Unravelling the impact of pesticides on the microbiota-gut-brain axis

The gut microbiota exists within a dynamic ecosystem influenced by various factors, including exposure to xenobiotics such as pesticides. There is an increasing emphasis on the role of the gut microbiota in maintaining host health, including growing evidence for its role in regulating brain function and behaviour. Given the pervasive use of pesticides in modern agriculture and domestic settings, it is imperative to evaluate the collateral effects of these exposures on the gut microbiota of non-target organisms. A growing body of studies has shown that pesticides can disrupt the gut microbiota and adversely affect host physiology while emerging evidence links these disruptions to behavioural impairments. However, research replicating real-life exposure scenarios, such as chronic, low-dose exposure through natural routes, remains limited. Therefore, this thesis investigates whether pesticide-induced alterations in gut microbiota contribute to behavioural changes, focusing on realistic exposure conditions. Using preclinical rodent models, the effects of selected pesticides, including herbicides, fungicides, and insecticides, on the microbiota-gut-brain axis were assessed. Our findings reveal a compound-dependent interaction between pesticides, gut microbiota, and host health. Low-dose glyphosate, one of the most widely used herbicides, exposure altered the gut microbiota community, prompting investigations into its role in behavioural outcomes through microbiota transplantation experiments (Chapter 2). These experiments revealed domain-specific transfer of behavioural phenotypes: social cognition impairments were mediated by glyphosate-remodelled gut microbiota, whereas anxiety-like behaviour presented to be microbiota-independent. Additionally, transcriptomic changes in the brain were not directly linked to these behavioural shifts, suggesting decoupled mechanisms. Notably, sex-dependent effects were observed, with males and females exhibiting unique microbiota profiles and behavioural outcomes following glyphosate exposure. Building on these findings, we took advantage of an ongoing long-term herbicide exposure study in which additional herbicides—Roundup® (a glyphosate-based formulation), MCPA, and paraquat—were also included (Chapter 3). Although, all exposures shifted the gut microbiota community structure, glyphosate exhibited the least pronounced effects among the compounds tested. Interestingly, commercial formulations, such as Roundup®, posed greater risks than pure glyphosate. MCPA, an understudied herbicide, caused the most significant perturbations in gut microbiota composition and functionality. Altered gene expression in brain regions including the amygdala, hippocampus, and prefrontal cortex implicated pathways involved in neuroimmunity, neurotransmission, blood-brain barrier integrity, fatty acid signalling, and neuroplasticity, suggesting potential systemic impacts beyond the gut microbiota. Extending our investigation beyond herbicides, we evaluated the effects of the fungicide tebuconazole and the insecticide acetamiprid (Chapter 4). Both compounds impaired gut barrier integrity in a region-specific manner, highlighting distinct vulnerabilities in certain gut areas—a phenomenon not observed with glyphosate. Behavioural outcomes were modest but exhibited a non-linear, dose-dependent pattern on social cognition impairments. Additionally, baseline chemokine levels were altered, pointing to potential shifts in immune homeostasis although changes in immune response were not observed. Overall, this thesis highlights the importance of having a better understanding of the impact of pesticides on the microbiota-gut-brain axis. These findings emphasize that even subtle microbiota alterations, particularly under real-life exposure scenarios, can have significant implications for host behaviour. By highlighting these effects, we aim to foster public awareness and encourage sustainable pesticide use to mitigate potential health risks.

Grantor dc:publisher

University College Cork

Year dc:date.issued

2024

Author dc:creator

• Matsuzaki, Rie

Advisor dc:contributor.advisor

• Cryan, John

• Behaviour
• Environment
• Insecticide
• Fungicide
• Glyphosate
• Gut bacteria
• Herbicide
• Microbiota transfer

Statement dc:rights

• © 2024, Rie Matsuzaki.

Licence dc:rights.uri

• https://creativecommons.org/licenses/by-nc-nd/4.0/

Language dc:language.iso

en

Handle dc:identifier.uri

https://hdl.handle.net/10468/17500

OAI identifier oai:identifier

oai:cora.ucc.ie:10468/17500