ANIKA LIN Dzierlenga
$648,691
University of Washington
Washington
National Institute of Environmental Health Sciences (NIEHS)
Benzalkonium chlorides (BACs) are widely used antimicrobials in disinfecting products, medical products, and food processing industries, suggesting humans may be exposed chronically to BACs through various routes. The ongoing COVID-19 pandemic has led to greatly increased use of disinfectants, resulting in a 174% increase in median BAC levels in human blood. We recently analyzed 15 de-identified human fecal samples collected during COVID-19 and detected BACs in all of them, ranging from 55 nM to 2.74 ยตM (a 50-fold difference). BACs are potent antimicrobials, but their effect on the gut microbiome has not been examined, which is the major gap that this proposal aims to fill. Our goal is to characterize the effect of BAC exposure on gut microbiome compo- sition and function, microbiota metabolism, and altered liver metabolism via the gut-liver axis. We previously reported that BACs are metabolized by human cytochromes P450 (CYP) in the liver. Our preliminary data sup- port biliary excretion from the liver to the intestine being the major route of elimination for BACs. Thus, exposure of gut microbiome to BACs is inevitable regardless of the route of exposure. Disruption of the gut microbiome can lead to changes in endogenous and xenobiotic metabolism through modulating the ligand availability for the bile acid-sensing farnesoid X receptor (FXR), the lipid-sensing peroxisome proliferator-activated receptor-alpha (PPARa), and xenobiotic-sensing constitutive androstane receptor (CAR) and pregnane X receptor (PXR). Im- portantly, in a preliminary study, we found that BAC exposure in mice significantly upregulated the expression of Cyp2c38, Cyp2j6, Cyp4a10, and Cyp4f13 in the liver, which is consistent with the inhibition of CAR and/or acti- vation of PPARa. Thus, we hypothesize that BACs reduce gut microbiome diversity and alter the metabolism of xenobiotics, bile acids, sterols, and lipids in the liver by modulating the activities of nuclear receptors. In Aim 1, we will characterize the impact of BAC exposure at different doses and exposure regimes on gut microbiome diversity and function in mice. We will then correlate the changes in microbiome functional genes with the changes in the gut bile acid, sterol, and lipid profiles. In Aim 2, we will measure the effect of BAC exposure on bile acid, sterol, lipid, and xenobiotic metabolism in the liver of conventional and germ-free mice. Relationships between bile acid, sterol, and lipid profiles and relevant gene expression levels in the liver will be evaluated. Activation or inhibition of nuclear receptors regulating xenobiotic-metabolizing enzymes (XMEs) will be as- sessed. In Aim 3, we will evaluate the relationship between BAC levels and gut microbiome diversity and function in humans. The significance of this project lies in that it will allow us to begin to understand the impact of in- creased BAC exposure on gut microbiome and gut-liver interactions in humans. The innovation of this project lies in that a) it represents the first study to examine the impact of BAC exposure on gut-liver interactions, and b) alteration of XME gene expression by BAC exposure represents a novel gene-environment interaction that could affect the metabolism of endogenous metabolites and other xenobiotics.