bacteria and potentially reduce anxiety.
This is significant for a broad range of individuals experiencing gut-related anxiety, even if they may not be diagnosed with severe anxiety disorders.
“People experience anxiety for many different reasons, not just due to a lack of microbiota. It’s important to identify individuals whose anxiety is linked to gastrointestinal issues, as they are more likely to benefit from this intervention,” said Associate Professor Hyunsoo Shawn Je from Duke-NUS Neuroscience and Behavioural Disorders Programme.
However, microbiome composition varies between individuals, making standardised treatments ineffective. This is driving a shift toward precision medicine, where health benchmarks are becoming more personalised.
“This is the future of precision medicine. The concept of ‘normal’ is fading away, and you essentially become your own reference for future treatments.
“A potential scenario could involve banking microbiome samples at different points in time. If a problem arises later, you could compare your past and present profiles and restore what’s missing. This approach is already being explored in ongoing trials,” said Professor Sven Pettersson from the Department of Research, National Neuroscience Institute of Singapore.
However, at this point, he is focusing on plans to conduct a proof-of-concept clinical trial with human participants, where researchers will examine the effects of indoles on anxiety and its related conditions.
Potential areas of concern include sleep disorders and appetite regulation. Dr Je and Prof Pettersson mentioned previous research studies, where they observed that animals with anxious behaviour sleep less, though the exact cause remains unclear.
They added that anxiety could also be linked to appetite regulation, as animals with low indole levels exhibit eating problems, suggesting shared signalling pathways between anxiety and dietary habits.
What are indoles?
Indoles are organic compounds found in vegetables such as cabbage, broccoli, and Brussels sprouts. They can also be produced when gut bacteria break down the amino acid tryptophan, an essential amino acid found in foods like meat, eggs, and certain vegetables.
Tryptophan is a key precursor for serotonin, a neurotransmitter that regulates mood and anxiety. Some indole derivatives, such as indole-3-propionic acid (IPA) and indole-3-aldehyde (IAld), have been shown to reduce inflammation, strengthen the gut barrier, and influence the gut-brain axis.
By modulating neurotransmitter activity and reducing stress-related inflammation, indoles may help regulate anxiety-related behaviours. This connection has led the researchers to explore indole-based supplements as potential natural interventions for mental health conditions.
The effectiveness of an indole-based supplement may depend on dietary factors, but the precise dietary components needed to optimise indole levels remain unclear, said Prof Pettersson. He explained that this will require collaboration with clinicians and nutrition experts to develop an optimal combination for potential therapeutic benefits.
“I can give you a recommendation – eat one kilogram of broccoli a day, you could mix it with cabbage and Brussels sprouts, and it’ll keep the doctor away. But that’s not exactly appealing. This is where supplementation tailored to the individual comes in.
“However, determining the right concentration for human use remains a challenge. We know the effective range in rodents, but you can’t just scale up the dosage for a person, it doesn’t work that way,” said Prof Pettersson, referencing the study that he was involved in, where researchers observed the effects of indoles on germ-free mice.
Indole supplementation reduced anxiety in germ-free mice
The germ-free mice, which lacked gut microbes, exhibited heightened anxiety-like behaviours that resembled agoraphobia, said Dr Je. The mice would stay near the wall and appear to be afraid of heights when placed on an elevated maze.
Notably, the mice displayed significantly less anxiety-related behaviour when they consumed water with 200μM indole for six weeks.
There was also reduced activity in the basolateral amygdala – a part of the brain that plays a key role in anxiety and fear.
This suggested a direct link between microbiota and mental conditions.
“Importantly, these changes can be restored by conventionalisation [introducing gut microbes] or dietary supplementation with indole, a gut microbe-derived metabolite.
“This suggests a potential alternative treatment option to reduce anxiety levels in individuals with anxiety-related disorders,” wrote researchers in EMBO Molecular Medicine.
Prof Pettersson said that these findings open an alternative way to manage anxiety by combining diet with tailored molecules derived from microbes. This approach is generally considered safer and has fewer side effects compared to traditional pharmaceuticals.
Industry potential
Most anxiety medications act on the neurotransmitter system, but they come with long-terms side effects.
For example, benzodiazepines can cause sedation, cognitive impairment, and memory issues. There are also selective serotonin reuptake inhibitors (SSRIs), which can cause weight gain, sexual dysfunction, and gastrointestinal issues. These pharmaceutical drugs may also lead to withdrawal symptoms if discontinued. Additionally, some individuals cannot take them due to pre-existing conditions or contraindications with other medications.
While indoles offer a safer, natural alternative, there are challenges to overcome.
“One challenge within the industry is that companies tend to focus on bacteria-based products because they are cost-effective, and they often avoid conducting clinical trials. There’s a constant conflict between what we believe is necessary and what companies are willing to invest in.
“That said, we have started working with small biotech companies in Singapore, Malaysia, and Sweden. Our plan is to integrate indoles into dietary strategies as part of this research. This approach may also benefit from the cultural acceptance of bacteria-based products in Asia, where there is a stronger tradition of probiotic consumption compared to the West,” said Prof Pettersson.
He added that indoles could be a promising alternative therapy, with the implications of their research likely extending beyond anxiety, but further studies are needed to explore these possibilities.
For example, new unpublished data suggest that the ability to generate a specific type of brain cell may be regulated by indoles during foetal development. However, after birth, the body loses the ability to produce these cells, said Prof Pettersson.
Investigations into indole levels in pregnant women have also revealed significant variations between individuals, which could have far-reaching implications.
“If we connect this to our mouse study, it suggests that these variations may influence behavioural tendencies and anxiety risk. This could also have implications for pregnancy, potentially affecting a woman’s susceptibility to anxiety during pregnancy and even the risk of preterm birth,” said Prof Pettersson.
However, he said that there is no established optimal level of indole in the body, calling it a “billion-dollar question” yet to be addressed. He also pointed out that the study of microbial metabolites in the bloodstream remains an unexplored frontier but expects this to become a key area of research in the next five to 10 years.
