Document text
Principal Investigator: Libin Xu
Organization: UNIVERSITY OF WASHINGTON
Fiscal Year: 2024
Award: $648,691
Funding agency: National Institute of Environmental Health Sciences
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 µM (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.
Terms: <Affect><Animal Model><Animal Models and Related Studies><Antiseptics><Bacteria><Benzalkonium Chloride><Bile Acids><Biliary><Biological><Blood><Blood Plasma><Blood Reticuloendothelial System><Blood Sample><Blood specimen><COVID crisis><COVID epidemic><COVID pandemic><COVID-19><COVID-19 crisis><COVID-19 epidemic><COVID-19 era><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 pandemic><COVID-19 period><COVID-19 public health crisis><COVID-19 years><CPD6><CV-19><CYP 2D6><CYP2D><CYP2D6><CYP2D6 gene><CYP2DL1><CYPIID6><Cell Communication and Signaling><Cell Signaling><Chronic><Coronavirus Infectious Disease 2019><Cytochrome P-450><Cytochrome P-450 CYP2D6><Cytochrome P-450 Enzyme System><Cytochrome P450><Cytochrome P450 2D6><Cytochrome P450 Family Gene><Cytochrome P450 Subfamily IID Polypeptide 6><Data><Debrisoquine 4-Hydroxylase><Debrisoquine 4-Monooxygenase><Debrisoquine Hydroxylase><Detection><Disinfectants><Dose><Environmental Pollutants><Enzyme Gene><Enzymes><Excretory function><Exposure to><Feces><Food processing industry><Foundations><Frequencies><Future><GI microbiome><Gene Expression><Gene x Environment Interaction><Genes><Germ-Free><Goals><GxE interaction><Health><Hepatic Disorder><Human><Imipramine 2-Hydroxylase><Individual><Intermediary Metabolism><Intestinal><Intestines><Intracellular Communication and Signaling><Isoforms><Knowledge><Ligands><Lipids><Liver><Liver Microsomes><Liver diseases><Local Anti-Infective Agents><Measures><Medical><Metabolic><Metabolic Diseases><Metabolic Disorder><Metabolic Pathway><Metabolic Processes><Metabolism><Mice><Mice Mammals><Modern Man><Murine><Mus><NIH><National Institutes of Health><Nuclear Receptors><Oral><Outcome><P450><P450-2D6><P450-DB1><P450C2D><P450DB1><PPAR alpha><PPAR-α><PPARalpha><PPARα><PXR receptor><Peroxisome Proliferator-Activated Receptor alpha><Peroxisome Proliferator-Activated Receptor α><Plasma><Plasma Serum><Population><Prevention><Protein Isoforms><RNA Seq><RNA sequencing><RNAseq><Receptor Protein><Receptor Signaling><Reporting><Research><Reticuloendothelial System, Serum, Plasma><Risk><Role><Route><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 pandemic><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><Safety><Sampling><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 pandemic><Shotguns><Signal Transduction><Signal Transduction Systems><Signaling><Sparteine Monooxygenase><Sterols><Subfamily IID Cytochrome P450><Subfamily IID-Like 1 Cytochrome P450><Thesaurismosis><Topical Anti-Infective Agents><United States National Institutes of Health><Xenobiotic Metabolism><Xenobiotics><anti-microbial><antimicrobial><bile acid metabolism><bile metabolism><biologic><biological signal transduction><bowel><constitutive androstane receptor><consumer product><coronavirus disease 2019><coronavirus disease 2019 crisis><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 pandemic><coronavirus disease 2019 public health crisis><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease pandemic><coronavirus disease-19><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><coronavirus infectious disease-19><digestive tract microbiome><enteric microbiome><environment effect on gene><environmental contaminant><excretion><exposure route><fat metabolism><fecal microbiome><fecal sample><gastrointestinal microbiome><gene environment interaction><gut microbiome><gut-associated microbiome><gut-liver axis><hepatic body system><hepatic disease><hepatic metabolism><hepatic organ system><hepatopathy><human disease><innovate><innovation><innovative><intestinal biome><intestinal microbiome><lipid metabolism><lipidomics><liver disorder><liver function><liver metabolism><metabolism disorder><metabolome><metabonome><metagenome sequencing><metagenomic sequencing><meter><microbial><microbial consortia><microbial flora><microbiome><microbiome community composition><microbiome composition><microbiome species composition><microbiome structure><microbiota><microflora><model of animal><multispecies consortia><novel><pandemic><pandemic disease><pre-pandemic><pregnane X receptor><receptor><response><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><shot gun><social role><stool><stool microbiome><stool sample><stool specimen><stool-associated microbiome><transcriptome sequencing><transcriptomic sequencing>