Banishing bacteria from the body with antibiotics around birth may cause haywire signals in the brain and lasting behavioral changes, a series of studies suggests.

In the latest study, involving only mice, researchers found that low doses of penicillin given to pups before and after birth spurred changes in their blood-brain barrier and brain chemistry. The mice grew up to be more aggressive and have impaired social behavior, researchers reported Monday in Nature Communications.

That study backs up earlier work in mice, as well as in humans, showing that the microbes residing in our guts can, indeed, spark changes in our brains. In one small, notable study from 2014, researchers found that eating two servings of bacteria-loaded yogurt a day for four weeks altered brain chemistry in a dozen healthy women. This January, New Zealand researchers published a study involving 871 kids that found a correlation between getting antibiotics in the first year of life and having more behavioral problems and symptoms of depression when the kids reached the ages of seven and 11.

While the evidence for the so-called “gut-brain axis” mounts, it’s still unclear how exactly antibiotics and gut microbes interfere with our noggins. Antibiotics certainly don’t directly cause these changes. And gut microbes aren’t moving on up to better, brainier digs. Instead, researchers hypothesize that antibiotics and other disturbances in the microbial force could alter the brain and our behavior via chemical signals that sway the immune system, metabolism, and the brain itself. Gut microbes have been caught making most of the neurotransmitters our brains use to regulate themselves, including GABA, serotonin, dopamine, and norepinephrine. Gut microbes also make short-chain fatty acids, such as butyrate, propionate, and acetate, which can be involved in energy balance and metabolism. And, the intestinal-dwellers can influence cytokines, chemical signals used by the immune system.

The brain on antibiotics

While researchers are feverishly working to figure out how these manipulative microbes may help cause—or cure—diseases, the findings raise new concerns about altering microbial communities with unnecessary antibiotic doses while the brain and body are still developing. As Ars has reported before, antibiotics given to human babies early in life may set them up for obesity later. And previous research in mice has found that high doses of antibiotics can cause long-lasting brain and metabolic changes in adult and adolescent mice.

In the new study, a group of researchers from McMaster University in Canada wanted to look at the more clinically relevant effect of low doses on babies. Mouse pups were exposed to low doses of penicillin via their mothers before and after birth through blood and breast milk. When they hit six weeks old, researchers then put them through a battery of behavioral tests and assessed their brain development.

Using a total of 72 mice, researchers found that mice exposed to penicillin were less social, a little less anxious, and more aggressive than mice who weren’t exposed. In an aggression test, 42 percent of the exposed mice were scored as feisty compared with only 9 percent in the unexposed control group. Using a separate group of mice, researchers found that simultaneous doses of the probiotic, Lactobacillus rhamnosus, could partially block the effects of the antibiotic.

When the researchers peeked into the brains of the mice, they found thinned blood-brain barriers in exposed mice, plus relatively high activity of a gene linked to aggressive behavior. They also found increased expression of cytokines in the brain.

“While all these data obtained in rodents cannot be directly extrapolated to humans,” the authors write, “they add support to the necessity to carefully consider the potential negative long-term effects of early-life AB [antibiotic] exposure.”

In addition to the problem of extrapolating mouse data to human health, the study had some other limitations. When researchers go to repeat and extend this line of research, it will be important to pick apart the effects of antibiotic exposure before and after birth. It’s possible that the antibiotics given to the mother mice disrupted their microbial communities, which they pass on to their pups. Disentangling maternal microbiome effects from post-natal antibiotic effects will be important. Also, the period of antibiotic exposure for the pups was rather long. Future studies should look at shorter, more common, exposures.

Indeed, “these results warrant further studies on the potential role of early-life antibiotic use in the development of neuropsychiatric disorders, and the possible attenuation of these by beneficial bacteria,” the authors conclude.

Nature Communications, 2017. DOI: 10.1038/ncomms15062 (About DOIs).