Male rats exposed to glyphosate exhibit some anxiety-like behaviors, according to Demetrio Sierra-Mercado, Ph.D., an associate professor at the University of Puerto Rico School of Medicine. He shared his studies exploring how the gut-brain connection may underpin these effects during a Sept. 25 Keystone Science Lecture at NIEHS.

“Daily consumption of glyphosate via drinking water for several months, at levels considered safe, does increase some types of anxiety-like behaviors in these animals,” said Sierra-Mercado. “There is reduced exploration. We also observed increased threat response to novel stimuli consistent with increased anxiety or negative anticipation. We also see increased activity in brain regions that are implicated in anxiety, and our preliminary analyses demonstrate decreased abundance of bacteria that are thought to produce serotonin.”

Glyphosate is the active ingredient in common herbicides, and trace amounts of it have been found in a variety of products consumed by humans, including soy, corn, beer, and bottled water, according to Sierra-Mercado. Last year, Sierra-Mercado received an R21 grant from NIEHS to study glyphosate, and its potential link to anxiety and fear responses.

“What he’s working on is a really understudied area,” said Jonathan Hollander, Ph.D., a health scientist administrator in the NIEHS Division of Extramural Research and Training and Sierra-Mercado’s host for the Keystone Lecture event. “Dr. Sierra-Mercado’s research provides insight into how chemical factors may impact mental health and risk for psychiatric disorders, as well as highlights the importance of gut-brain signaling as a potential underlying mechanism.”

Evidence of anxiety in the brain

In a series of experiments over four months, Sierra-Mercado and his team exposed male rats to a daily dose of glyphosate — 2.0 mg/kg — that the Environmental Protection Agency has deemed safe for humans to be exposed to daily over a lifetime. The scientists observed changes in how the rats that were exposed through drinking water behaved during different kinds of tests. They found rats exposed to glyphosate exhibited reduced body weight, decreased exploratory behavior, and increased anxiety-like behaviors and threat responses.

Next, the scientists examined the brains of the rats to determine what could be driving the behavioral differences. The glyphosate-exposed rats showed increased cellular activity in the bed nucleus of the stria terminalis (BNST) region of the brain, a physiological change consistent with anxiety.

Gut-brain connection

To assess whether glyphosate, once consumed, could be acting on gut bacteria and affecting the brain through the gut-brain connection, Sierra-Mercado and his collaborators examined the rats’ fecal bacteria. Specifically, they observed that the feces had less abundance of Lactobacillus, the bacteria involved in the production of serotonin, the body’s feel-good hormone.

The next step, according to Sierra-Mercado, is to delve into whether sex-specific differences exist and whether potential therapeutic targets can be identified by analyzing the gut microbes.

“Arguably if the key player in anxiety is changes in the gut, then perhaps treatment for anxiety could be prebiotics or probiotics, and that’s something that we could explore as an alternative to common pharmacological adjuncts,” Sierra-Mercado said.