ORIGINAL ABSTRACT

Planetary and human health including mental health are closely interrelated. Increasing evidence also points to a role for the microbiota-gut-brain axis in maintaining optimum mental health. Emerging evidence raises concerns about the unintended toxicity of environmental exposure to xenobiotics, any substance foreign to the body, on the brain and behavior. Glyphosate is one of the most widely used active ingredients for herbicides for both agricultural and domestic applications. However, investigations on the effects of glyphosate at regulatory reference dose exposures on this axis are currently neglected.Adult male and female mice were exposed to regulatory reference doses of glyphosate via drinking water for 7 weeks to assess its impact on gut microbiota composition, gut barrier function, physiology and behaviors including social interaction, anxiety, cognition, and the stress response. To establish causality, we conducted a microbiota transplantation examining whether behavioral phenotypes were phenocopied in naïve animals.Regulatory reference dose glyphosate exposure primarily affected male mice, leading to impaired social novelty preference and increased anxiety-like behavior, whereas females exhibited a reduction in locomotor activity without other robust behavioral alterations. Transcriptomic analysis of the amygdala revealed gene expression changes consistent with observed behavioral deficits in males. Importantly, microbiota transfer from glyphosate-exposed donors selectively reproduced the social impairments in recipient mice, establishing the role of the glyphosate-remodeled microbiota in modifying social behavior.These findings underscore the importance of evaluating ecologically relevant regulatory reference dose pesticide exposure and provide evidence that glyphosate impacts the microbiota-gut-brain axis to modify behavior. It further supports the concept that xenobiotics in the environment can impact mental health processes and further validates the concept of ecological psychiatry.