New Study Shows Gut Compound that Leads to Anxious Behaviors in Mice

A new study by researchers at Caltech, has discovered that a small-molecule metabolite, produced by bacteria in the gut, can travel to the brain and increase the anxiety levels in mice. The study helps uncover a molecular explanation of how the gut interactions with the brain, also known as gut-brain axis, can influence emotional behaviors. The research was published in the journal Nature. 

Multiple studies evaluating the microbiome have shown that bacteria in the intestines of animals influence the immune system and metabolism, and recent studies have linked the microbiome with the brain function, cognition, and mood. 

Studies in mice have shown that manipulating these communities can alter neurodevelopmental and neurodegenerative states, either ameliorating or exacerbating symptoms.

The researchers focused on the metabolite called 4-ethylphenyl sulfate, or 4EPS, which is produced by microbes in the intestines and absorbed into the bloodstream, and then circulates throughout the body in humans and mice. 

One study in autistic patients showed that they had 7 times higher 4EPS levels when compared to non-autistic individuals. 

The team focused on the effects of 4EPS on mouse models of anxiety, which in mice is measured by their willingness to explore or hide in a new space as well as the time spent in a risky environment. Bold mice will explore a new space, sniffing around, but anxious mice will hide, as if facing a predator, instead of exploring.

The study used 2 groups of mice, one that was colonized with a pair of bacteria that produced 4EPS, and a control group of mice colonized with bacteria that lacked the ability to produce 4EPS. Then introduced to a new arena and researchers evaluated their behavior. 

They found that the mice colonized with 4EPS spent much less time exploring the area and more hiding as compared with the control group. Also, brain scans showed some of the brain regions associated with fear and anxiety to be more activated. They also found that these regions had alterations in cells called oligodendrocytes, which produce myelin in neurons and axons. The team found that in the presence of 4EPS, oligodendrocytes are less mature and consequently produce less myelin.

The researchers are planning further steps to examine the mechanisms through which this metabolite affects oligodendrocytes.  


California Institute of Technology. “A microbial compound in the gut leads to anxious behaviors in mice.” ScienceDaily. ScienceDaily, 14 February 2022. <>. 

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