Investigating the implications of oral microplastic exposure within the context of the gut-brain axis

Abstract

Microplastics are emerging environmental contaminants due to increasing global plastic production and waste. Microplastics, defined as plastic particles less than 5 mm in diameter, are formed through degradation of larger plastics via sunlight, weathering, and microbes. These plastic compounds are widely detected in water, soil, food, as well as human stool and blood. Recent studies have found microplastic particles in organ systems throughout the human body, including bio-compartments associated with the developing fetus, highlighting both the ubiquitous nature of microplastic bioaccumulation as well as the immediacy of public health concern regarding environmental microplastic contamination. Although detection and environmental fate of microplastic particles is important for elucidating the environmental fate and transport of microplastic particles, little is known regarding oral microplastic exposure and its implications within the gut-brain axis. The gut microbiome, often referred to as our second genome, is important in human health and is the primary point of contact for orally ingested microplastics. The gut environment and its associated gut microbiome are known to influence the nutrient absorption and gut barrier function which both directly and indirectly regulates the circulatory metabolome and in turn other organ systems around the body such as the brain. Apolipoprotein-E (APOE) is an important lipid shuttling protein that is implicated in progressive neurodegenerative disorders, particularly in homozygous APOE4 allele carriers. APOE4 genotype is also known to influence xenobiotic exposure outcomes and to differentially impact the host gut microbiome and gut environment. Therefor the goal of this dissertation thesis is to strategically investigate the impact of microplastic exposure to the gut microbial composition, associated metabolome, and immunological CNS endpoints of interest with the addition of host genetics to further elucidate potential gene-environment interactions. My central hypothesis is that microplastic particles will induce gut dysbiosis, disrupt the gut microbiome associated metabolome, and impact the gut-brain axis. Microplastic induced changes to the gut microbiome and associated metabolome along with accumulation of microplastic particles may lead to a weakened gut barrier and thus causing the host to exhibit leaky gut physiology. The leaky gut barrier may introduce bacterial biproducts, metabolites, and other xenobiotics that may induce tissue damage, increased inflammatory cytokines, and a decrease in neuroprotective microbial metabolites. Second, these harmful substances may be more bioavailable to the brain, in the brain this can cause increased inflammation, oxidative stress, and cell death (molecular level). I have shown that oral microplastic exposure differentially regulates the gut microbial composition and associated serum metabolism in a dose and sex dependent manner. Additionally, I observed that in the presence of humanized APOE3/E4 genotype, OMP exposure significantly regulated more microbial taxa and serum associated metabolic pathways within APOE4 male and female mice, providing evidence of host gene modulation of microplastic associated implications within the gut micro-environment and associated serum metabolome.