Proceedings of The Physiological Society

Europhysiology 2018 (London, UK) (2018) Proc Physiol Soc 41, PCB117

Poster Communications

Gestational and developmental exposure to polychlorinated biphenyls (PCBs) in the maternal diet causes impaired intestinal physiology and altered host-microbe interactions in genetically susceptible mice

K. Rude1, J. Sladek1, M. Pusceddu1, S. Sethi2, K. Keil2, I. Pessah2, P. Lein2, M. Gareau1

1. Anatomy, Physiology and Cell Biology, University of California Davis, Davis, California, United States. 2. Molecular Biosciences, University of California Davis, Davis, California, United States.

The microbiota-gut-brain (MGB)-axis is increasingly being recognized as an important physiological pathway for maintaining health and homeostasis with disruptions identified in numerous disease states, including inflammatory bowel disease (IBD), major depressive disorders, and autism spectrum disorders (ASD). Early neonatal life is an important stage for normal colonization of the microbiota, development of gastrointestinal physiology and neuronal growth and maturation, which together form the MGB-axis. Exposure to pathophysiological stimuli during development can potentially impact the MGB axis detrimentally. Exposure of the developing brain to neurotoxicants, including polychlorinated biphenyls (PCBs) and intestinal dysbiosis have independently be implicated in the origin of neurodevelopmental disorders (NDDs). Therefore, we hypothesized that PCB-induced dysbiosis causes intestinal pathophysiology, including mucosal barrier deficits and subsequent inflammation in a genetically susceptible host. Intestinal physiology and the composition of the microbiota were assessed following developmental exposure to PCBs during late gestational and early neonatal life in both neurotypic and mice expressing risk genes for neurodevelopmental disorders (NDD). Both wild type (WT - C57BL/6-SV129) and double mutant (DM - Ryr1[T4826I] gain of function mutation and X-linked FMR1 premutation [180-200 CGG repeats]) juvenile mice (P28-30) mice were used to assess host-microbe interactions and gene by environment interactions following PCB exposure. Dams were exposed to a mixture of PCB congeners starting 2 weeks prior to mating and continued until weaning. Developmental PCB exposure caused ileal and colonic mucosal barrier defects (increased secretory state and permeability deficits), alterations in the ileal and colonic inflammatory profile (increased pro-inflammatory and decreased anti-inflammatory cytokines) in DM mice at P29-P30. Dysbiosis, including decreased beta-diversity and changes in abundance at the phylum level, were also observed at P28-P30 in DM mice vs. WT controls. These PCB-induced changes were only observed in DM mice following administration of 1 mg/kg of PCBs but not 0.1 or 6 mg/kg, suggesting a non-linear dose effect in a genetically susceptible host. In conclusion, we demonstrated that maternal exposure to developmental neurotoxicants can negatively impact both colonization of the gut microbiota and establishment of intestinal mucosal barrier function in weanling mice that are genetically susceptible to NDD.

Where applicable, experiments conform with Society ethical requirements