Gut bacteria influence mice social behavior through smell

Amazing stuff! Why do humans use perfume and deodorants?

When one metabolite molecule regulates aggressiveness of individuals!

"In a new study, Northwestern University neurobiologists discovered that gut bacteria and the nose work together to shape social behavior in mice, including who fights and who backs down. Using a combination of genetic and behavioral experiments, the scientists found gut microbes produce a pungent odor that other animals can smell. When detected, these scents trigger aggression and shape social hierarchies. The discovery reveals a previously unknown way the microbiome influences social interactions. ...

"Over the past 20 years, there's been a growing realization that microbes in the gut have profound influences on behavior and physiology," ... "They produce bioactive chemicals that affect the function of many organ systems, including the immune system, and can even cross the blood-brain barrier to affect behavior. These chemicals can also affect social behaviors through the sense of smell. While species use microbiome-derived chemicals for social communication, our study is the first to uncover the underlying mechanism." ...

In the new study, ... team focused on trimethylamine (TMA), a molecule produced in the gut that smells like dead, rotten fish. When gut bacteria break down choline-rich foods, such as eggs and meat, they generate TMA as a byproduct. The body's liver then converts TMA into an odorless metabolite. But in adult male mice, testosterone suppresses the liver enzyme that typically neutralizes TMA, allowing it to accumulate in urine.

"It seemed like mice use TMA as a male-specific odor," ...

To better understand why adult male mice produce this odor, ... team imaged the olfactory bulb within the brain to see which neurons respond to TMA. They specifically focused on trace amine-associated receptors (TAARs), a small family of odor detectors that are especially sensitive to strong-smelling molecules. Among the 14 TAARs in mice, the team found that TAAR5 is the most sensitive receptor to TMA and plays a central role in detecting the odor. ...

From scent to social hierarchy

When mice detect this scent, it changes how they behave. Dominant animals initiate fights, while subordinate mice adopt defensive postures—patterns that quickly establish a social hierarchy. 

But when ... team disabled TAAR5 in mice, those distinctions blurred. Mice still interacted with one another, but their behavior became more evenly matched. Without this signal, it took longer for clear dominant-subordinate relationships to emerge. ..."

From the highlights and abstract:

"Highlights

• TAAR5 deletion alters aggression and social dominance in male mice

• The effect of TAAR5 on social behavior occurs via the main olfactory pathway

• Blocking production of the TAAR5 ligand TMA by gut microbes reduces aggression

• A microbiome-derived chemical cue shapes mammalian social behavior via olfaction

Summary

Many species use microbiome-derived metabolites as chemosensory cues, yet the chemicals involved and the sensory pathways that detect and process them remain poorly understood.

Trimethylamine (TMA) is a volatile metabolite that is produced by the gut microbiome and selectively accumulated in the urine of sexually mature male mice.

Here, we show that TMA regulates inter-male aggression and social dominance by activating trace amine-associated receptor 5 (TAAR5) in the main olfactory system.

In wild-type mice, early aggressive behavior during male-male encounters strongly predicts eventual social status: dominant males initiate more attacks, whereas subordinate males display more defensive behaviors.

Deletion of TAAR5 eliminated this asymmetry, with dominant and subordinate mice showing similar levels of aggressive and defensive behaviors.

Strikingly, restoring TAAR5 expression in olfactory sensory neurons (OSNs) rescued the behavioral asymmetry, indicating that this effect is mediated by the main olfactory system and arguing against contributions from proposed TAAR5 expression in the brain.

Finally, pharmacological suppression of microbial TMA production reduced inter-male aggression, and this effect was reversed by painting treated males with TMA, showing that microbiome-derived TMA is the key volatile ligand for TAAR5 in this context.

Taken together, our findings identify TMA as a critical olfactory cue that signals the presence of sexually mature males and facilitates social hierarchy formation. More broadly, our results demonstrate that a microbiome-derived metabolite can shape mammalian social interactions through the main olfactory system and uncover a previously unrecognized role for the TAAR family in regulating social behavior."

Gut bacteria may influence social behavior through smell

A microbiome-derived olfactory signal regulates inter-male aggression and social dominance in mice (open access)

Graphical abstract