A series of experiments on mice has found that they become more aggressive when their gut microbiome is depleted. Additionally, transplanting gut microbiota from human infants exposed to antibiotics led to heightened aggression in mice compared to those receiving microbiome transplants from non-exposed infants. The research was published in Brain, Behavior, and Immunity.
In the past decade, scientists have discovered a complex communication pathway linking gut microbiota—the trillions of microorganisms living in the human gut—with the brain. This pathway is called the microbiota-gut-brain axis. It regulates various physiological functions, including digestion and immunity, but also affects mood and behavior. The gut microbiota produces neurotransmitters and other metabolites that can influence brain function through neural, immune, and endocrine pathways.
Recent studies have demonstrated that symptoms of various disorders, once considered primarily psychological or neurological, can be transferred to rodents by transplanting gut microbiota from humans with these disorders. For example, researchers have shown that transplanting gut microorganisms from people with Alzheimer’s disease into mice (whose gut microbiota had been depleted to enhance transplant effectiveness) resulted in cognitive impairments in the mice. Similarly, symptoms of anxiety have been induced in mice by transplanting gut microbiota from humans with social anxiety.
Study author Atara Uzan-Yulzari and her colleagues wanted to explore the links between aggression and gut microbiota composition in mice. They also sought to investigate the role antibiotics might play in this relationship. Antibiotics, commonly used to treat bacterial infections, can disrupt the composition of the normal gut microbiota by killing bacteria, including beneficial ones.
The study was conducted on Swiss Webster mice, a genetically diverse strain of laboratory mice. The mice were divided into several groups: germ-free mice, specific pathogen-free mice (which served as the control group with normal microbiota), antibiotic-treated mice (with disrupted microbiota due to antibiotic treatment), and germ-free mice that were later colonized with normal microbiota. Another set of germ-free mice were colonized with microbiota from human infants—either from those who had been treated with antibiotics or those who had not.
For the humanized mice, the researchers obtained fecal samples from infants who had been exposed to antibiotics shortly after birth, as well as from unexposed infants. These samples were transplanted into five-week-old germ-free mice. The researchers then waited for four weeks before testing the mice for aggression.
To measure aggression, the researchers employed the resident-intruder test, a well-established behavioral assay in which a male mouse (the “resident”) is introduced to another unfamiliar male mouse (the “intruder”) in its home cage. Aggression was quantified based on the latency to the first attack (how quickly the resident mouse attacked the intruder) and the total number of attacks during a 10-minute period.
The results showed that mice raised without gut bacteria (germ-free) and those treated with antibiotics exhibited higher levels of aggression compared to the control group. These mice attacked more frequently and were quicker to initiate aggressive behavior in the resident-intruder test.
The researchers found that humanized mice receiving fecal microbiota from antibiotic-exposed infants were significantly more aggressive than those receiving transplants from non-exposed infants. Even though the infants’ microbiomes had a month to recover after antibiotic exposure, the aggressive behavior was still evident in the recipient mice.
Biochemical analyses revealed that aggressive mice (both germ-free and antibiotic-treated) had distinct metabolite profiles compared to control mice. Specifically, levels of tryptophan—a precursor to serotonin, a neurotransmitter associated with mood and behavior—were elevated in these mice. Additionally, the levels of certain metabolites associated with microbial activity, such as indole-3-lactic acid, were reduced in the aggressive mice, suggesting that the absence of a healthy microbiome might alter key biochemical pathways involved in aggression.
Similar changes were observed for the neurotransmitter serotonin and its metabolite in the brain of these mice. When the study authors used antibiotics to deplete the gut microbiota, this resulted in an increase in tryptophan levels and a decrease in serotonin levels in the brain. This disruption in serotonin metabolism was associated with changes in the activity of specific aggression-related genes in the brain, indicating that antibiotic-induced alterations to the microbiome can influence the molecular mechanisms underlying aggressive behavior.
“The present study provides insights into the role of the gut microbiome in modulating aggression in a murine model [mice] and in humanized mice [mice to which human gut microbiota were transplanted], supporting the involvement of the microbiota-gut-brain axis in regulating social behaviors – namely aggression – consistent with previous research. However, our findings not only demonstrate the causative impact of gut microbiome on aggression, through use of FMT [fecal microbiota transplant], but also reveal its influence on multiple factors and pathways that regulate this behavior,” the study authors concluded.
The study sheds light on the role of the gut microbiome in modulating aggression in mice. However, it should be emphasized that this study was conducted on mice, not on humans. While mice and humans share many physiological similarities, they are still very distinct species. Because of this, effects on humans might not be identical.
The paper, “A gut reaction? The role of the microbiome in aggression,” was authored by Atara Uzan-Yulzari, Sondra Turjeman, Lelyan Moadi, Dmitriy Getselter, Samuli Rautava, Erika Isolauri, Soliman Khatib, Evan Elliott, and Omry Koren.
